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Sample records for bronchial-associated lymphoid tissue

  1. Bronchial lesions of mouse model of asthma are preceded by immune complex vasculitis and induced bronchial associated lymphoid tissue (iBALT).

    PubMed

    Guest, Ian C; Sell, Stewart

    2015-08-01

    We systematically examined by immune histology the lungs of some widely used mouse models of asthma. These models include sensitization by multiple intraperitoneal injections of soluble ovalbumin (OVA) or of OVA with alum, followed by three intranasal or aerosol challenges 3 days apart. Within 24 h after a single challenge there is fibrinoid necrosis of arterial walls with deposition of immunoglobulin (Ig) and OVA and infiltration of eosinophilic polymorphonuclear cells that lasts for about 3 days followed by peribronchial B-cell infiltration and slight reversible goblet cell hypertrophy (GCHT). After two challenges, severe eosinophilic vasculitis is present at 6 h, increases by 72 h, and then declines; B-cell proliferation and significant GCHT and hyperplasia (GCHTH) and bronchial smooth muscle hypertrophy recur more prominently. After three challenges, there is significantly increased induced bronchus-associated lymphoid tissue (iBALT) formation, GCHTH, and smooth muscle hypertrophy. Elevated levels of Th2 cytokines, IL-4, IL-5, and IL-13, are present in bronchial lavage fluids. Sensitized mice have precipitating antibody and positive Arthus skin reactions but also develop significant levels of IgE antibody to OVA but only 1 week after challenge. We conclude that the asthma like lung lesions induced in these models is preceded by immune complex-mediated eosinophilic vasculitis and iBALT formation. There are elevations of Th2 cytokines that most likely produce bronchial lesions that resemble human asthma. However, it is unlikely that mast cell-activated atopic mechanisms are responsible as we found only a few presumed mast cells by toluidine blue and metachromatic staining limited to the most proximal part of the main stem bronchus, and none in the remaining main stem bronchus or in the lung periphery. PMID:26006019

  2. Tissue residency of innate lymphoid cells in lymphoid and non-lymphoid organs

    PubMed Central

    Gasteiger, Georg; Fan, Xiying; Dikiy, Stanislav; Lee, Sue Y.; Rudensky, Alexander Y.

    2015-01-01

    Innate lymphoid cells (ILC) contribute to barrier immunity, tissue homeostasis, and immune regulation at various anatomical sites throughout the body. How ILCs maintain their presence in lymphoid and peripheral tissues is currently unknown. We found that in the lymphoid and non-lymphoid organs of adult mice, ILC are tissue-resident cells that were maintained and expanded locally under physiologic conditions, upon systemic perturbation of immune homeostasis, and during acute helminth infection. However, at later time points post-infection, cells from hematogenous sources helped to partially replenish the pool of resident ILCs. Thus, ILC are maintained by self-renewal in broadly different microenvironments and physiological settings. Such an extreme “sedentary” lifestyle is consistent with the proposed roles of ILCs as sentinels and local keepers of tissue function. PMID:26472762

  3. Tertiary Lymphoid Organs in Cancer Tissues

    PubMed Central

    Hiraoka, Nobuyoshi; Ino, Yoshinori; Yamazaki-Itoh, Rie

    2016-01-01

    Tertiary lymphoid organs (TLOs) are induced postnatally in non-lymphoid tissues such as those affected by chronic infections, autoimmune diseases, and chronic allograft rejection, and also in cancer tissues. TLOs are thought to provide important lymphocytic functional environments for both cellular and humoral immunity, similar to lymph nodes or Peyer’s patches. TLOs have a structure similar to that of lymph nodes or Peyer’s patches, including T cell zones, B cell follicles, and high endothelial venules (HEV) without encapsulation. Here, we review recent advances in our knowledge of TLOs in human solid cancers, including their location, structure, methods of evaluation, and clinicopathological impact. We also discuss the formation and/or maintenance of TLOs in cancer tissues in association with the tumor immune microenvironment, cancer invasion, and the tissue structure of the cancer stroma. PMID:27446075

  4. Duct-associated lymphoid tissue (DALT) of minor salivary glands and mucosal immunity.

    PubMed Central

    Nair, P N; Schroeder, H E

    1986-01-01

    Minor salivary glands (MSG) play a substantial role in the secretory immunoglobulin A (sIgA)-mediated immunity of the oral cavity. There are two possibilities for the induction of this immunity: (i) an explicitly local antigenic stimulus, or (ii) a remote stimulus as part of the so-called 'common mucosal immune system'. This communication is an attempt to consolidate available evidence in support of both possibilities and to address the former in detail. Although there is strong circumstantial evidence supporting the feasibility of MSG functioning as a part of the common mucosal immune system, direct experimental evidence is yet to emerge. On the other hand, there is increasing structural and physiological evidence in support of MSG serving as a local immunological organ. The purely local response is attributed to the presence of MSG duct-associated lymphoid tissue (DALT), which is comparable to gut- or bronchial-associated lymphoid tissue (GALT or BALT) in origin, tissue organization and function. DALT is accessible to oral antigens by retrograde passage through MSG ducts. Repeated topical antigenic challenging via the oral mucosa may result in the appearance of interacinar plasma cells carrying specific homologous antibodies in MSG. Gut or enteric priming of the same antigen, by passing the oral mucosa by gastric intubation, need not evoke a remote immune response in MSG. Since DALT is more likely to occur in healthy, young growing individuals, who are less likely to undergo bioptic examination of MSG, it has not yet been documented in humans. The physiologically induced DALT is apt to be confused with focal accumulations of lymphoid tissue in pathologically altered MSG, as a consequence of local and some systemic autoimmune diseases. An attempt is made to demarcaate healthy and pathological MSG on the basis of currently available clinical, serological, immunological and genetic evidence. Images Figure 1 Figure 2 PMID:3512423

  5. Lymphoid Tissue Mesenchymal Stromal Cells in Development and Tissue Remodeling

    PubMed Central

    2016-01-01

    Secondary lymphoid organs (SLOs) are sites that facilitate cell-cell interactions required for generating adaptive immune responses. Nonhematopoietic mesenchymal stromal cells have been shown to play a critical role in SLO function, organization, and tissue homeostasis. The stromal microenvironment undergoes profound remodeling to support immune responses. However, chronic inflammatory conditions can promote uncontrolled stromal cell activation and aberrant tissue remodeling including fibrosis, thus leading to tissue damage. Despite recent advancements, the origin and role of mesenchymal stromal cells involved in SLO development and remodeling remain unclear. PMID:27190524

  6. Lymphoid Tissue Mesenchymal Stromal Cells in Development and Tissue Remodeling.

    PubMed

    Genovese, Luca; Brendolan, Andrea

    2016-01-01

    Secondary lymphoid organs (SLOs) are sites that facilitate cell-cell interactions required for generating adaptive immune responses. Nonhematopoietic mesenchymal stromal cells have been shown to play a critical role in SLO function, organization, and tissue homeostasis. The stromal microenvironment undergoes profound remodeling to support immune responses. However, chronic inflammatory conditions can promote uncontrolled stromal cell activation and aberrant tissue remodeling including fibrosis, thus leading to tissue damage. Despite recent advancements, the origin and role of mesenchymal stromal cells involved in SLO development and remodeling remain unclear. PMID:27190524

  7. Morphology of mucosa-associated lymphoid tissue in odontocetes.

    PubMed

    Silva, Fernanda M O; Guimarães, Juliana P; Vergara-Parente, Jociery E; Carvalho, Vitor L; Carolina, Ana; Meirelles, O; Marmontel, Miriam; Oliveira, Bruno S S P; Santos, Silvanise M; Becegato, Estella Z; Evangelista, Janaina S A M; Miglino, Maria Angelica

    2016-09-01

    This study describes the mucosa-associated lymphoid tissue (MALT) in odontocetes from the Brazilian coast and freshwater systems. Seven species were evaluated and tissue samples were analyzed by light, scanning and transmission electron microscopy, and immunohistochemistry. Laryngeal tonsil was a palpable oval mass located in the larynx, composed of a lymphoepithelial complex. Dense collections of lymphocytes were found in the skin of male fetus and calf. Clusters of lymphoid tissue were found in the uterine cervix of a reproductively active juvenile female and along the pulmonary artery of an adult female. Lymphoid tissues associated with the gastrointestinal tract were characterized by diffusely arranged or organized lymphocytes. The anal tonsil was composed of an aggregate of lymphoid tissue occurring exclusively in the anal canal, being composed of squamous epithelium branches. MALT was present in different tissues and organic systems of cetaceans, providing constant protection against mucosal pathogens present in their environment. PMID:27380767

  8. Dynamics of HIV infection in lymphoid tissue network.

    PubMed

    Nakaoka, Shinji; Iwami, Shingo; Sato, Kei

    2016-03-01

    Human immunodeficiency virus (HIV) is a fast replicating ribonucleic acid virus, which can easily mutate in order to escape the effects of drug administration. Hence, understanding the basic mechanisms underlying HIV persistence in the body is essential in the development of new therapies that could eradicate HIV infection. Lymphoid tissues are the primary sites of HIV infection. Despite the recent progress in real-time monitoring technology, HIV infection dynamics in a whole body is unknown. Mathematical modeling and simulations provide speculations on global behavior of HIV infection in the lymphatic system. We propose a new mathematical model that describes the spread of HIV infection throughout the lymphoid tissue network. In order to represent the volume difference between lymphoid tissues, we propose the proportionality of several kinetic parameters to the lymphoid tissues' volume distribution. Under this assumption, we perform extensive numerical computations in order to simulate the spread of HIV infection in the lymphoid tissue network. Numerical computations simulate single drug treatments of an HIV infection. One of the important biological speculations derived from this study is a drug saturation effect generated by lymphoid network connection. This implies that a portion of reservoir lymphoid tissues to which drug is not sufficiently delivered would inhibit HIV eradication despite of extensive drug injection. PMID:26507442

  9. Quantitative Image Analysis of HIV-1 Infection in Lymphoid Tissue

    NASA Astrophysics Data System (ADS)

    Haase, Ashley T.; Henry, Keith; Zupancic, Mary; Sedgewick, Gerald; Faust, Russell A.; Melroe, Holly; Cavert, Winston; Gebhard, Kristin; Staskus, Katherine; Zhang, Zhi-Qiang; Dailey, Peter J.; Balfour, Henry H., Jr.; Erice, Alejo; Perelson, Alan S.

    1996-11-01

    Tracking human immunodeficiency virus-type 1 (HIV-1) infection at the cellular level in tissue reservoirs provides opportunities to better understand the pathogenesis of infection and to rationally design and monitor therapy A quantitative technique was developed to determine viral burden in two important cellular compartments in lymphoid tissues. Image analysis and in situ hybridization were combined to show that in the presymptomatic stages of infection there is a large, relatively stable pool of virions on the surfaces of follicular dendritic cells and a smaller pool of productively infected cells Despite evidence of constraints on HIV-1 replication in the infected cell population in lymphoid tissues, estimates of the numbers of these cells and the virus they could produce are consistent with the quantities of virus that have been detected in the bloodstream. The cellular sources of virus production and storage in lymphoid tissues can now be studied with this approach over the course of infection and treatment.

  10. Chemokines and Chemokine Receptors in Lymphoid Tissue Dynamics.

    PubMed

    Schulz, Olga; Hammerschmidt, Swantje I; Moschovakis, G Leandros; Förster, Reinhold

    2016-05-20

    The continuous migration of immune cells between lymphoid and nonlymphoid organs is a key feature of the immune system, facilitating the distribution of effector cells within nearly all compartments of the body. Furthermore, reaching their correct position within primary, secondary, or tertiary lymphoid organs is a prerequisite to ensure immune cells' unimpaired differentiation, maturation, and selection, as well as their activation or functional silencing. The superfamilies of chemokines and chemokine receptors are of major importance in guiding immune cells to and within lymphoid and nonlymphoid tissues. In this review we focus on the role of the chemokine system in the migration dynamics of immune cells within lymphoid organs at the steady state and on how these dynamics are affected by infectious and inflammatory processes. PMID:26907216

  11. Endobronchial recurrence of gastric mucosa-associated lymphoid tissue lymphoma.

    PubMed

    McCollum, Charles R; VanAsselberg, Chad B; Cook-Glen, Celeste L; Bhagat, Rajesh; Abraham, George E

    2012-10-01

    Mucosa-associated lymphoid tissue (MALT) lymphoma is a diagnostic challenge when arising from bronchiolar submucosal tissue. The case herein describes a man with a lung mass and a remote history of gastric MALT lymphoma. After undergoing a bronchoscopic examination and tissue sampling, he was diagnosed with pulmonary recurrence of gastric MALT lymphoma. The diagnosis of MALT lymphoma in the lung can be challenging. Radiographic findings are typically nonspecific, and tissue biopsy by surgical means is often required. The diagnosis of bronchus-associated lymphoid tissue lymphoma has been previously demonstrated bronchoscopically when a needle aspiration is performed. This case supports the position that bronchoscopy with needle aspiration, and flow cytometry should be performed in all patients in whom pulmonary MALT lymphoma is suspected. PMID:23207539

  12. Quantitative image analysis of HIV-1 infection in lymphoid tissue

    SciTech Connect

    Haase, A.T.; Zupancic, M.; Cavert, W.

    1996-11-08

    Tracking human immunodeficiency virus-type 1 (HIV-1) infection at the cellular level in tissue reservoirs provides opportunities to better understand the pathogenesis of infection and to rationally design and monitor therapy. A quantitative technique was developed to determine viral burden in two important cellular compartments in lymphoid developed to determine viral burden in two important cellular compartments in lymphoid tissues. Image analysis and in situ hybridization were combined to show that in the presymptomatic stages of infection there is a large, relatively stable pool of virions on the surfaces of follicular dendritic cells and a smaller pool of productivity infected cells. Despite evidence of constraints on HIV-1 replication in the infected cell population in lymphoid tissues, estimates of the numbers of these cells and the virus they could produce are consistent with the quantities of virus that have been detected in the bloodstream. The cellular sources of virus production and storage in lymphoid tissues can now be studied with this approach over the course of infection and treatment. 22 refs., 2 figs., 2 tabs.

  13. Vitamin A Controls the Presence of RORγ+ Innate Lymphoid Cells and Lymphoid Tissue in the Small Intestine.

    PubMed

    Goverse, Gera; Labao-Almeida, Carlos; Ferreira, Manuela; Molenaar, Rosalie; Wahlen, Sigrid; Konijn, Tanja; Koning, Jasper; Veiga-Fernandes, Henrique; Mebius, Reina E

    2016-06-15

    Changes in diet and microbiota have determining effects on the function of the mucosal immune system. For example, the active metabolite of vitamin A, retinoic acid (RA), has been described to maintain homeostasis in the intestine by its influence on both lymphocytes and myeloid cells. Additionally, innate lymphoid cells (ILCs), important producers of cytokines necessary for intestinal homeostasis, are also influenced by vitamin A in the small intestines. In this study, we show a reduction of both NCR(-) and NCR(+) ILC3 subsets in the small intestine of mice raised on a vitamin A-deficient diet. Additionally, the percentages of IL-22-producing ILCs were reduced in the absence of dietary vitamin A. Conversely, mice receiving additional RA had a specific increase in the NCR(-) ILC3 subset, which contains the lymphoid tissue inducer cells. The dependence of lymphoid tissue inducer cells on vitamin A was furthermore illustrated by impaired development of enteric lymphoid tissues in vitamin A-deficient mice. These effects were a direct consequence of ILC-intrinsic RA signaling, because retinoic acid-related orphan receptor γt-Cre × RARα-DN mice had reduced numbers of NCR(-) and NCR(+) ILC3 subsets within the small intestine. However, lymphoid tissue inducer cells were not affected in these mice nor was the formation of enteric lymphoid tissue, demonstrating that the onset of RA signaling might take place before retinoic acid-related orphan receptor γt is expressed on lymphoid tissue inducer cells. Taken together, our data show an important role for vitamin A in controlling innate lymphoid cells and, consequently, postnatal formed lymphoid tissues within the small intestines. PMID:27183576

  14. The Detection of Glycosaminoglycans in Pancreatic Islets and Lymphoid Tissues

    PubMed Central

    Bogdani, Marika; Simeonovic, Charmaine; Nagy, Nadine; Johnson, Pamela Y.; Chan, Christina K.; Wight, Thomas N.

    2014-01-01

    Summary In this chapter, we describe the detection of the glycosaminoglycans hyaluronan and heparan sulfate in pancreatic islets and lymphoid tissues. The identification of hyaluronan in tissues is achieved by utilizing a highly specific hyaluronan binding protein (HABP) probe that interacts with hyaluronan in tissue sections. The HABP probe is prepared by enzymatic digestion of the chondroitin sulfate proteoglycan aggrecan which is present in bovine nasal cartilage, and is then biotinylated in the presence of bound hyaluronan and the link protein. Hyaluronan is then removed by gel filtration chromatography. The biotinylated HABP - link protein complex is applied to tissue sections and binding of the complex to tissue hyaluronan is visualized by enzymatic precipitation of chromogenic substrates. To determine hyaluronan content in tissues, tissues are first proteolytically digested to release hyaluronan from the macromolecular complexes that this molecule forms with other extracellular matrix constituents. Digested tissue is then incubated with HABP. The hyaluronan - HABP complexes are extracted and the hyaluronan concentration in the tissue is determined using an ELISA-like assay. Heparan sulfate is identified in mouse tissues by Alcian blue histochemistry and indirect immunohistochemistry. In human tissues, heparan sulfate is best detected by indirect immunohistochemistry using a specific anti-heparan sulfate monoclonal antibody. A biotinylated secondary antibody is then applied in conjunction with streptavidin-peroxidase and its binding to the anti-heparan sulfate antibody is visualized by enzymatic precipitation of chromogenic substrates. PMID:25325969

  15. Type 3 innate lymphoid cell depletion is mediated by TLRs in lymphoid tissues of simian immunodeficiency virus-infected macaques.

    PubMed

    Xu, Huanbin; Wang, Xiaolei; Lackner, Andrew A; Veazey, Ronald S

    2015-12-01

    Innate lymphoid cells (ILCs) type 3, also known as lymphoid tissue inducer cells, plays a major role in both the development and remodeling of organized lymphoid tissues and the maintenance of adaptive immune responses. HIV/simian immunodeficiency virus (SIV) infection causes breakdown of intestinal barriers resulting in microbial translocation, leading to systemic immune activation and disease progression. However, the effects of HIV/SIV infection on ILC3 are unknown. Here, we analyzed ILC3 from mucosal and systemic lymphoid tissues in chronically SIV-infected macaques and uninfected controls. ILC3 cells were defined and identified in macaque lymphoid tissues as non-T, non-B (lineage-negative), c-Kit(+)IL-7Rα(+) (CD117(+)CD127(+)) cells. These ILC3 cells highly expressed CD90 (∼ 63%) and aryl hydrocarbon receptor and produced IL-17 (∼ 63%), IL-22 (∼ 36%), and TNF-α (∼ 72%) but did not coexpress CD4 or NK cell markers. The intestinal ILC3 cell loss correlated with the reduction of total CD4(+) T cells and T helper (Th)17 and Th22 cells in the gut during SIV infection (P < 0.001). Notably, ILC3 could be induced to undergo apoptosis by microbial products through the TLR2 (lipoteichoic acid) and/or TLR4 (LPS) pathway. These findings indicated that persistent microbial translocation may result in loss of ILC3 in lymphoid tissues in SIV-infected macaques, further contributing to the HIV-induced impairment of gut-associated lymphoid tissue structure and function, especially in mucosal tissues. PMID:26283536

  16. Multispectral imaging fluorescence microscopy for lymphoid tissue analysis

    NASA Astrophysics Data System (ADS)

    Monici, Monica; Agati, Giovanni; Fusi, Franco; Mazzinghi, Piero; Romano, Salvatore; Pratesi, Riccardo; Alterini, Renato; Bernabei, Pietro A.; Rigacci, Luigi

    1999-01-01

    Multispectral imaging autofluorescence microscopy (MIAM) is used here for the analysis of lymphatic tissues. Lymph node biopsies, from patients with lympthoadenopathy of different origin have been examined. Natural fluorescence (NF) images of 3 micrometers sections were obtained using three filters peaked at 450, 550 and 680 nm with 50 nm bandpass. Monochrome images were combined together in a single RGB image. NF images of lymph node tissue sections show intense blue-green fluorescence of the connective stroma. Normal tissue shows follicles with faintly fluorescent lymphocytes, as expected fro the morphologic and functional characteristics of these cells. Other more fluorescent cells (e.g., plasma cells and macrophages) are evidenced. Intense green fluorescence if localized in the inner wall of the vessels. Tissues coming from patients affected by Hodgkin's lymphoma show spread fluorescence due to connective infiltration and no evidence of follicle organization. Brightly fluorescent large cells, presumably Hodgkin cells, are also observed. These results indicate that MIAM can discriminate between normal and pathological tissues on the basis of their natural fluorescence pattern, and, therefore, represent a potentially useful technique for diagnostic applications. Analysis of the fluorescence spectra of both normal and malignant lymphoid tissues resulted much less discriminatory than MIAM.

  17. Colonic mucosa-associated lymphoid tissue lymphoma identified by chromoendoscopy.

    PubMed

    Seo, Sang-Wook; Lee, Seung-Hwa; Lee, Duck-Joo; Kim, Kwang-Min; Kang, Joon-Koo; Kim, Do-Wan; Lee, Jeong-Hun

    2014-12-28

    Colonic mucosa-associated lymphoid tissue (MALT) lymphomas are a rare occurrence and the definitive treatment has not been established. Solitary or multiple, elevated or polypoid lesions are the usual appearances of MALT lymphoma in the large intestine and sometimes the surface may reveal abnormal vascularity. Herein, we report a case of MALT lymphoma and review the relevant literature. Upon colonoscopy, a suspected pathologic lesion was observed in the proximal transverse colon. The lesion could be distinguished more prominently after using narrow-band imaging mode and indigo carmine-dye spraying chromoendoscopy. Histopathologic examination of this biopsy specimen revealed lymphoepithelial lesions with diffuse proliferation of atypical lymphoid cells effacing the glandular architecture and centrocyte-like cells infiltrating the lamina propria. Immunohistochemical analyses showed that tumor cells were positive for CD20 and Bcl-2e, and negative for CD10, CD23, and Bcl-6. According to Ann-Arbor staging system, the patient had stage IIE. A partial colectomy with dissection of the paracolic lymph nodes was performed. Until now, there is no recurrence of lymphoma at follow-up. PMID:25561821

  18. Colonic mucosa-associated lymphoid tissue lymphoma identified by chromoendoscopy

    PubMed Central

    Seo, Sang-Wook; Lee, Seung-Hwa; Lee, Duck-Joo; Kim, Kwang-Min; Kang, Joon-Koo; Kim, Do-Wan; Lee, Jeong-Hun

    2014-01-01

    Colonic mucosa-associated lymphoid tissue (MALT) lymphomas are a rare occurrence and the definitive treatment has not been established. Solitary or multiple, elevated or polypoid lesions are the usual appearances of MALT lymphoma in the large intestine and sometimes the surface may reveal abnormal vascularity. Herein, we report a case of MALT lymphoma and review the relevant literature. Upon colonoscopy, a suspected pathologic lesion was observed in the proximal transverse colon. The lesion could be distinguished more prominently after using narrow-band imaging mode and indigo carmine-dye spraying chromoendoscopy. Histopathologic examination of this biopsy specimen revealed lymphoepithelial lesions with diffuse proliferation of atypical lymphoid cells effacing the glandular architecture and centrocyte-like cells infiltrating the lamina propria. Immunohistochemical analyses showed that tumor cells were positive for CD20 and Bcl-2e, and negative for CD10, CD23, and Bcl-6. According to Ann-Arbor staging system, the patient had stage IIE. A partial colectomy with dissection of the paracolic lymph nodes was performed. Until now, there is no recurrence of lymphoma at follow-up. PMID:25561821

  19. Cellular Localization of Simian Immunodeficiency Virus in Lymphoid Tissues

    PubMed Central

    Ringler, D. J.; Wyand, M. S.; Walsh, D. G.; MacKey, J. J.; Chalifoux, L. V.; Popovic, M.; Minassian, A. A.; Sehgal, P. K.; Daniel, M. D.; Desrosiers, R. C.; King, N. W.

    1989-01-01

    Simian immunodeficiency virus (SIV) is a lentivirus with genetic relatedness to the human immunodeficiency viruses (HIV-1 and HIV-2). It induces a fatal syndrome in rhesus monkeys that closely parallels the clinical course of AIDS in humans. The authors used double-labeling immunohistochemical procedures on rhesus lymph node and spleen taken during different time periods after SIV infection to localize the p27 gag protein to specific cellular immunophenotypes. In animals with follicular hyperplasia, viral protein was found associated predominantly with follicular dendritic cells. Many of these cells showed ultrastructural alterations consisting of swollen dendritic processes contaning electron-dense material. Lentiviral particles were found associated with this cell type only rarely. In lymphoid tissues with other histopathologic changes, macrophages and multinucleate giant cells were the predominant cell types containing detectable quantities of viral protein; smaller numbers of p27+ lymhocytes were present. Ultrastructurally, viral particles were found within the extracellular spce adjacent to tissue macrophages and within membrane-bound vacuoles of giant cells and tissue macrophage. These results show that certain histologic patterns seen during the course of infection correlate with the localization of viral antigen to specific cellular immunophenotypes and that during the disease course, viral protein is preferentially localized in sections of lymphonode and spleen to cells of the macrophage and dendritic cell lineage. ImagesFigure 1Figure 2Figure 3A, B PMID:2537016

  20. Defining HIV and SIV Reservoirs in Lymphoid Tissues

    PubMed Central

    Deleage, Claire; Wietgrefe, Stephen W.; Del Prete, Gregory; Morcock, David R.; Hao, Xing Pei; Piatak, Michael; Bess, Julian; Anderson, Jodi L.; Perkey, Katherine E.; Reilly, Cavan; McCune, Joseph M.; Haase, Ashley T.; Lifson, Jeffrey D.; Schacker, Timothy W.; Estes, Jacob D.

    2016-01-01

    A primary obstacle to an HIV-1 cure is long-lived viral reservoirs, which must be eliminated or greatly reduced. Cure strategies have largely focused on monitoring changes in T cell reservoirs in peripheral blood (PB), even though the lymphoid tissues (LT) are primary sites for viral persistence. To track and discriminate viral reservoirs within tissue compartments we developed a specific and sensitive next-generation in situ hybridization approach to detect vRNA, including vRNA+ cells and viral particles (“RNAscope”), vDNA+ cells (“DNAscope”) and combined vRNA and vDNA with immunohistochemistry to detect and phenotype active and latently infected cells in the same tissue section. RNAscope is highly sensitive with greater speed of analysis compared to traditional in situ hybridization. The highly sensitive and specific DNAscope detected SIV/HIV vDNA+ cells, including duplexed detection of vDNA and vRNA or immunophenotypic markers in the same section. Analysis of LT samples from macaques prior to and during combination antiretroviral therapy demonstrated that B cell follicles are an important anatomical compartment for both latent and active viral persistence during treatment. These new tools should allow new insights into viral reservoir biology and evaluation of cure strategies. PMID:27430032

  1. Single-cell analysis defines the divergence between the innate lymphoid cell lineage and lymphoid tissue-inducer cell lineage.

    PubMed

    Ishizuka, Isabel E; Chea, Sylvestre; Gudjonson, Herman; Constantinides, Michael G; Dinner, Aaron R; Bendelac, Albert; Golub, Rachel

    2016-03-01

    The precise lineage relationship between innate lymphoid cells (ILCs) and lymphoid tissue-inducer (LTi) cells is poorly understood. Using single-cell multiplex transcriptional analysis of 100 lymphoid genes and single-cell cultures of fetal liver precursor cells, we identified the common proximal precursor to these lineages and found that its bifurcation was marked by differential induction of the transcription factors PLZF and TCF1. Acquisition of individual effector programs specific to the ILC subsets ILC1, ILC2 and ILC3 was initiated later, at the common ILC precursor stage, by transient expression of mixed ILC1, ILC2 and ILC3 transcriptional patterns, whereas, in contrast, the development of LTi cells did not go through multilineage priming. Our findings provide insight into the divergent mechanisms of the differentiation of the ILC lineage and LTi cell lineage and establish a high-resolution 'blueprint' of their development. PMID:26779601

  2. Characteristics of submucosal lymphoid tissue located in the proximal colon of the rat.

    PubMed Central

    Crouse, D A; Perry, G A; Murphy, B O; Sharp, J G

    1989-01-01

    In this study we have examined the morphology and steroid sensitivity of proximal colonic lymphoid tissue in the Fisher 344 rat. A time course study was conducted in which groups of animals were injected subcutaneously with hydrocortisone sodium succinate (125 mg/kg body weight) and killed on Days 0-4. Thymus, jejunal and ileal Peyer's patches and proximal colonic lymphoid tissue were excised, weighed and processed for histological analysis. The results showed that the maximum cytoreductive effects of the hydrocortisone were evident on Day 2. Thymus and proximal colonic lymphoid tissue weight decreased to 5 and 18% of the control values respectively, before returning towards control values over the next two days. In contrast, jejunal and ileal Peyer's patch weights were unaltered. A dose response experiment was conducted using the same endpoints. Rats were injected subcutaneously with hydrocortisone at 60, 120, 200 and 300 mg/kg body weight and killed on Day 2. The results of this experiment showed that the proximal colonic lymphoid tissue, like thymus, responded with a dose-dependent loss of tissue weight. The spleen and Peyer's patches showed only a slight weight decrease compared to the control. These data showed that the response of proximal colonic lymphoid tissue to steroids was more similar to that of thymus, a primary lymphoid tissue, than to other secondary lymphoid tissues. Finally, grafts of fetal proximal colon under the kidney capsule of syngeneic adults supported the development of this lymphoid aggregate in the absence of luminal antigenic stimulation. These results suggest that the development and functional contribution of proximal colonic lymphoid tissue to the immune system warrants a more detailed examination. Images Fig. 2 Fig. 3 Fig. 5 Fig. 6 PMID:2808123

  3. Lymphoid tissue during irradiation of tumors with pulsing laser's radiation

    NASA Astrophysics Data System (ADS)

    Moskalik, Konstantin G.

    2002-06-01

    The structure of the regional lymph nodes and the thymus was studied in the experiments upon the mice of the line C57BL with the subcutaneous interwoven melanoma B16 in the periods from one hour to 12 days after the radiation of melanoma with one irradiation impulse of the Nd laser with the energy density of 400 J/cm2. During the first 3 days after the irradiation of tumor with laser radiation the impoverishment of lymph nodes and thymus with lymphocytes takes place because of their intensified migration from these organs to the blood channel. Then one can see the restoration of the lymph nodes and thymus structure. The restoration of lymphopoiesis in the lymph nodes went on in the first place because of the poiesis in the follicles which consist of B-lymphocytes. Consequently, the lymphoid tissue plays a great role in the reorganization of the immunological status of the organism. Reorganization can be seen during the treatment of tumors with laser radiation, and it takes place in the first instance because of the reinforcement of the humoral immunity.

  4. Scrapie-specific pathology of sheep lymphoid tissues.

    PubMed

    McGovern, Gillian; Jeffrey, Martin

    2007-01-01

    Transmissible spongiform encephalopathies (TSEs) or prion diseases often result in accumulation of disease-associated PrP (PrP(d)) in the lymphoreticular system (LRS), specifically in association with follicular dendritic cells (FDCs) and tingible body macrophages (TBMs) of secondary follicles. We studied the effects of sheep scrapie on lymphoid tissue in tonsils and lymph nodes by light and electron microscopy. FDCs of sheep were grouped according to morphology as immature, mature or regressing. Scrapie was associated with FDC dendrite hypertrophy and electron dense deposit or vesicles. PrP(d) was located using immunogold labelling at the plasmalemma of FDC dendrites and, infrequently, mature B cells. Abnormal electron dense deposits surrounding FDC dendrites were identified as immunoglobulins suggesting that excess immune complexes are retained and are indicative of an FDC dysfunction. Within scrapie-affected lymph nodes, macrophages outside the follicle and a proportion of germinal centre TBMs accumulated PrP(d) within endosomes and lysosomes. In addition, TBMs showed PrP(d) in association with the cell membrane, non-coated pits and vesicles, and also with discrete, large and random endoplasmic reticulum networks, which co-localised with ubiquitin. These observations suggest that PrP(d) is internalised via the caveolin-mediated pathway, and causes an abnormal disease-related alteration in endoplasmic reticulum structure. In contrast to current dogma, this study shows that sheep scrapie is associated with cytopathology of germinal centres, which we attribute to abnormal antigen complex trapping by FDCs and abnormal endocytic events in TBMs. The nature of the sub-cellular changes in FDCs and TBMs differs from those of scrapie infected neurones and glial cells suggesting that different PrP(d)/cell membrane interactions occur in different cell types. PMID:18074028

  5. Lymphocyte trafficking and HIV infection of human lymphoid tissue in a rotating wall vessel bioreactor

    NASA Technical Reports Server (NTRS)

    Margolis, L. B.; Fitzgerald, W.; Glushakova, S.; Hatfill, S.; Amichay, N.; Baibakov, B.; Zimmerberg, J.

    1997-01-01

    The pathogenesis of HIV infection involves a complex interplay between both the infected and noninfected cells of human lymphoid tissue, the release of free viral particles, the de novo infection of cells, and the recirculatory trafficking of peripheral blood lymphocytes. To develop an in vitro model for studying these various aspects of HIV pathogenesis we have utilized blocks of surgically excised human tonsils and a rotating wall vessel (RWV) cell culture system. Here we show that (1) fragments of the surgically excised human lymphoid tissue remain viable and retain their gross cytoarchitecture for at least 3 weeks when cultured in the RWV system; (2) such lymphoid tissue gradually shows a loss of both T and B cells to the surrounding growth medium; however, this cellular migration is reversible as demonstrated by repopulation of the tissue by labeled cells from the growth medium; (3) this cellular migration may be partially or completely inhibited by embedding the blocks of lymphoid tissue in either a collagen or agarose gel matrix; these embedded tissue blocks retain most of the basic elements of a normal lymphoid cytoarchitecture; and (4) both embedded and nonembedded RWV-cultured blocks of human lymphoid tissue are capable of productive infection by HIV-1 of at least three various strains of different tropism and phenotype, as shown by an increase in both p24 antigen levels and free virus in the culture medium, and by the demonstration of HIV-1 RNA-positive cells inside the tissue identified by in situ hybridization. It is therefore reasonable to suggest that gel-embedded and nonembedded blocks of human lymphoid tissue, cocultured with a suspension of tonsillar lymphocytes in an RWV culture system, constitute a useful model for simulating normal lymphocyte recirculatory traffic and provide a new tool for testing the various aspects of HIV pathogenesis.

  6. Nasal Associated Lymphoid Tissue of the Syrian Golden Hamster Expresses High Levels of PrPC

    PubMed Central

    Clouse, Melissa D.; Shikiya, Ronald A.; Bartz, Jason C.; Kincaid, Anthony E.

    2015-01-01

    The key event in the pathogenesis of the transmissible spongiform encephalopathies is a template-dependent misfolding event where an infectious isoform of the prion protein (PrPSc) comes into contact with native prion protein (PrPC) and changes its conformation to PrPSc. In many extraneurally inoculated models of prion disease this PrPC misfolding event occurs in lymphoid tissues prior to neuroinvasion. The primary objective of this study was to compare levels of total PrPC in hamster lymphoid tissues involved in the early pathogenesis of prion disease. Lymphoid tissues were collected from golden Syrian hamsters and Western blot analysis was performed to quantify PrPC levels. PrPC immunohistochemistry (IHC) of paraffin embedded tissue sections was performed to identify PrPC distribution in tissues of the lymphoreticular system. Nasal associated lymphoid tissue contained the highest amount of total PrPC followed by Peyer’s patches, mesenteric and submandibular lymph nodes, and spleen. The relative levels of PrPC expression in IHC processed tissue correlated strongly with the Western blot data, with high levels of PrPC corresponding with a higher percentage of PrPC positive B cell follicles. High levels of PrPC in lymphoid tissues closely associated with the nasal cavity could contribute to the relative increased efficiency of the nasal route of entry of prions, compared to other routes of infection. PMID:25642714

  7. Peripheral Tissue Homing Receptor Control of Naïve, Effector, and Memory CD8 T Cell Localization in Lymphoid and Non-Lymphoid Tissues

    PubMed Central

    Brinkman, C. Colin; Peske, J. David; Engelhard, Victor Henry

    2013-01-01

    T cell activation induces homing receptors that bind ligands on peripheral tissue vasculature, programing movement to sites of infection and injury. There are three major types of CD8 effector T cells based on homing receptor expression, which arise in distinct lymphoid organs. Recent publications indicate that naïve, effector, and memory T cell migration is more complex than once thought; while many effectors enter peripheral tissues, some re-enter lymph nodes (LN), and contain central memory precursors. LN re-entry can depend on CD62L or peripheral tissue homing receptors. Memory T cells in LN tend to express the same homing receptors as their forebears, but often are CD62Lneg. Homing receptors also control CD8 T cell tumor entry. Tumor vasculature has low levels of many peripheral tissue homing receptor ligands, but portions of it resemble high endothelial venules (HEV), enabling naïve T cell entry, activation, and subsequent effector activity. This vasculature is associated with positive prognoses in humans, suggesting it may sustain ongoing anti-tumor responses. These findings reveal new roles for homing receptors expressed by naïve, effector, and memory CD8 T cells in controlling entry into lymphoid and non-lymphoid tissues. PMID:23966998

  8. Peripheral tissue homing receptor control of naïve, effector, and memory CD8 T cell localization in lymphoid and non-lymphoid tissues.

    PubMed

    Brinkman, C Colin; Peske, J David; Engelhard, Victor Henry

    2013-01-01

    T cell activation induces homing receptors that bind ligands on peripheral tissue vasculature, programing movement to sites of infection and injury. There are three major types of CD8 effector T cells based on homing receptor expression, which arise in distinct lymphoid organs. Recent publications indicate that naïve, effector, and memory T cell migration is more complex than once thought; while many effectors enter peripheral tissues, some re-enter lymph nodes (LN), and contain central memory precursors. LN re-entry can depend on CD62L or peripheral tissue homing receptors. Memory T cells in LN tend to express the same homing receptors as their forebears, but often are CD62Lneg. Homing receptors also control CD8 T cell tumor entry. Tumor vasculature has low levels of many peripheral tissue homing receptor ligands, but portions of it resemble high endothelial venules (HEV), enabling naïve T cell entry, activation, and subsequent effector activity. This vasculature is associated with positive prognoses in humans, suggesting it may sustain ongoing anti-tumor responses. These findings reveal new roles for homing receptors expressed by naïve, effector, and memory CD8 T cells in controlling entry into lymphoid and non-lymphoid tissues. PMID:23966998

  9. Human Lymphoid Tissues Harbor a Distinct CD69+CXCR6+ NK Cell Population.

    PubMed

    Lugthart, Gertjan; Melsen, Janine E; Vervat, Carly; van Ostaijen-Ten Dam, Monique M; Corver, Willem E; Roelen, Dave L; van Bergen, Jeroen; van Tol, Maarten J D; Lankester, Arjan C; Schilham, Marco W

    2016-07-01

    Knowledge of human NK cells is based primarily on conventional CD56(bright) and CD56(dim) NK cells from blood. However, most cellular immune interactions occur in lymphoid organs. Based on the coexpression of CD69 and CXCR6, we identified a third major NK cell subset in lymphoid tissues. This population represents 30-60% of NK cells in marrow, spleen, and lymph node but is absent from blood. CD69(+)CXCR6(+) lymphoid tissue NK cells have an intermediate expression of CD56 and high expression of NKp46 and ICAM-1. In contrast to circulating NK cells, they have a bimodal expression of the activating receptor DNAX accessory molecule 1. CD69(+)CXCR6(+) NK cells do not express the early markers c-kit and IL-7Rα, nor killer cell Ig-like receptors or other late-differentiation markers. After cytokine stimulation, CD69(+)CXCR6(+) NK cells produce IFN-γ at levels comparable to CD56(dim) NK cells. They constitutively express perforin but require preactivation to express granzyme B and exert cytotoxicity. After hematopoietic stem cell transplantation, CD69(+)CXCR6(+) lymphoid tissue NK cells do not exhibit the hyperexpansion observed for both conventional NK cell populations. CD69(+)CXCR6(+) NK cells constitute a separate NK cell population with a distinct phenotype and function. The identification of this NK cell population in lymphoid tissues provides tools to further evaluate the cellular interactions and role of NK cells in human immunity. PMID:27226093

  10. Suppression of HIV Replication by Lymphoid Tissue CD8+ Cells Correlates with the Clinical State of HIV-Infected Individuals

    NASA Astrophysics Data System (ADS)

    Blackbourn, David J.; Mackewicz, Carl E.; Barker, Edward; Hunt, Thomas K.; Herndier, Brian; Haase, Ashley T.; Levy, Jay A.

    1996-11-01

    Lymphoid tissues from asymptomatic HIV-infected individuals, as compared with symptomatic HIV-infected subjects, show limited histopathological changes and lower levels of HIV expression. In this report we correlate the control of HIV replication in lymph nodes to the non-cytolytic anti-HIV activity of lymphoid tissue CD8+ cells. Five subjects at different stages of HIV-related disease were studied and the ability of their CD8+ cells, isolated from both lymphoid tissue and peripheral blood, to inhibit HIV replication was compared. CD8+ cells from lymphoid tissue and peripheral blood of two HIV-infected long-term survivors suppressed HIV replication at a low CD8+:CD4+ cell ratio of 0.1. The CD8+ cells from the lymphoid tissue of a third asymptomatic subject suppressed HIV replication at a CD8+:CD4+ cell ratio of 0.25; the subject's peripheral blood CD8+ cells showed this antiviral response at a lower ratio of 0.05. The lymphoid tissue CD8+ cells from two AIDS patients were not able to suppress HIV replication, and the peripheral blood CD8+ cells of only one of them suppressed HIV replication. The plasma viremia, cellular HIV load as well as the extent of pathology and virus expression in the lymphoid tissue of the two long-term survivors, were reduced compared with these parameters in the three other subjects. The data suggest that the extent of anti-HIV activity by CD8+ cells from lymphoid tissue relative to peripheral blood correlates best with the clinical state measured by lymphoid tissue pathology and HIV burden in lymphoid tissues and blood. The results and further emphasis to the importance of this cellular immune response in controlling HIV pathogenesis.

  11. Bystander CD4+ T lymphocytes survive in HIV-infected human lymphoid tissue

    NASA Technical Reports Server (NTRS)

    Grivel, Jean-Charles; Biancotto, Angelique; Ito, Yoshinori; Lima, Rosangela G.; Margolis, Leonid B.

    2003-01-01

    HIV infection is associated with depletion of CD4(+) T cells. The mechanisms of this phenomenon remain to be understood. In particular, it remains controversial whether and to what extent uninfected ("bystander") CD4(+) T cells die in HIV-infected individuals. We address this question using a system of human lymphoid tissue ex vivo. Tissue blocks were inoculated with HIV-1. After productive infection was established, they were treated with the reverse transcriptase inhibitor nevirapine to protect from infection those CD4(+) T cells that had not yet been infected. These CD4(+) T cells residing in HIV-infected tissue are by definition bystanders. Our results demonstrate that after nevirapine application the number of bystander CD4(+) T cells is conserved. Thus, in the context of HIV-infected human lymphoid tissue, productive HIV infection kills infected cells but is not sufficient to cause the death of a significant number of uninfected CD4(+) T cells.

  12. Post-conversion sialylation of prions in lymphoid tissues

    PubMed Central

    Srivastava, Saurabh; Makarava, Natallia; Katorcha, Elizaveta; Savtchenko, Regina; Brossmer, Reinhard; Baskakov, Ilia V.

    2015-01-01

    Sialylated glycans on the surface of mammalian cells act as part of a “self-associated molecular pattern,” helping the immune system to recognize “self” from “altered self” or “nonself.” To escape the host immune system, some bacterial pathogens have evolved biosynthetic pathways for host-like sialic acids, whereas others recruited host sialic acids for decorating their surfaces. Prions lack nucleic acids and are not conventional pathogens. Nevertheless, prions might use a similar strategy for invading and colonizing the lymphoreticular system. Here we show that the sialylation status of the infectious, disease-associated state of the prion protein (PrPSc) changes with colonization of secondary lymphoid organs (SLOs). As a result, spleen-derived PrPSc is more sialylated than brain-derived PrPSc. Enhanced sialylation of PrPSc is recapitulated in vitro by incubating brain-derived PrPSc with primary splenocytes or cultured macrophage RAW 264.7 cells. General inhibitors of sialyltranserases (STs), the enzymes that transfer sialic acid residues onto terminal positions of glycans, suppressed extrasialylation of PrPSc. A fluorescently labeled precursor of sialic acid revealed ST activity associated with RAW macrophages. This study illustrates that, upon colonization of SLOs, the sialylation status of prions changes by host STs. We propose that this mechanism is responsible for camouflaging prions in SLOs and has broad implications. PMID:26627256

  13. The requirement of membrane lymphotoxin for the presence of dendritic cells in lymphoid tissues.

    PubMed

    Wu, Q; Wang, Y; Wang, J; Hedgeman, E O; Browning, J L; Fu, Y X

    1999-09-01

    Although several cytokines, including tumor necrosis factor (TNF), can promote the growth of dendritic cells (DCs) in vitro, the cytokines that naturally regulate DC development and function in vivo have not been well defined. Here, we report that membrane lymphotoxin (LT), instead of TNF, regulates the migration of DCs in the spleen. LTalpha(-/-) mice, lacking membrane LTalpha/beta and LTalpha(3), show markedly reduced numbers of DCs in the spleen. Unlike wild-type mice and TNF(-/-) mice that have densely clustered DCs in the T cell zone and around the marginal zone, splenic DCs in LTalpha(-/-) mice are randomly distributed. The reduced number of DCs in lymphoid tissues of LTalpha(-/-) mice is associated with an increased number of DCs in nonlymphoid tissues. The number of splenic DCs in LTalpha(-/-) mice is restored when additional LT-expressing cells are provided. Blocking membrane LTalpha/beta in wild-type mice markedly diminishes the accumulation of DCs in lymphoid tissues. These data suggest that membrane LT is an essential ligand for the presence of DCs in the spleen. Mice deficient in TNF receptor, which is the receptor for both soluble LTalpha(3) and TNF-alpha(3) trimers, have normal numbers of DCs. However, LTbetaR(-/-) mice show reduced numbers of DCs, similar to the mice lacking membrane LT alpha/beta. Taken together, these results support the notion that the signaling via LTbetaR by membrane LTalpha/beta is required for the presence of DCs in lymphoid tissues. PMID:10477548

  14. African Lungfish Reveal the Evolutionary Origins of Organized Mucosal Lymphoid Tissue in Vertebrates.

    PubMed

    Tacchi, Luca; Larragoite, Erin T; Muñoz, Pilar; Amemiya, Chris T; Salinas, Irene

    2015-09-21

    One of the most remarkable innovations of the vertebrate adaptive immune system is the progressive organization of the lymphoid tissues that leads to increased efficiency of immune surveillance and cell interactions. The mucosal immune system of endotherms has evolved organized secondary mucosal lymphoid tissues (O-MALT) such as Peyer's patches, tonsils, and adenoids. Primitive semi-organized lymphoid nodules or aggregates (LAs) were found in the mucosa of anuran amphibians, suggesting that O-MALT evolved from amphibian LAs ∼250 million years ago. This study shows for the first time the presence of O-MALT in the mucosa of the African lungfish, an extant representative of the closest ancestral lineage to all tetrapods. Lungfish LAs are lymphocyte-rich structures associated with a modified covering epithelium and express all IGH genes except for IGHW2L. In response to infection, nasal LAs doubled their size and increased the expression of CD3 and IGH transcripts. Additionally, de novo organogenesis of inducible LAs resembling mammalian tertiary lymphoid structures was observed. Using deep-sequencing transcriptomes, we identified several members of the tumor necrosis factor (TNF) superfamily, and subsequent phylogenetic analyses revealed its extraordinary diversification within sarcopterygian fish. Attempts to find AICDA in lungfish transcriptomes or by RT-PCR failed, indicating the possible absence of somatic hypermutation in lungfish LAs. These findings collectively suggest that the origin of O-MALT predates the emergence of tetrapods and that TNF family members play a conserved role in the organization of vertebrate mucosal lymphoid organs. PMID:26344090

  15. African Lungfish Reveal the Evolutionary Origins of Organized Mucosal Lymphoid Tissue in Vertebrates

    PubMed Central

    Tacchi, Luca; Larragoite, Erin T.; Muñoz, Pilar; Amemiya, Chris T.

    2016-01-01

    SUMMARY One of the most remarkable innovations of the vertebrate adaptive immune system is the progressive organization of the lymphoid tissues that leads to increased efficiency of immune surveillance and cell interactions. The mucosal immune system of endotherms has evolved organized secondary mucosal lymphoid tissues (O-MALT) such as Peyer’s patches, tonsils, and adenoids. Primitive semi-organized lymphoid nodules or aggregates (LAs) were found in the mucosa of anuran amphibians [1], suggesting that O-MALT evolved from amphibian LAs_250 million years ago [1–4]. This study shows for the first time the presence of O-MALT in the mucosa of the African lungfish, an extant representative of the closest ancestral lineage to all tetrapods. Lungfish LAs are lymphocyte-rich structures associated with a modified covering epithelium and express all IGH genes except for IGHW2L. In response to infection, nasal LAs doubled their size and increased the expression of CD3 and IGH transcripts. Additionally, de novo organogenesis of inducible LAs resembling mammalian tertiary lymphoid structures was observed. Using deep-sequencing transcriptomes, we identified several members of the tumor necrosis factor (TNF) superfamily, and subsequent phylogenetic analyses revealed its extraordinary diversification within sarcopterygian fish. Attempts to find AICDA in lungfish transcriptomes or by RT-PCR failed, indicating the possible absence of somatic hypermutation in lungfish LAs. These findings collectively suggest that the origin of O-MALT predates the emergence of tetrapods and that TNF family members play a conserved role in the organization of vertebrate mucosal lymphoid organs. PMID:26344090

  16. A case of conjunctival follicular lymphoma mimicking mucosa-associated lymphoid tissue lymphoma.

    PubMed

    Abd Al-Kader, Lamia; Sato, Yasuharu; Takata, Katsuyoshi; Ohshima, Koh-Ichi; Sogabe, Yuka; Fujii, Kazuhiro; Iwaki, Noriko; Yoshino, Tadashi

    2013-01-01

    Ocular adnexal lymphoma may involve the eyelids, conjunctiva, orbital tissue, or lacrimal structures. The majority are non-Hodgkin's B-cell lymphomas of mucosa-associated lymphoid tissue (MALT) lymphoma type. Follicular lymphomas represent a small percentage of ocular adnexa lymphomas, particularly in Japan. We report a 68-year-old female patient who presented with a salmon pink patch-like lesion of the left conjunctiva, suspected of being (MALT) lymphoma. However, histologic and immunohistologic examinations were consistent with follicular lymphoma. This case demonstrates the importance of considering such rare lymphomas when making a diagnosis of ocular adnexal lymphoid neoplasms. [J Clin Exp Hematop 53(1): 49-52, 2013]. PMID:23801133

  17. B cell clonality in gastric lymphoid tissues of patients with Sjögren's syndrome.

    PubMed Central

    Ferraccioli, G F; Sorrentino, D; De Vita, S; Casatta, L; Labombarda, A; Avellini, C; Dolcetti, R; Di Luca, D; Beltrami, C A; Boiocchi, M; Bartoli, E

    1996-01-01

    OBJECTIVE: To determine the prevalence of mucosa associated lymphoid tissue (MALT) in the stomach and of a possible antigen driven proliferation, in patients with Sjögren's syndrome (SS). METHODS: Twenty one patients with primary SS and 80 dyspeptic controls underwent upper endoscopy. Lymphoid tissue and Helicobacter pylori were assessed by histopathological analysis. Epstein-Barr virus (EBV) or human herpes virus-6 (HHV-6) genome were studied by polymerase chain reaction (PCR) DNA amplification. Two PCR VDJ procedures were used to detect immunoglobulin heavy chain (IgH) gene rearrangement. RESULTS: Organised MALT was found in 33.3% of the patients, compared with 21.5% of the controls (NS). H pylori infection was seen in 71% of patients and 63% of controls. Genomic EBV or HHV-6 was found in a minor portion of SS gastric tissues. B cell expansion was detected in nine of the 21 patients. Infectious agents in the stomach might have contributed to B cell clonality only in 55.5% of the cases. No strict relationship was found between lymphoid follicles and clonality. CONCLUSION: Lymphoid accumulation in the gastric mucosa is common in Sjögren's syndrome, but full evidence for an antigen driven B cell expansion could not be demonstrated. Only a portion of those with clonal B cell expansion had evidence of an infectious agent. Other unknown infectious agents or factors related to the underlying disease (autoantigen) and its tissue environment may have a further role as possible causes of B clonal expansion in the gastric mucosa. Images PMID:8660105

  18. Ectopic Tertiary Lymphoid Tissue in Inflammatory Bowel Disease: Protective or Provocateur?

    PubMed Central

    McNamee, Eóin N.; Rivera-Nieves, Jesús

    2016-01-01

    Organized lymphoid tissues like the thymus first appeared in jawed vertebrates around 500 million years ago and have evolved to equip the host with a network of specialized sites, strategically located to orchestrate strict immune-surveillance and efficient immune responses autonomously. The gut-associated lymphoid tissues maintain a mostly tolerant environment to dampen our responses to daily dietary and microbial products in the intestine. However, when this homeostasis is perturbed by chronic inflammation, the intestine is able to develop florid organized tertiary lymphoid tissues (TLT), which heralds the onset of regional immune dysregulation. While TLT are a pathologic hallmark of Crohn’s disease (CD), their role in the overall process remains largely enigmatic. A critical question remains; are intestinal TLT generated by the immune infiltrated intestine to modulate immune responses and rebuild tolerance to the microbiota or are they playing a more sinister role by generating dysregulated responses that perpetuate disease? Herein, we discuss the main theories of intestinal TLT neogenesis and focus on the most recent findings that open new perspectives to their role in inflammatory bowel disease. PMID:27579025

  19. Ectopic Tertiary Lymphoid Tissue in Inflammatory Bowel Disease: Protective or Provocateur?

    PubMed

    McNamee, Eóin N; Rivera-Nieves, Jesús

    2016-01-01

    Organized lymphoid tissues like the thymus first appeared in jawed vertebrates around 500 million years ago and have evolved to equip the host with a network of specialized sites, strategically located to orchestrate strict immune-surveillance and efficient immune responses autonomously. The gut-associated lymphoid tissues maintain a mostly tolerant environment to dampen our responses to daily dietary and microbial products in the intestine. However, when this homeostasis is perturbed by chronic inflammation, the intestine is able to develop florid organized tertiary lymphoid tissues (TLT), which heralds the onset of regional immune dysregulation. While TLT are a pathologic hallmark of Crohn's disease (CD), their role in the overall process remains largely enigmatic. A critical question remains; are intestinal TLT generated by the immune infiltrated intestine to modulate immune responses and rebuild tolerance to the microbiota or are they playing a more sinister role by generating dysregulated responses that perpetuate disease? Herein, we discuss the main theories of intestinal TLT neogenesis and focus on the most recent findings that open new perspectives to their role in inflammatory bowel disease. PMID:27579025

  20. Neutrophils and monocytes transport tumor cell antigens from the peritoneal cavity to secondary lymphoid tissues

    SciTech Connect

    Terasawa, Masao; Nagata, Kisaburo; Kobayashi, Yoshiro

    2008-12-12

    Antigen-transporting cells take up pathogens, and then migrate from sites of inflammation to secondary lymphoid tissues to induce an immune response. Among antigen-transporting cells, dendritic cells (DCs) are believed to be the most potent and professional antigen-presenting cells that can stimulate naive T cells. However, the cells that transport antigens, tumor cell antigens in particular, have not been clearly identified. In this study we have analyzed what types of cells transport tumor cell antigens to secondary lymphoid tissues. We show that neutrophils, monocytes and macrophages but not DCs engulf X-irradiated P388 leukemic cells after their injection into the peritoneal cavity, and that neutrophils and monocytes but not macrophages migrate to the parathymic lymph nodes (pLN), the blood, and then the spleen. The monocytes in the pLN comprise Gr-1{sup -} and Gr-1{sup +} ones, and some of these cells express CD11c. Overall, this study demonstrates that neutrophils and monocytes transport tumor cell antigens from the peritoneal cavity to secondary lymphoid tissues.

  1. Characteristics of Nasal-Associated Lymphoid Tissue (NALT) and Nasal Absorption Capacity in Chicken

    PubMed Central

    Kang, Haihong; Yan, Mengfei; Yu, Qinghua; Yang, Qian

    2013-01-01

    As the main mucosal immune inductive site of nasal cavity, nasal-associated lymphoid tissue (NALT) plays an important role in both antigen recognition and immune activation after intranasal immunization. However, the efficiency of intranasal vaccines is commonly restricted by the insufficient intake of antigen by the nasal mucosa, resulting from the nasal mucosal barrier and the nasal mucociliary clearance. The distribution of NALT and the characteristic of nasal cavity have already been described in humans and many laboratory rodents, while data about poultry are scarce. For this purpose, histological sections of the chicken nasal cavities were used to examine the anatomical structure and histological characteristics of nasal cavity. Besides, the absorptive capacity of chicken nasal mucosa was also studied using the materials with different particle size. Results showed that the NALT of chicken was located on the bottom of nasal septum and both sides of choanal cleft, which mainly consisted of second lymphoid follicle. A large number of lymphocytes were distributed under the mucosal epithelium of inferior nasal meatus. In addition, there were also diffuse lymphoid tissues located under the epithelium of the concha nasalis media and the walls of nasal cavity. The results of absorption experiment showed that the chicken nasal mucosa was capable to absorb trypan blue, OVA, and fluorescent latex particles. Inactivated avian influenza virus (IAIV) could be taken up by chicken nasal mucosa except for the stratified squamous epithelium sites located on the forepart of nasal cavity. The intake of IAIV by NALT was greater than that of the nasal mucosa covering on non-lymphoid tissue, which could be further enhanced after intranasal inoculation combined with sodium cholate or CpG DNA. The study on NALT and nasal absorptive capacity will be benefit for further understanding of immune mechanisms after nasal vaccination and development of nasal vaccines for poultry. PMID

  2. Role of lymphotoxin and homeostatic chemokines in the development and function of local lymphoid tissues in the respiratory tract

    PubMed Central

    Rangel-Moreno, Javier; Carragher, Damian; Randall, Troy D.

    2009-01-01

    Summary Secondary lymphoid organs are strategically placed to recruit locally activated antigen presenting cells (APCs) as well as naïve, recirculating T and B cells. The structure of secondary lymphoid organs - separated B and T zones, populations of specialized stromal cells, high endothelial venules and lymphatic vessles - has also evolved to maximize encounters between APCs and lymphocytes and to facilitate the expansion and differentiation of antigen-stimulated T and B cells. Many of the general mechanisms that govern the development and organization of secondary lymphoid organs have been identified over the last decade. However, the specific cellular and molecular interactions involved in the development and organization of each secondary lymphoid organ are slightly different and probably reflect the cell types available at that time and location. Here we review the mechanisms involved in the development, organization and function of local lymphoid tissues in the respiratory tract, including Nasal Associated Lymphoid Tissue (NALT) and inducible Bronchus Associated Lymphoid Tissue (iBALT). PMID:20552039

  3. Inducible Bronchus-Associated Lymphoid Tissue: Taming Inflammation in the Lung

    PubMed Central

    Hwang, Ji Young; Randall, Troy D.; Silva-Sanchez, Aaron

    2016-01-01

    Following pulmonary inflammation, leukocytes that infiltrate the lung often assemble into structures known as inducible Bronchus-Associated Lymphoid Tissue (iBALT). Like conventional lymphoid organs, areas of iBALT have segregated B and T cell areas, specialized stromal cells, high endothelial venules, and lymphatic vessels. After inflammation is resolved, iBALT is maintained for months, independently of inflammation. Once iBALT is formed, it participates in immune responses to pulmonary antigens, including those that are unrelated to the iBALT-initiating antigen, and often alters the clinical course of disease. However, the mechanisms that govern immune responses in iBALT and determine how iBALT impacts local and systemic immunity are poorly understood. Here, we review our current understanding of iBALT formation and discuss how iBALT participates in pulmonary immunity. PMID:27446088

  4. Toxoplasma gondii inhibits R5 HIV-1 replication in human lymphoid tissues ex vivo

    PubMed Central

    Sassi, Atfa; Brichacek, Beda; Hieny, Sara; Yarovinsky, Felix; Golding, Hana; Grivel, Jean-Charles; Sher, Alan; Margolis, Leonid

    2016-01-01

    Critical events of HIV-1 pathogenesis occur in lymphoid tissues where HIV-1 is typically accompanied by infections with other pathogens (HIV co-pathogens). Co-pathogens greatly affect the clinical course of the disease and the transmission of HIV. The apicomplexan parasite Toxoplasma gondii is a common HIV co-pathogen associated with AIDS development. Here, we examined the interaction of T. gondii and HIV in coinfected human lymphoid tissue ex vivo. Both pathogens readily replicate in ex vivo infected blocks of human tonsillar tissue. Surprisingly, we found that live T. gondii preferentially inhibits R5 HIV-1 replication in coinfected tissues. This effect is reproduced by treatment of the tissue blocks with recombinant C-18, a T. gondii -encoded cyclophilin that binds to CCR5. These ex vivo findings raise the possibility that, in addition to being a co-factor in HIV disease, T. gondii may influence the outcome of viral infection by preferentially suppressing R5 variants. PMID:19671446

  5. Gut-associated lymphoid tissue, gut microbes and susceptibility to experimental autoimmune encephalomyelitis.

    PubMed

    Stanisavljević, S; Lukić, J; Momčilović, M; Miljković, M; Jevtić, B; Kojić, M; Golić, N; Mostarica Stojković, M; Miljković, D

    2016-06-01

    Gut microbiota and gut-associated lymphoid tissue have been increasingly appreciated as important players in pathogenesis of various autoimmune diseases, including multiple sclerosis. Experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis that can be induced with an injection of spinal cord homogenate emulsified in complete Freund's adjuvant in Dark Agouti (DA) rats, but not in Albino Oxford (AO) rats. In this study, mesenteric lymph nodes (MLN), Peyer's patches (PP) and gut microbiota were analysed in these two rat strains. There was higher proportion of CD4(+) T cells and regulatory T cells in non-immunised DA rats in comparison to AO rats. Also, DA rat MLN and PP cells were higher producers of pro-inflammatory cytokines interferon-γ and interleukin-17. Finally, microbial analyses showed that uncultivated species of Turicibacter and Atopostipes genus were exclusively present in AO rats, in faeces and intestinal tissue, respectively. Thus, it is clear that in comparison of an EAE-susceptible with an EAE-resistant strain of rats, various discrepancies at the level of gut associated lymphoid tissue, as well as at the level of gut microbiota can be observed. Future studies should determine if the differences have functional significance for EAE pathogenesis. PMID:26839070

  6. Pulmonary infiltration with eosinophilia complicated with mucosa-associated lymphoid tissue lymphoma: A case report

    PubMed Central

    Liu, Yin; Tangsun, Yinyan; Xiao, Yonglong; Zhang, Deping; Cao, Min

    2016-01-01

    Tissue eosinophilia is rarely observed in cases of non-Hodgkin's lymphoma of B cell origin. The present study describes a rare case of mucosa-associated lymphoid tissue (MALT) lymphoma, which was initially misdiagnosed as eosinophilic pneumonia. The initial diagnosis was formed based on the results of chest radiography, peripheral eosinophilia tests and bronchoalveolar lavage, and the clinical course of the patient. Following administration of methylprednisolone (40 mg/day) for 4 days and oral administration of prednisolone (30 mg/day), the clinical course rapidly improved and the eosinophil count immediately decreased a to normal level. However, abnormal shadows observed on computed tomography (CT) scans of the chest did not diminish. At 6 months after the initiation of treatment, CT-guided percutaneous lung biopsy was performed, and a final diagnosis of primary pulmonary mucosa-associated lymphoid tissue lymphoma was made based on immunohistochemical examination. Primary lung MALT lymphoma remains a rare entity, with an indolent course and a reasonably favorable prognosis, whose diagnosis may be challenging. PMID:27588128

  7. Fibronectin and the adhesive properties of rat lymphocytes obtained from different peripheral lymphoid tissues.

    PubMed

    Altankov, G; Kostadinov, A; Marinova, L

    1990-01-01

    A comparative investigation has been carried out on the effect of plasma fibronectin (Fn) on the adhesive properties of normal rat lymphocytes obtained from different lymphoid tissues: blood, spleen, mesenteric and tonsillar lymph nodes. Fn was immobilized on the basis of its ability to bind to gelatin. We established that concentrations of 40-50 micrograms/ml are sufficient for a saturation effect on Fn coating. For spleen cells an adhesion of 55.7 +/- 9.3%, for mesenteric lymph nodes 34.5 +/- 8.7% and for tonsillar cells 33.8 +/- 3.2% was observed. Blood lymphocytes showed the lowest adhesion, 21.3 +/- 4.2%. Compared to the other lymphoid tissues, the spleen cells exhibited a "basal" adherence to surfaces coated with gelatin only: 19.2 +/- 4.1%. T lymphocytes participate to a greater extent in the process, since their number was significantly reduced in cell suspensions after adhesion to both gelatin and gelatin-Fn coated surfaces. The addition of soluble Fn leads to a competitive inhibition of the lymphocyte adhesion to gelatin-Fn coated surfaces. The data demonstrated the important role of Fn for the adhesive interactions of lymphocytes during their functional distribution in the tissues. PMID:2076848

  8. Migration of cells with immunoglobulin/c-myc recombinations in lymphoid tissues of mice.

    PubMed

    Müller, J R; Jones, G M; Janz, S; Potter, M

    1997-01-01

    Recombinations between c-myc and immunoglobulin (Ig) sequences that typically occur in pristane-induced mouse plasmacytomas were detected in secondary lymphoid tissues from normal mice, chiefly in the gut-associated lymphoid tissue. Based on the analysis of recombination sequences as clonotypic markers, migration of c-myc recombination-positive cells was observed between Peyer's patches and into the intestine. Treatment of plasmacytoma-susceptible BALB/cAn mice with pristane induced proliferation and migration of these cells into mesenteric lymph node, spleen, and oil granuloma within 7 days. Plasmacytoma-resistant strains of mice (DBA/2N, C3H/HeJ, C57BL/6) differed in that (1) they harbored fewer clones (Ig/c-myc recombinations were detected in 33% of resistant mice versus 91% of BALB/cAn mice after pristane treatment); (2) Ig/c-myc-positive cells were rarely detected in the oil granuloma, and (3) c-myc recombined predominantly with the Ig alpha locus in BALB/cAn mice (72%), but with the Ig mu locus in DBA/2N and in C57BL/6 (67%). The results demonstrate that normal mice generate a large number of lymphocytes with aberrant c-myc in intestinal tissues without developing tumors. PMID:8978304

  9. Tertiary Lymphoid Tissue Forms in Retinas of Mice with Spontaneous Autoimmune Uveitis and Has Consequences on Visual Function.

    PubMed

    Kielczewski, Jennifer L; Horai, Reiko; Jittayasothorn, Yingyos; Chan, Chi-Chao; Caspi, Rachel R

    2016-02-01

    During chronic inflammation, tertiary lymphoid tissue (TLT) can form within an inflamed organ, including the CNS. However, little is known about TLT formation in the neuroretina. In a novel spontaneous autoimmune mouse model of uveitis (R161H), we identified well-organized lymphoid aggregates in the retina and examined them for TLT characteristics. Presence of immune cells, tissue-specific markers, and gene expression patterns typically associated with germinal centers and T follicular helper cells were examined using immunohistochemistry and gene analysis of laser capture microdissected retina. Our data revealed the retinal lymphoid structures contained CD4(+) T cells and B cells in well-defined zonal areas that expressed classic germinal center markers, peanut lectin (agglutinin) and GL-7. Gene expression analysis showed upregulation of T follicular helper cell markers, most notably CXCR5 and its ligand CXCL13, and immunohistochemical analysis confirmed CXCR5 expression, typically associated with CD4(+) T follicular helper cells. Highly organized stromal cell networks, a hallmark of organized lymphoid tissue, were also present. Positive staining for phospho-Zap70 in retina-specific T cells indicated CD4(+) T cells were being activated within these lymphoid structures. CD138(+)/B220(+) plasma cells were detected, suggesting the retinal lymphoid aggregates give rise to functional germinal centers, which produce Abs. Interestingly, eyes with lymphoid aggregates exhibited lower inflammatory scores by fundus examination and a slower initial rate of loss of visual function by electroretinography, compared with eyes without these structures. Our findings suggest that the lymphoid aggregates in the retina of R161H mice represent organized TLT, which impact the course of chronic uveitis. PMID:26712943

  10. Innate lymphoid cells as regulators of immunity, inflammation and tissue homeostasis.

    PubMed

    Klose, Christoph S N; Artis, David

    2016-06-21

    Research over the last 7 years has led to the formal identification of innate lymphoid cells (ILCs), increased the understanding of their tissue distribution and has established essential functions of ILCs in diverse physiological processes. These include resistance to pathogens, the regulation of autoimmune inflammation, tissue remodeling, cancer and metabolic homeostasis. Notably, many ILC functions appear to be regulated by mechanisms distinct from those of other innate and adaptive immune cells. In this Review, we focus on how group 2 ILC (ILC2) and group 3 ILC (ILC3) responses are regulated and how these cells interact with other immune and non-immune cells to mediate their functions. We highlight experimental evidence from mouse models and patient-based studies that have elucidated the effects of ILCs on the maintenance of tissue homeostasis and the consequences for health and disease. PMID:27328006

  11. Establishment of an in vitro system representing the chicken gut-associated lymphoid tissue.

    PubMed

    Alitheen, Noorjahan Banu; McClure, Susan Jane; Yeap, Swee Keong; Kristeen-Teo, Ye Wen; Tan, Sheau Wei; McCullagh, Peter

    2012-01-01

    The bursa of Fabricius is critical for B cell development and differentiation in chick embryos. This study describes the production in vitro, from dissociated cell suspensions, of cellular agglomerates with functional similarities to the chicken bursa. Co-cultivation of epithelial and lymphoid cells obtained from embryos at the appropriate developmental stage regularly led to agglomerate formation within 48 hours. These agglomerates resembled bursal tissue in having lymphoid clusters overlaid by well organized epithelium. Whereas lymphocytes within agglomerates were predominantly Bu-1a(+), a majority of those emigrating onto the supporting membrane were Bu-1a(-) and IgM(+). Both agglomerates and emigrant cells expressed activation-induced deaminase with levels increasing after 24 hours. Emigrating cells were actively proliferating at a rate in excess of both the starting cell population and the population of cells remaining in agglomerates. The potential usefulness of this system for investigating the response of bursal tissue to avian Newcastle disease virus (strain AF2240) was examined. PMID:23185307

  12. The effect of PrPSc accumulation on inflammatory gene expression within sheep peripheral lymphoid tissue

    PubMed Central

    Gossner, Anton G.; Hopkins, John

    2015-01-01

    Accumulation of the misfolded prion protein, PrPSc in the central nervous system (CNS) is strongly linked to progressive neurodegenerative disease. For many transmissible spongiform encephalopathies (TSEs), peripheral lymphoid tissue is an important site of PrPSc amplification but without gross immunological consequence. Susceptible VRQ homozygous New Zealand Cheviot sheep were infected with SSBP/1 scrapie by inoculation in the drainage area of the prescapular lymph nodes. The earliest time that PrPSc was consistently detected by immunohistology in these nodes was D50 post infection. This transcriptomic study of lymph node taken before (D10) and after (D50) the detection of PrPSc, aimed to identify the genes and physiological pathways affected by disease progression within the nodes as assessed by PrPSc detection. Affymetrix Ovine Gene arrays identified 75 and 80 genes as differentially-expressed at D10 and D50, respectively, in comparison with control sheep inoculated with uninfected brain homogenate. Approximately 70% of these were repressed at each time point. RT-qPCR analysis of seven genes showed statistically significant correlation with the array data, although the results for IL1RN and TGIF were different between the two technologies. The ingenuity pathway analysis (IPA) and general low level of repression of gene expression in lymphoid tissue, including many inflammatory genes, contrasts with the pro-inflammatory and pro-apoptotic events that occur within the CNS at equivalent stages of disease progression as assessed by PrPSc accumulation. PMID:26507419

  13. Regulation of metabolic health and adipose tissue function by group 2 innate lymphoid cells.

    PubMed

    Cautivo, Kelly M; Molofsky, Ari B

    2016-06-01

    Adipose tissue (AT) is home to an abundance of immune cells. With chronic obesity, inflammatory immune cells accumulate and promote insulin resistance and the progression to type 2 diabetes mellitus. In contrast, recent studies have highlighted the regulation and function of immune cells in lean, healthy AT, including those associated with type 2 or "allergic" immunity. Although traditionally activated by infection with multicellular helminthes, AT type 2 immunity is active independently of infection, and promotes tissue homeostasis, AT "browning," and systemic insulin sensitivity, protecting against obesity-induced metabolic dysfunction and type 2 diabetes mellitus. In particular, group 2 innate lymphoid cells (ILC2s) are integral regulators of AT type 2 immunity, producing the cytokines interleukin-5 and IL-13, promoting eosinophils and alternatively activated macrophages, and cooperating with and promoting AT regulatory T (Treg) cells. In this review, we focus on the recent developments in our understanding of group 2 innate lymphoid cell cells and type 2 immunity in AT metabolism and homeostasis. PMID:27120716

  14. Cumulative mechanisms of lymphoid tissue fibrosis and T cell depletion in HIV-1 and SIV infections

    PubMed Central

    Zeng, Ming; Smith, Anthony J.; Wietgrefe, Stephen W.; Southern, Peter J.; Schacker, Timothy W.; Reilly, Cavan S.; Estes, Jacob D.; Burton, Gregory F.; Silvestri, Guido; Lifson, Jeffrey D.; Carlis, John V.; Haase, Ashley T.

    2011-01-01

    The hallmark of HIV-1 and SIV infections is CD4+ T cell depletion. Both direct cell killing and indirect mechanisms related to immune activation have been suggested to cause the depletion of T cells. We have now identified a mechanism by which immune activation-induced fibrosis of lymphoid tissues leads to depletion of naive T cells in HIV-1 infected patients and SIV-infected rhesus macaques. The T regulatory cell response to immune activation increased procollagen production and subsequent deposition as fibrils via the TGF-β1 signaling pathway and chitinase 3-like-1 activity in fibroblasts in lymphoid tissues from patients infected with HIV-1. Collagen deposition restricted T cell access to the survival factor IL-7 on the fibroblastic reticular cell (FRC) network, resulting in apoptosis and depletion of T cells, which, in turn, removed a major source of lymphotoxin-β, a survival factor for FRCs during SIV infection in rhesus macaques. The resulting loss of FRCs and the loss of IL-7 produced by FRCs may thus perpetuate a vicious cycle of depletion of T cells and the FRC network. Because this process is cumulative, early treatment and antifibrotic therapies may offer approaches to moderate T cell depletion and improve immune reconstitution during HIV-1 infection. PMID:21393864

  15. Transcriptional programs of lymphoid tissue capillary and high endothelium reveal control mechanisms for lymphocyte homing

    PubMed Central

    Lee, Mike; Kiefel, Helena; LaJevic, Melissa D.; Macauley, Matthew S.; Kawashima, Hiroto; O'Hara, Edward; Pan, Junliang; Paulson, James C.; Butcher, Eugene C.

    2014-01-01

    Lymphocytes are recruited from blood by high-endothelial venules (HEVs). We performed transcriptomic analyses and identified molecular signatures that distinguish HEVs from capillary endothelium and that define tissue-specific HEV specialization. Capillaries displayed gene programs for vascular development. HEVs were enriched in genes for immune defense and lymphocyte migration. We identify capillary and HEV markers and candidate mechanisms for regulated lymphocyte recruitment including a lymph node HEV-selective transmembrane mucin; transcriptional control of functionally specialized carbohydrate ligands for lymphocyte L-selectin; HEV expression of molecules for transendothelial migration; and metabolic programs for lipid mediators of lymphocyte motility and chemotaxis. We also elucidate a carbohydrate recognition pathway that targets B cells to intestinal lymphoid tissues, defining CD22 as a lectin-homing receptor for mucosal HEVs. PMID:25173345

  16. Mucosa-associated lymphoid tissue lymphoma masquerading as herniated orbital fat.

    PubMed

    Hwang, Cindy S; Diaz-Marchan, Pedro; Marx, Douglas P

    2014-01-01

    Lymphomas are the most common primary orbital malignancies in adults. The authors present a 62-year-old Hispanic woman with a 2-year history of slowly enlarging bilateral lower eyelid masses that the patient described as "bags." On palpation, firm, mobile, nontender masses with associated tear trough deformities were noted. Biopsy of the left lower eyelid mass was consistent with a mucosa-associated lymphoid tissue lymphoma. Herniated orbital fat is an extremely common finding in the aging population and is often associated with a prominent tear trough. The patient with orbital lymphoma appeared to have herniated orbital fat with associated tear trough deformities. Lymphoma resembling herniated orbital fat is uncommon but should be considered in all patients with prominence in the periorbital region. PMID:24614565

  17. [Pulmonary mucosa-associated lymphoid tissue (MALT) lymphoma accompanied with cystic change].

    PubMed

    Nagahiro, Itaru; Nouso, Hiroshi; Kawai, Tsuyoshi; Toda, Keisuke; Nobuhisa, Tetsuji; Endou, Yoshikatsu; Watanabe, Takanori; Matsumoto, Yusuke; Kai, Kyohei; Ishizuka, Shinji; Satou, Shizou

    2010-04-01

    A 64-year-old male with throat discomfort visited our hospital, and a chest computed tomography (CT) scan revealed a cystic lesion with a central solid component in the right lung (in the lower lobe, 4.1 x 3.9 cm in diameter). Transbronchial lung biopsy was performed and the lesion was diagnosed as mucosa-associated lymphoid tissue (MALT) lymphoma of the lung. No other lymphoma lesion was detected and it was diagnosed as the stage I-E, and a right lower lobectomy was performed. The cystic lesion derived from alveolus and bronchus destroyed by lymphoma infiltration and it might be caused by air retention due to check-valve mechanism. PMID:20387510

  18. Synchronous Upper and Lower Gastrointestinal Mucosa-Associated Lymphoid Tissue Lymphomas

    PubMed Central

    McFarlane, Michael; Wong, John Lin Hieng; Paneesha, Shankara; Rudzki, Zbigniew; Arasaradnam, Ramesh; Nwokolo, Chuka

    2016-01-01

    Mucosa-associated lymphoid tissue lymphoma (MALToma) is a subtype of B-cell non-Hodgkin's lymphoma, comprising ∼17% of all gastrointestinal (GI) tract lymphomas. It is associated with chronic inflammation and autoimmunity, for example Helicobacter pylori gastritis and Sjogren's syndrome, respectively. Approximately 50% of GI MALTomas occur in the stomach, with small bowel and colonic lesions being less frequent. Synchronous upper and lower GI MALTomas occur rarely, with few cases reported. We present the case of a 73-year-old patient who presented with change in bowel habit and was found to have synchronous multifocal upper and lower GI MALTomas, which did not respond to H. pylori cure or to rituximab therapy, but did respond to a combination of surgery and chemotherapy with rituximab and bendamustine.

  19. The engagement of oral-associated lymphoid tissues during oral versus gastric antigen administration.

    PubMed

    Bankvall, Maria; Östberg, Anna-Karin; Jontell, Mats; Wold, Agnes; Östman, Sofia

    2016-09-01

    The role of oral-associated lymphoid tissues during induction of oral tolerance still remains elusive. Therefore, the aim was to compare T-cell activation and induction of tolerance to ovalbumin (OVA) presented through either of two routes; deposited into the oral cavity, or the stomach, thereby bypassing the oral cavity. OVA was administered by the oral or gastric route to BALB/c mice that had received OVA-specific DO11.10+ CD4(+) T cells, stained with CellTrace(™) Violet dye, through intravenous injection. Proliferating OVA-specific T cells were detected in the nose-associated lymphoid tissues (NALT) and the cervical, mesenteric and peripheral lymph nodes at different time-points following OVA exposure. OVA-specific T-cell proliferation was initially observed in the NALT 1 hr after oral, but not gastric, administration. However, at day 1, proliferation at this site was also detected after gastric administration and profound proliferation was observed at all sites by day 4. For the oral route the degree of proliferation observed was lower in the peripheral lymph nodes by day 4 compared with the other sites. These results demonstrate a similar activation pattern achieved by the two routes. However, the NALT distinguishes itself as a site of rapid T-cell activation towards fed antigens irrespective of feeding regimen. To evaluate induction of tolerance a semi-effective OVA dose was used, to detect differences in the degree of tolerance achieved. This was performed in a model of OVA-induced airway hypersensitivity. No differences in tolerance induction were observed between the two administration routes. PMID:27288650

  20. Distribution pattern of bovine viral diarrhoea virus type 1 genome in lymphoid tissues of experimentally infected sheep.

    PubMed

    Karikalan, M; Rajukumar, K; Mishra, N; Kumar, M; Kalaiyarasu, S; Rajesh, K; Gavade, V; Behera, S P; Dubey, S C

    2016-06-01

    In this study, cellular localization and the distribution pattern of BVDV genome in lymphoid tissues during the course of experimental acute BVDV-1 infection of sheep was investigated. Tonsils, mesenteric lymph nodes (MLN) and spleen were collected on 3, 6, 9, 12 and 15 days post infection (dpi) from twenty 4-month-old lambs, experimentally inoculated intra-nasally with 5 × 10(5) TCID50 of a non-cytopathic (ncp) BVDV-1 isolate, Ind-17555. Tissues collected from ten mock-infected lambs served as controls. In situ hybridization (ISH) was carried out in paraformaldehyde fixed paraffin embedded tissue sections using digoxigenin labelled riboprobe targeting 5'-UTR of BVDV-1. BVDV genome was detected at all the intervals from 3 dpi to 15 dpi in the lymphoid tissues with variations between the intervals and also amongst the infected sheep. During the early phase of acute infection, presence of viral genome was more in tonsils than MLN and spleen, whereas the distribution was higher in MLN during later stages. BVDV-1 genome positive cells included lymphocytes, macrophages, plasma cells, reticular cells and sometimes crypt epithelial cells. Genome distribution was frequently observed in the lymphoid follicles of tonsils, MLN and spleen, besides the crypt epithelium in tonsils, paracortex and medullary sinus and cords of MLN. Most abundant and widespread distribution of BVDV-1 genome was observed on 6 dpi while there was a reduction in number and intensity of positive signals by 15 dpi in most of the infected animals. This is the first attempt made to study the localisation of BVDV-1 in lymphoid tissues of acutely infected sheep by in situ hybridization. The results show that the kinetics of BVDV-1 distribution in lymphoid tissues of experimentally infected non-pregnant sheep follows almost a similar pattern to that demonstrated in BVDV infected cattle. PMID:26996785

  1. Lymphoid-Tissue-Resident Commensal Bacteria Promote Members of the IL-10 Cytokine Family to Establish Mutualism.

    PubMed

    Fung, Thomas C; Bessman, Nicholas J; Hepworth, Matthew R; Kumar, Nitin; Shibata, Naoko; Kobuley, Dmytro; Wang, Kelvin; Ziegler, Carly G K; Goc, Jeremy; Shima, Tatsuichiro; Umesaki, Yoshinori; Sartor, R Balfour; Sullivan, Kaede V; Lawley, Trevor D; Kunisawa, Jun; Kiyono, Hiroshi; Sonnenberg, Gregory F

    2016-03-15

    Physical separation between the mammalian immune system and commensal bacteria is necessary to limit chronic inflammation. However, selective species of commensal bacteria can reside within intestinal lymphoid tissues of healthy mammals. Here, we demonstrate that lymphoid-tissue-resident commensal bacteria (LRC) colonized murine dendritic cells and modulated their cytokine production. In germ-free and antibiotic-treated mice, LRCs colonized intestinal lymphoid tissues and induced multiple members of the IL-10 cytokine family, including dendritic-cell-derived IL-10 and group 3 innate lymphoid cell (ILC3)-derived IL-22. Notably, IL-10 limited the development of pro-inflammatory Th17 cell responses, and IL-22 production enhanced LRC colonization in the steady state. Furthermore, LRC colonization protected mice from lethal intestinal damage in an IL-10-IL-10R-dependent manner. Collectively, our data reveal a unique host-commensal-bacteria dialog whereby selective subsets of commensal bacteria interact with dendritic cells to facilitate tissue-specific responses that are mutually beneficial for both the host and the microbe. PMID:26982365

  2. Sensitive detection of PrPCWD in rectoanal mucosa-associated lymphoid tissue from preclinical white-tailed deer

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This report summarizes the comparative diagnostic performance of postmortem rectoanal mucosa-associated lymphoid tissue (RAMALT) sampling in four white-tailed deer test populations: from Wisconsin, a sample of free-ranging deer and a captive herd; and from Saskatchewan, Canada, two captive herds. Th...

  3. CD30 ligand expression in nonmalignant and Hodgkin's disease-involved lymphoid tissues.

    PubMed Central

    Gruss, H. J.; Pinto, A.; Gloghini, A.; Wehnes, E.; Wright, B.; Boiani, N.; Aldinucci, D.; Gattei, V.; Zagonel, V.; Smith, C. A.; Kadin, M. E.; von Schilling, C.; Goodwin, R. G.; Herrmann, F.; Carbone, A.

    1996-01-01

    The CD30 ligand (CD30L) is a type II transmembrane glycoprotein of the tumor necrosis factor ligand superfamily. Recent cloning of CD30L has enabled studies to explore its function and tissue distribution. For instance, recombinant CD30L has been shown to co-stimulate T cells and to act as mitogen for Hodgkin's disease (HD)-derived cell lines. The counter-receptor for CD30L, ie, CD30, is a type I cytokine receptor that is highly expressed by activated T cells, Hodgkin and Reed-Sternberg (H-RS) cells, and anaplastic large cell lymphoma cells. In the present study, recombinant membrane-bound and soluble human CD30L were instrumental to raise a monoclonal antibody (M80) recognizing membrane-bound CD30L on transfected and native cells. With this reagent, a panel of cultured lymphoma-derived cell lines as well as primary normal, reactive, and HD-involved lymphoid tissues were examined for expression of CD30L by immunostaining and flow cytometry. In reactive lymphnodes and tonsils, CD30L was expressed by a small subset of lymphoid cells, histiocytes, and granulocytes. Higher levels of CD30L expression were noted in HD lesions among bystander cells; ie, T cells and granulocytes that surrounded H-RS cells. Native CD30L displayed at the cell surface was functionally active as shown by the ability of fixed granulocytes to interact with CD30+ cell lines. Moreover, CD30L was detectable, although to a lower staining intensity, in primary H-RS cells of all HD tissues investigated regardless of the histological subtype and the phenotype of H-RS cells (ie, CD30+/CD40+ versus CD30-/CD40+). Co-expression of CD30 and CD30L that was seen on H-RS cells of all, except the CD30- nodular lymphocyte predominant, subtypes of HD may point to the use of this pair of molecules in paracrine and/or autocrine mitogenic cell interactions. Monoclonal antibody M80 may thus represent a useful tool for studying CD30L expression on cultured cell lines and primary cells from normal, reactive, and

  4. Induction of mixed-function oxidase activity in mouse lymphoid tissues by polycyclic aromatic hydrocarbons

    SciTech Connect

    Griffin, G.D.; Egan, B.Z.; Lee, N.E.; Burtis, C.A.

    1986-01-01

    Polycyclic aromatic hydrocarbon (PAH) exposure can cause mixed-function oxidase (MFO) enzyme induction in certain tissues of various organisms. Measurements of such induction might serve as a useful bioindicator of human exposure to PAHs, provided readily obtainable human tissues can be utilized for such measurements. The authors have investigated the MFO activity in various lymphoid tissues of the C3H mouse as a model system and have studied the effect of systemic PAH treatment on such enzyme activity. An MFO enzyme assay was used to measure the activity of 7-ethoxyresorufin deethylase, an enzyme activity that may be specific for the cytochrome P-448 subset of MFO enzymes (those enzymes that are induced in cells or tissues following PAH administration). Intraperitoneal injection of mice with 180 mg/kg (4.6 mg) benzo(a)pyrene (BaP) or 160 mg/kg (4.0 mg) 3-methylcholanthrene (MC) produced a significant induction in MFO activity in mouse spleen S9 fractions 48 h after the injection. Induction ratios (induced activity/control activity) between 4 and 5 were seen with BaP; MC produced induction ratios of 2.5-3.0. Enzyme activity was not induced in the spleen within 16 h following BaP or MC administration. Other experiments indicated that MFO activity could be induced in thymus cells 48 h after either BaP or MC treatment. Treatment with BaP or MC did produce significant enzyme induction in the liver and lung tissues from the animals both 16 and 48 h after chemical treatment.

  5. Marginal reticular cells: a stromal subset directly descended from the lymphoid tissue organizer

    PubMed Central

    Katakai, Tomoya

    2012-01-01

    The architecture of secondary lymphoid organs (SLOs) is supported by several non-hematopoietic stromal cells. Currently it is established that two distinct stromal subsets, follicular dendritic cells and fibroblastic reticular cells, play crucial roles in the formation of tissue compartments within SLOs, i.e., the follicle and T zone, respectively. Although stromal cells in the anlagen are essential for SLO development, the relationship between these primordial cells and the subsets in adulthood remains poorly understood. In addition, the roles of stromal cells in the entry of antigens into the compartments through some tissue structures peculiar to SLOs remain unclear. A recently identified stromal subset, marginal reticular cells (MRCs), covers the margin of SLOs that are primarily located in the outer edge of follicles and construct a unique reticulum. MRCs are closely associated with specialized endothelial or epithelial structures for antigen transport. The similarities in marker expression profiles and successive localization during development suggest that MRCs directly descend from organizer stromal cells in the anlagen. Therefore, MRCs are thought to be a crucial stromal component for the organization and function of SLOs. PMID:22807928

  6. Disease-Associated Prion Protein in Neural and Lymphoid Tissues of Mink (Mustela vison) Inoculated with Transmissible Mink Encephalopathy

    PubMed Central

    Schneider, D. A.; Harrington, R. D.; Zhuang, D.; Yan, H.; Truscott, T. C.; Dassanayake, R. P.; O'Rourke, K. I.

    2012-01-01

    Summary Transmissible spongiform encephalopathies (TSEs) are diagnosed by immunodetection of disease-associated prion protein (PrPd). The distribution of PrPd within the body varies with the time-course of infection and between species, during interspecies transmission, as well as with prion strain. Mink are susceptible to a form of TSE known as transmissible mink encephalopathy (TME), presumed to arise due to consumption of feed contaminated with a single prion strain of ruminant origin. After extended passage of TME isolates in hamsters, two strains emerge, HY and DY, each of which is associated with unique structural isoforms of PrPTME and of which only the HY strain is associated with accumulation of PrPTME in lymphoid tissues. Information on the structural nature and lymphoid accumulation of PrPTME in mink is limited. In this study, 13 mink were challenged by intracerebral inoculation using late passage TME inoculum after which brain and lymphoid tissues were collected at preclinical and clinical time points. The distribution and molecular nature of PrPTME was investigated by techniques including blotting of paraffin wax-embedded tissue and epitope mapping by western blotting. PrPTME was detected readily in the brain and retropharyngeal lymph node during preclinical infection with delayed progression of accumulation within other lymphoid tissues. For comparison, three mink were inoculated by the oral route and examined during clinical disease. Accumulation of PrPTME in these mink was greater and more widespread, including follicles of rectoanal mucosa-associated lymphoid tissue. Western blot analyses revealed that PrPTME accumulating in the brain of mink is structurally most similar to that accumulating in the brain of hamsters infected with the DY strain. Collectively, the results of extended passage in mink are consistent with the presence of only a single strain of TME, the DY strain, capable of inducing accumulation of PrPTME in the lymphoid tissues of

  7. Tissue-specific expression of Le(Y) antigen in high endothelial venules of human lymphoid tissues.

    PubMed

    Tanegashima, A; Ushiyama, I; Nishi, K; Yamamoto, H; Fukunaga, T

    1999-12-01

    In this study, we demonstrated that the anti-Le(Y) antibody (BM-1) especially reacted with high endothelial venules (HEVs) in peripheral lymph nodes of blood group O individuals. The Le(Y) expression on HEVs showed a unique tissue-specific pattern, i.e., a large amount of the Le(Y) expression in peripheral lymph nodes and no or small amounts in mesenteric lymph node. Statistical analysis showed that there was the significant difference between the percentage of Le(Y)-positive HEVs in peripheral lymph nodes and mesenteric lymph nodes. No expression of Le(Y) was observed in vessels of Payer's patch, thymus, spleen and other non-lymphoid organs. In blood group A or B individuals, the reactivity between HEVs and anti-Le(Y) antibody increased after enzyme digestion with alpha-N-acetylgalactosaminidase or alpha-galactosidase. These findings show that the expression of difucosylated blood group ABH antigens are especially expressed on HEVs in peripheral lymph nodes. Furthermore, the tissue-specific pattern suggests that these antigens may be related to intercellular adhesion between lymphocytes and HEVs. PMID:11133021

  8. The immune modifying effects of amino acids on gut-associated lymphoid tissue

    PubMed Central

    2013-01-01

    The intestine and the gut-associated lymphoid tissue (GALT) are essential components of whole body immune defense, protecting the body from foreign antigens and pathogens, while allowing tolerance to commensal bacteria and dietary antigens. The requirement for protein to support the immune system is well established. Less is known regarding the immune modifying properties of individual amino acids, particularly on the GALT. Both oral and parenteral feeding studies have established convincing evidence that not only the total protein intake, but the availability of specific dietary amino acids (in particular glutamine, glutamate, and arginine, and perhaps methionine, cysteine and threonine) are essential to optimizing the immune functions of the intestine and the proximal resident immune cells. These amino acids each have unique properties that include, maintaining the integrity, growth and function of the intestine, as well as normalizing inflammatory cytokine secretion and improving T-lymphocyte numbers, specific T cell functions, and the secretion of IgA by lamina propria cells. Our understanding of this area has come from studies that have supplemented single amino acids to a mixed protein diet and measuring the effect on specific immune parameters. Future studies should be designed using amino acid mixtures that target a number of specific functions of GALT in order to optimize immune function in domestic animals and humans during critical periods of development and various disease states. PMID:23899038

  9. [Analysis of prognostic correlated factors of 49 patients with mucosa-associated lymphoid tissue lymphoma].

    PubMed

    Jing, Hong-Mei; Ke, Xiao-Yan; Dong, Fei

    2007-12-01

    The aim of this study was to investigate the clinical feature of mucosa-associated lymphoid tissue lymphoma and clarify the relationship between the pathological, clinical features, the expression of API2-MALT1 and the prognosis. A number of factors including pathological characters, grade, stage, prognosis and treatment of 49 cases of MALT lymphoma were analyzed, and the API2-MALT1 rearrangement was detected by RT-PCR. The results showed that 49 patients were diagnosed as MALT lymphoma, in which median age was 52.4 years. The percentage of patients older than 50 years was 67.3%. The majority of tumors were found in stomach (22 cases), intestine (13 cases), thyroid (6 cases) and so on. Among 49 patients, stage I, II was 77. 6%, stage III, IV was 22.4%. API2-MALT1 rearrangement were found 38.1% in low grade, and 12.5% in transform type. Among 18 patients with gastric MALT lymphoma, 9 cases (50.0%) were helicobacter pylori (HP) positive and received antibiotic treatment. The 3 years overall survival was 93.8%. It is concluded that MALT lymphoma is often seen in older patients, most of them were in low grade with slow progression. The site, grade, stage and molecular genetic changes are important prognostic factors, which can contribute to choosing suitable treatment for patients with MALT lymphoma. The antibiotic treatment is effective for patients with positive HP. PMID:18088487

  10. Stage IV intramucosal gastric marginal zone B cell lymphoma of mucosa-associated lymphoid tissue type.

    PubMed

    Ohtaka, Masahiko; Sato, Tadashi; Kobayashi, Shouji; Sueki, Ryouta; Yamaguchi, Tatsuya; Uetake, Tomoyoshi; Ohtsuka, Hiroyuki; Iwao, Noriaki; Kirito, Keita; Enomoto, Nobuyuki

    2013-04-01

    A 45-year-old woman with no symptoms underwent upper gastrointestinal endoscopy. A discolored area was noted at the greater curvature of the gastric upper body. Endoscopic ultrasonography demonstrated thickening of the second sonographic layer indicating that the depth of invasion was confined to the mucosa. A urea breath test and anti-Helicobacter pylori antibody test were negative. A computed tomography scan showed a consolidation at the right lung. Gastric biopsy and transbronchial lung biopsy (TBLB) demonstrated a monotonous proliferation of atypical small lymphocytes. A diagnosis of gastric marginal zone B cell lymphoma of mucosa-associated lymphoid tissue type (MALT lymphoma) was made. The clinical stage was stage IV. A genetic analysis showed rearrangement of the joining region of the immunoglobulin heavy chain gene and identical clones in both lesions. An API2-MALT1 fusion gene was detected in the gastric lesion. After H. pylori eradication treatment, combination treatment with rituximab plus CHOP (R-CHOP) was performed; 6 months later an endoscopy revealed complete disappearance of the lesion. Multiple gastric biopsies showed no infiltrating atypical lymphocytes. Similarly, the lesion in the lung showed complete remission (CR) on CT and TBLB. This report shows that a gastric MALT lymphoma located in the mucosa and disseminated to the lung maintained CR by R-CHOP. PMID:26181449

  11. Mucosa-associated lymphoid tissue (MALT) lymphoma of the stomach: results of a controlled clinical trial.

    PubMed

    Avilés, Agustin; Nambo, María Jesús; Neri, Natividad; Talavera, Alejandra; Cleto, Sergio

    2005-01-01

    Treatment of patients with early stage gastric mucosa-associated lymphoid tissue (MALT) remains undefined. We began a controlled clinical trial to evaluate efficacy and toxicity of the most common therapies. Two hundred and forty-one patients with gastric low-grade MALT lymphoma in early stage (IE and IIE) were randomized to surgery (80 cases), radiotherapy (78 cases), and chemotherapy (83 cases). With a median follow-up of 7.5 yr, actuarial curves at 10 yr showed that event-free survival was 52% in patients treated with surgery, 52% in radiotherapy arm, and 87% in the chemotherapy group (p < 0.01). However, overall survival did not showed any statistical differences: 80%, 75% and 87%, respectively (p = 0.4). Acute and late toxicities were mild. No death-related treatments were observed. No clear differences were observed between the most common therapies in patients with primary gastric MALT lymphoma in early stages, probably because this type of lymphoma has an high response rate to salvage treatment after failure to local treatment (surgery and radiotherapy). Thus considered, chemotherapy alone is an effective and safe therapeutic approach in this setting of patients. Surgery or radiotherapy will be reserved to patients that are not candidates for chemotherapy. PMID:15750197

  12. Characterisation of inorganic microparticles in pigment cells of human gut associated lymphoid tissue.

    PubMed Central

    Powell, J J; Ainley, C C; Harvey, R S; Mason, I M; Kendall, M D; Sankey, E A; Dhillon, A P; Thompson, R P

    1996-01-01

    Macrophages at the base of human gut associated lymphoid tissue (GALT), become loaded early in life with dark granular pigment that is rich in aluminium, silicon, and titanium. The molecular characteristics, intracellular distribution, and source of this pigment is described. Laser scanning and electron microscopy showed that pigmented macrophages were often closely related to collagen fibres and plasma cells in GALT of both small and large intestine and contained numerous phagolysosomes, previously described as granules, that are rich in electron dense submicron sized particles. Morphological assessment, x ray microanalysis, and image electron energy loss spectroscopy showed three distinct types of microparticle: type I - spheres of titanium dioxide, 100-200 nm diameter, characterised as the synthetic food-additive polymorph anatase; type II - aluminosilicates, < 100-400 nm in length, generally of flaky appearance, often with adsorbed surface iron, and mostly characteristic of the natural clay mineral kaolinite; and type III - mixed environmental silicates without aluminium, 100-700 nm in length and of variable morphology. Thus, this cellular pigment that is partly derived from food additives and partly from the environment is composed of inert inorganic microparticles and loaded into phagolysosomes of macrophages within the GALT of all human subjects. These observations suggest that the pathogenicity of this pigment should be further investigated since, in susceptible individuals, the same intracellular distribution of these three types of submicron particle causes chronic latent granulomatous inflammation. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 7 PMID:8675092

  13. Cancer Immunosurveillance by Tissue-Resident Innate Lymphoid Cells and Innate-like T Cells.

    PubMed

    Dadi, Saïda; Chhangawala, Sagar; Whitlock, Benjamin M; Franklin, Ruth A; Luo, Chong T; Oh, Soyoung A; Toure, Ahmed; Pritykin, Yuri; Huse, Morgan; Leslie, Christina S; Li, Ming O

    2016-01-28

    Malignancy can be suppressed by the immune system in a process termed immunosurveillance. However, to what extent immunosurveillance occurs in spontaneous cancers and the composition of participating cell types remains obscure. Here, we show that cell transformation triggers a tissue-resident lymphocyte response in oncogene-induced murine cancer models. Non-circulating cytotoxic lymphocytes, derived from innate, T cell receptor (TCR)αβ, and TCRγδ lineages, expand in early tumors. Characterized by high expression of NK1.1, CD49a, and CD103, these cells share a gene-expression signature distinct from those of conventional NK cells, T cells, and invariant NKT cells. Generation of these lymphocytes is dependent on the cytokine IL-15, but not the transcription factor Nfil3 that is required for the differentiation of tumor-infiltrating NK cells, and IL-15 deficiency, but not Nfil3 deficiency, results in accelerated tumor growth. These findings reveal a tumor-elicited immunosurveillance mechanism that engages unconventional type-1-like innate lymphoid cells and type 1 innate-like T cells. PMID:26806130

  14. Independent Bottlenecks Characterize Colonization of Systemic Compartments and Gut Lymphoid Tissue by Salmonella

    PubMed Central

    Lim, Chee Han; Voedisch, Sabrina; Wahl, Benjamin; Rouf, Syed Fazle; Geffers, Robert

    2014-01-01

    Vaccination represents an important instrument to control typhoid fever in humans and protects mice from lethal infection with mouse pathogenic serovars of Salmonella species. Mixed infections with tagged Salmonella can be used in combination with probabilistic models to describe the dynamics of the infection process. Here we used mixed oral infections with tagged Salmonella strains to identify bottlenecks in the infection process in naïve and vaccinated mice. We established a next generation sequencing based method to characterize the composition of tagged Salmonella strains which offers a fast and reliable method to characterise the composition of genome-tagged Salmonella strains. We show that initial colonization of Salmonella was distinguished by a non-Darwinian selection of few bacteria setting up the infection independently in gut associated lymphoid tissue and systemic compartments. Colonization of Peyer's patches fuels the sustained spread of bacteria into mesenteric lymph nodes via dendritic cells. In contrast, infection of liver and spleen originated from an independent pool of bacteria. Vaccination only moderately reduced invasion of Peyer's patches but potently uncoupled bacterial populations present in different systemic compartments. Our data indicate that vaccination differentially skews the capacity of Salmonella to colonize systemic and gut immune compartments and provide a framework for the further dissection of infection dynamics. PMID:25079958

  15. Clinicopathologic characteristics and treatment of marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma).

    PubMed

    Raderer, Markus; Kiesewetter, Barbara; Ferreri, Andrés J M

    2016-01-01

    Extranodal marginal zone lymphoma of the mucosa-associated lymphoid tissue (MALT lymphoma) accounts for 7% to 8% of newly diagnosed lymphomas. Because of its association with infectious causes, such as Helicobacter pylori (HP) or Chlamydophila psittaci (CP), and autoimmune diseases, it has become the paradigm of an antigen-driven malignancy. MALT lymphoma usually displays an indolent course, and watch-and-wait strategies are justified initially in a certain percentage of patients. In patients with gastric MALT lymphoma or ocular adnexal MALT lymphoma, antibiotic therapy against HP or CP, respectively, is the first-line management of choice, resulting in lymphoma response rates from 75% to 80% after HP eradication and from 33% to 65% after antibiotic therapy for CP. In patients who have localized disease that is refractory to antibiotics, radiation is widely applied in various centers with excellent local control, whereas systemic therapies are increasingly being applied, at least in Europe, because of the potentially systemic nature of the disease. Therefore, the objective of this review is to briefly summarize the clinicopathologic characteristics of this distinct type of lymphoma along with current data on management strategies. PMID:26773441

  16. Gastric B-cell mucosa associated lymphoid tissue lymphoma: a clinicopathological study in 56 patients.

    PubMed Central

    Castrillo, J M; Montalban, C; Obeso, G; Piris, M A; Rivas, M C

    1992-01-01

    Clinico-pathological features of 56 patients with primary gastric lymphoma were evaluated retrospectively. All cases were regraded according to a classification of Isaacson et al into high grade and low grade B-cell mucosa associated lymphoid tissue lymphoma. A third group of mixed grade was recognised in 11 patients with low grade who also had occasional areas of high grade. Low grade and mixed grade patients had a 100% actuarial survival at 156 months, which was significantly better (p < 0.01) than that of 52% for patients with high grade disease. Different treatment methods--surgery, chemotherapy, or a combination of both--did not significantly affect survival. Low grade tumours occurred mainly in men with a history of several years, and who presented with non-specific gastric symptoms without remarkable exploratory or laboratory findings: most patients were in stage IE-IIE and achieved remission and cure. High grade can have a shorter history, systemic symptoms, abnormal exploratory and laboratory findings, gastric tumour masses, stage IV disease, and a worse outcome. The only significant prognostic factors for survival were the type of lymphoma and stage IV disease. These findings support the Isaacson classification system which separates two extreme groups of gastric lymphomas with different morphology, behaviour, and outcome. The presence of limited areas of high grade in a specimen showing low grade does not change the outcome but suggests that primary gastric lymphoma forms a continuum between these extreme types. PMID:1446850

  17. Avian gut-associated lymphoid tissues and intestinal immune responses to Eimeria parasites.

    PubMed Central

    Lillehoj, H S; Trout, J M

    1996-01-01

    Coccidiosis, an intestinal infection caused by intracellular protozoan parasites belonging to several different species of Eimeria, seriously impairs the growth and feed utilization of livestock and poultry. Host immune responses to coccidial infection are complex. Animals infected with Eimeria spp. produce parasite-specific antibodies in both the circulation and mucosal secretions. However, it appears that antibody-mediated responses play a minor role in protection against coccidiosis. Furthermore, there is increasing evidence that cell-mediated immunity plays a major role in resistance to infection. T lymphocytes appear to respond to coccidial infection through both cytokine production and a direct cytotoxic attack on infected cells. The exact mechanisms by which T cells eliminate the parasites, however, remain unclear. Although limited information is available on the intestinal immune system of chickens, gut lymphoid tissues have evolved specialized features that reflect their role as the first line of defense at mucosal surfaces, including both immunoregulatory cells and effector cells. This review summarizes our current understanding of the avian intestinal immune system and mucosal immune responses to Eimeria spp., providing an overview of the complex cellular and molecular events involved in intestinal immune responses to enteric pathogens. PMID:8809465

  18. Primary thymic mucosa-associated lymphoid tissue lymphoma with multiple thin walled lung cysts: case report and literature review.

    PubMed

    Kang, Lung-Yun; Ho, Szu-Pei; Chou, Yi-Pin

    2013-06-01

    Mucosa-associated lymphoid tissue (MALT) lymphoma of the thymus is rare. We reported a case of a 37-year-old Chinese female with Sjögren's syndrome and hyperglobulinemia. She suffered from chronic cough for 3 weeks. Chest computed tomography (CT) demonstrated a multiloculated cystic mass in mediastinum prevascular space and multiple lung cysts. Laboratory exam of autoimmune markers showed positive of antinuclear antibody (ANA), Sjögren's syndrome A (SSA), Sjögren's syndrome B (SSB), and rheumatoid factors (RF). Thymectomy with lymph node dissection was performed. The pathology report revealed thymic extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue. Under immunohistochemical stains, CD20 and Bcl-2 were positive. No evidence of recurrence of disease was found. PMID:23825913

  19. An anti-human monocyte/macrophage monoclonal antibody, reacting most strongly with macrophages in lymphoid tissue.

    PubMed

    Hogg, N; Selvendran, Y

    1985-05-01

    In this report, we have described monoclonal antibody (mAb) 24 which bound specifically to a 174,000 polypeptide present on 45 +/- 16% of human monocytes. Expression of the 24 molecule increased on monocytes when they were cultured. When tissues were examined using immunohistochemical techniques, macrophages (Mph) associated with skin and with lymphoid organs strongly expressed the mAb 24 molecule, whereas, Mph in nonlymphoid organs were only weakly positive. mAb 24 reacted with cells of Mph morphology plus cells of interdigitating appearance in T-cell areas, suggesting that these cells might belong to the Mph cell lineage. There was no reaction with other types of cells, such as Langerhans cells, osteoclasts, dendritic reticulum cells, and endothelial cells. The fact that the molecule recognised by mAb 24 is particularly associated with Mph in lymphoid tissue suggests that it might have a function in immune responses. PMID:2581704

  20. Targeted delivery of antigen to hamster nasal lymphoid tissue with M-cell-directed lectins.

    PubMed Central

    Giannasca, P J; Boden, J A; Monath, T P

    1997-01-01

    The nasal cavity of a rodent is lined by an epithelium organized into distinct regional domains responsible for specific physiological functions. Aggregates of nasal lymphoid tissue (NALT) located at the base of the nasal cavity are believed to be sites of induction of mucosal immune responses to airborne antigens. The epithelium overlying NALT contains M cells which are specialized for the transcytosis of immunogens, as demonstrated in other mucosal tissues. We hypothesized that NALT M cells are characterized by distinct glycoconjugate receptors which influence antigen uptake and immune responses to transcytosed antigens. To identify glycoconjugates that may distinguish NALT M cells from other cells of the respiratory epithelium (RE), we performed lectin histochemistry on sections of the hamster nasal cavity with a panel of lectins. Many classes of glycoconjugates were found on epithelial cells in this region. While most lectins bound to sites on both the RE and M cells, probes capable of recognizing alpha-linked galactose were found to label the follicle-associated epithelium (FAE) almost exclusively. By morphological criteria, the FAE contains >90% M cells. To determine if apical glycoconjugates on M cells were accessible from the nasal cavity, an M-cell-selective lectin and a control lectin in parallel were administered intranasally to hamsters. The M-cell-selective lectin was found to specifically target the FAE, while the control lectin did not. Lectin bound to M cells in vivo was efficiently endocytosed, consistent with the role of M cells in antigen transport. Intranasal immunization with lectin-test antigen conjugates without adjuvant stimulated induction of specific serum immunoglobulin G, whereas antigen alone or admixed with lectin did not. The selective recognition of NALT M cells by a lectin in vivo provides a model for microbial adhesin-host cell receptor interactions on M cells and the targeted delivery of immunogens to NALT following intranasal

  1. Pulmonary mucosa-associated lymphoid tissue lymphoma associated with pulmonary sarcoidosis: a case report and literature review.

    PubMed

    Kokuho, Nariaki; Terasaki, Yasuhiro; Urushiyama, Hirokazu; Terasaki, Mika; Kunugi, Shinobu; Morimoto, Taisuke; Azuma, Arata; Usuda, Jitsuo; Gemma, Akihiko; Eishi, Yoshinobu; Shimizu, Akira

    2016-05-01

    Differentiating low-grade lymphoma from preexisting sarcoidosis is difficult because of their pathological similarity. This article describes a case of pulmonary mucosa-associated lymphoid tissue lymphoma associated with pulmonary sarcoidosis. The patient, a 45-year-old Japanese man, presented with a 10-year history of pulmonary sarcoidosis and 5-year history of ocular sarcoidosis with histologic findings. Because only the right S3 lung nodule had gradually enlarged, partial resection was performed. Pathological study revealed noncaseous epithelioid granulomas with lymphoplasmacytic proliferation but also marked lymphoid cell proliferation with lymphoepithelial lesion findings that differed from findings of typical sarcoid lesions. Our lymphoepithelial lesion evaluation via immunohistochemistry and analysis of Ig heavy-chain gene rearrangements with assessment of Propionibacterium acnes-specific antibody reactions allow us to report, for the first time, this case of pulmonary mucosa-associated lymphoid tissue lymphoma associated with pulmonary sarcoidosis in exactly the same location, which may be significant for differentiating these diseases and understanding their pathogenic association. PMID:27067783

  2. Decreased human immunodeficiency virus type 1 plasma viremia during antiretroviral therapy reflects downregulation of viral replication in lymphoid tissue.

    PubMed Central

    Cohen, O J; Pantaleo, G; Holodniy, M; Schnittman, S; Niu, M; Graziosi, C; Pavlakis, G N; Lalezari, J; Bartlett, J A; Steigbigel, R T

    1995-01-01

    Although several immunologic and virologic markers measured in peripheral blood are useful for predicting accelerated progression of human immunodeficiency virus (HIV) disease, their validity for evaluating the response to antiretroviral therapy and their ability to accurately reflect changes in lymphoid organs remain unclear. In the present study, changes in certain virologic markers have been analyzed in peripheral blood and lymphoid tissue during antiretroviral therapy. Sixteen HIV-infected individuals who were receiving antiretroviral therapy with zidovudine for > or = 6 months were randomly assigned either to continue on zidovudine alone or to add didanosine for 8 weeks. Lymph node biopsies were performed at baseline and after 8 weeks. Viral burden (i.e., HIV DNA copies per 10(6) mononuclear cells) and virus replication in mononuclear cells isolated from peripheral blood and lymph node and plasma viremia were determined by semiquantitative polymerase chain reaction assays. Virologic and immunologic markers remained unchanged in peripheral blood and lymph node of patients who continued on zidovudine alone. In contrast, a decrease in virus replication in lymph nodes was observed in four of six patients who added didanosine to their regimen, and this was associated with a decrease in plasma viremia. These results indicate that decreases in plasma viremia detected during antiretroviral therapy reflect downregulation of virus replication in lymphoid tissue. Images Fig. 1 Fig. 2 Fig. 3 PMID:7597072

  3. [Detection of mixed lymphoid chimerism after allogeneic bone marrow transplantation: demonstration by interphase cytogenetics in paraffin-embedded tissue].

    PubMed

    Friedrich, T; Ott, G; Kalla, J; Helbig, W; Schwenke, H; Kubel, M; Pönisch, W; Feyer, P; Friedrich, A

    1994-01-01

    In bone marrow transplantation (BMT) the detection of residual host lymphoid or haematopoietic cells surviving conditioning therapy is because of its association to graft-versus-host disease, graft-versus-leukemia reaction, and relapse of leukemia a matter of great interest. We studied the occurrence of this mixed lymphoid chimerism (MC) in the formol-fixed lymphatic tissue of lymph nodes and spleen from 21 autopsies after allogeneic sex-mismatched BMT (5 females, 16 males, survival 5 to 1140 days after BMT). In situ hybridisation with biotinylated centromer-specific anti-X- and anti-Y-chromosome probes was performed on pepsin-digested paraffin sections. The number of double X-, single X-, and Y-chromosome bearing cells was analysed microscopically. Because of artefacts only 14 cases remained for valid investigation. MC was detected in 6 cases (5 out of 11 males 5 days to 840 days and 1 out of 3 females 76 days after BMT). MC occurred after whole body irradiation with 10 Gy (n = 5) and 7 Gy (n = 1). In 1 autopsy relapse of leukemia caused host cell infiltration. Cases with MC did not express histological signs of acute or chronic graft-versus-host disease, but 5 out of 8 with complete lymphoid chimerism did. The sensitivity of interphase cytogenetics on paraffin embedded tissue is low. PMID:7534002

  4. RANKL regulates differentiation of microfold cells in mouse nasopharynx-associated lymphoid tissue (NALT).

    PubMed

    Mutoh, Mami; Kimura, Shunsuke; Takahashi-Iwanaga, Hiromi; Hisamoto, Meri; Iwanaga, Toshihiko; Iida, Junichiro

    2016-04-01

    Murine nasopharynx-associated lymphoid tissue (NALT), located at the base of the nasal cavity, serves as a major site for the induction of mucosal immune responses against airway antigens. The follicle-associated epithelium (FAE) covering the luminal surface of NALT is characterized by the presence of microfold cells (M cells), which take up and transport luminal antigens to lymphocytes. Glycoprotein 2 (GP2) has recently been identified as a reliable marker for M cells in Peyer's patches of the intestine. However, the expression of GP2 and other functional molecules in the M cells of NALT has not yet been examined. We have immunohistochemically detected GP2-expressing cells in the FAE of NALT and the simultaneous expression of other intestinal M-cell markers, namely Tnfaip2, CCL9, and Spi-B. These cells have been further identified as M cells because of their higher uptake capacity of luminal microbeads. Electron microscopic observations have shown that GP2-expressing cells on the FAE display morphological features typical of M cells: they possess short microvilli and microfolds on the luminal surface and are closely associated with intraepithelial lymphocytes. We have also found that the receptor activator of nuclear factor kappa-B ligand (RANKL) is expressed by stromal cells underneath the FAE, which provides its receptor RANK. The administration of RANKL markedly increases the number of GP2(+)Tnfaip2(+) cells on the NALT FAE and that of intestinal M cells. These results suggest that GP2(+)Tnfaip2(+) cells in NALT are equivalent to intestinal M cells, and that RANKL-RANK signaling induces their differentiation. PMID:26553655

  5. Gastric mucosa-associated lymphoid tissue lymphomas and Helicobacter pylori infection: A Colombian perspective

    PubMed Central

    Yepes, Sally; Torres, Maria Mercedes; Saavedra, Carlos; Andrade, Rafael

    2012-01-01

    AIM: To assess the significance of chromosome translocation t(11;18)(q21;q21), B-cell lymphoma 10 (BCL-10) protein and Helicobacter pylori (H. pylori) infection in gastric mucosa-associated lymphoid tissue (MALT) lymphoma in Colombia. METHODS: Fifty cases of gastric MALT lymphoma and their respective post-treatment follow-up biopsies were examined to assess the presence of the translocation t(11;18)(q21;q21) as identified by fluorescence in situ hybridization; to detect protein expression patterns of BCL10 using immunohistochemistry; and for evaluation of tumor histology to determine the correlation of these factors and resistance to H. pylori eradication. RESULTS: Infection with H. pylori was confirmed in all cases of gastric MALT lymphoma in association with chronic gastritis. Bacterial eradication led to tumor regression in 66% of cases. The translocation t(11;18)(q21;q21) was not present in any of these cases, nor was there evidence of tumor transformation to diffuse large B-cell lymphoma. Thirty-four percent of the patients showed resistance to tumor regression, and within this group, 7 cases, representing 14% of all those analyzed, were considered to be t(11;18)(q21;q21)-positive gastric MALT lymphomas. Protein expression of BCL10 in the nucleus was associated with the presence of translocation and treatment resistance. Cases that were considered unresponsive to therapy were histologically characterized by the presence of homogeneous tumor cells and a lack of plasmacytic differentiation. Responder cases exhibited higher cellular heterogeneity and a greater frequency of plasma cells. CONCLUSION: Both t(11;18)(q21;q21)-positive MALT lymphoma cases and those with nuclear BCL10 expression are considered resistant to H. pylori eradication. It is suggested that chronic antigenic stimulation is not a dominant event in resistant cases. PMID:22363141

  6. Helicobacter pylori-negative gastric mucosa-associated lymphoid tissue lymphomas: A review.

    PubMed

    Asano, Naoki; Iijima, Katsunori; Koike, Tomoyuki; Imatani, Akira; Shimosegawa, Tooru

    2015-07-14

    Since Isaacson and Wright first reported on the extra-nodal marginal zone B-cell lymphoma of the stomach in 1983, following studies have clarified many aspects of this disease. We now know that the stomach is the most affected organ by this disease, and approximately 90% of gastric mucosa-associated lymphoid tissue (MALT) lymphomas are related to Helicobacter pylori (H. pylori) infection. This implies that approximately 10% of gastric MALT lymphomas occur independent of H. pylori infection. The pathogenesis of these H. pylori-negative gastric MALT lymphomas remains unclear. To date, there have been several speculations. One possibility is that genetic alterations result in nuclear factor-kappa B (NF-κB) activation. Among these alterations, t(11;18)(q21;q21) is more frequently observed in H. pylori-negative gastric MALT lymphomas, and such translocation results in the synthesis of fusion protein API2-MALT1, which causes canonical and noncanonical NF-κB activation. Another possibility is infection with bacteria other than H. pylori. This could explain why H. pylori eradication therapy can cure some proportions of H. pylori-negative gastric MALT lymphoma patients, although the bacteria responsible for MALT lymphomagenesis are yet to be defined. Recent advances in endoscopy suggest magnifying endoscopy with narrow band imaging as a useful tool for both detecting gastric MALT lymphoma lesions and judging the response to treatment. A certain proportion of H. pylori-negative gastric MALT lymphoma patients respond to eradication therapy; hence, H. pylori eradication therapy could be considered as a first-line treatment for gastric MALT lymphomas regardless of their H. pylori infection status. PMID:26185372

  7. Treatment Effects and Sequelae of Radiation Therapy for Orbital Mucosa-Associated Lymphoid Tissue Lymphoma

    SciTech Connect

    Hata, Masaharu; Omura, Motoko; Koike, Izumi; Tomita, Naoto; Iijima, Yasuhito; Tayama, Yoshibumi; Odagiri, Kazumasa; Minagawa, Yumiko; Ogino, Ichiro; Inoue, Tomio

    2011-12-01

    Purpose: Among extranodal lymphomas, orbital mucosa-associated lymphoid tissue (MALT) lymphoma is a relatively rare presentation. We performed a review to ascertain treatment efficacy and toxicity of radiation therapy for orbital MALT lymphoma. We also evaluated changes in visual acuity after irradiation. Methods and Materials: Thirty patients with orbital MALT lymphoma underwent radiation therapy with curative intent. Clinical stages at diagnosis were stage I{sub E}A in 29 patients and stage II{sub E}A in 1 patient. Total doses of 28.8 to 45.8 Gy (median, 30 Gy) in 15 to 26 fractions (median, 16 fractions) were delivered to the tumors. Results: All irradiated tumors were controlled during the follow-up period of 2 to 157 months (median, 35 months) after treatment. Two patients had relapses that arose in the cervical lymph node and the ipsilateral palpebral conjunctiva outside the radiation field at 15 and 67 months after treatment, respectively. The 5-year local progression-free and relapse-free rates were 100% and 96%, respectively. All 30 patients are presently alive; the overall and relapse-free survival rates at 5 years were 100% and 96%, respectively. Although 5 patients developed cataracts of grade 2 at 8 to 45 months after irradiation, they underwent intraocular lens implantation, and their eyesight recovered. Additionally, there was no marked deterioration in the visual acuity of patients due to irradiation, with the exception of cataracts. No therapy-related toxicity of grade 3 or greater was observed. Conclusions: Radiation therapy was effective and safe for patients with orbital MALT lymphoma. Although some patients developed cataracts after irradiation, visual acuity was well preserved.

  8. Mucosa-Associated Lymphoid Tissue Lymphoma of the Lacrimal Gland: Sustained Remission after Eradication of Helicobacter Pylori Infection

    PubMed Central

    Hasosah, Mohammed; Baothman, Abdullah; Satti, Mohamed; Kutbi, Suzanne; Alghamdi, Khaled; Jacobson, Kevan

    2011-01-01

    Mucosa-associated lymphoid tissue (MALT) lymphoma is the third most common non-Hodgkin lymphoma, and it is strongly associated with helicobacter pylori infection of the stomach. MALT lymphoma of the lacrimal gland usually presents as a localized disease process in extranodal tissues. The treatment options of MALT lymphoma of the lacrimal gland chiefly include radiation of the tumor, chemotherapy, surgical removal, or a combination of these strategies. We report a case of localized MALT lymphoma of the lacrimal gland, with prolonged sustained remission after eradication of gastric Helicobacter pylori (H. Pylori) infection. He sustains in remission of lacrimal MALT lymphoma for four years without chemotherapy or radiotherapy. PMID:22606434

  9. A Protocol for the Comprehensive Flow Cytometric Analysis of Immune Cells in Normal and Inflamed Murine Non-Lymphoid Tissues

    PubMed Central

    Yu, Yen-Rei A.; O’Koren, Emily G.; Hotten, Danielle F.; Kan, Matthew J.; Kopin, David; Nelson, Erik R.; Que, Loretta; Gunn, Michael D.

    2016-01-01

    Flow cytometry is used extensively to examine immune cells in non-lymphoid tissues. However, a method of flow cytometric analysis that is both comprehensive and widely applicable has not been described. We developed a protocol for the flow cytometric analysis of non-lymphoid tissues, including methods of tissue preparation, a 10-fluorochrome panel for cell staining, and a standardized gating strategy, that allows the simultaneous identification and quantification of all major immune cell types in a variety of normal and inflamed non-lymphoid tissues. We demonstrate that our basic protocol minimizes cell loss, reliably distinguishes macrophages from dendritic cells (DC), and identifies all major granulocytic and mononuclear phagocytic cell types. This protocol is able to accurately quantify 11 distinct immune cell types, including T cells, B cells, NK cells, neutrophils, eosinophils, inflammatory monocytes, resident monocytes, alveolar macrophages, resident/interstitial macrophages, CD11b- DC, and CD11b+ DC, in normal lung, heart, liver, kidney, intestine, skin, eyes, and mammary gland. We also characterized the expression patterns of several commonly used myeloid and macrophage markers. This basic protocol can be expanded to identify additional cell types such as mast cells, basophils, and plasmacytoid DC, or perform detailed phenotyping of specific cell types. In examining models of primary and metastatic mammary tumors, this protocol allowed the identification of several distinct tumor associated macrophage phenotypes, the appearance of which was highly specific to individual tumor cell lines. This protocol provides a valuable tool to examine immune cell repertoires and follow immune responses in a wide variety of tissues and experimental conditions. PMID:26938654

  10. Genomic Modifiers of Natural Killer Cells, Immune Responsiveness and Lymphoid Tissue Remodeling Together Increase Host Resistance to Viral Infection

    PubMed Central

    Lee, Heather; Prince, Jessica; Stadnisky, Michael D.; Anderson, Monique; Nash, William; Rival, Claudia; Wei, Hairong; Gamache, Awndre; Farber, Charles R.; Tung, Kenneth; Brown, Michael G.

    2016-01-01

    The MHC class I Dk molecule supplies vital host resistance during murine cytomegalovirus (MCMV) infection. Natural killer (NK) cells expressing the Ly49G2 inhibitory receptor, which specifically binds Dk, are required to control viral spread. The extent of Dk-dependent host resistance, however, differs significantly amongst related strains of mice, C57L and MA/My. As a result, we predicted that relatively small-effect modifier genetic loci might together shape immune cell features, NK cell reactivity, and the host immune response to MCMV. A robust Dk-dependent genetic effect, however, has so far hindered attempts to identify additional host resistance factors. Thus, we applied genomic mapping strategies and multicolor flow cytometric analysis of immune cells in naive and virus-infected hosts to identify genetic modifiers of the host immune response to MCMV. We discovered and validated many quantitative trait loci (QTL); these were mapped to at least 19 positions on 16 chromosomes. Intriguingly, one newly discovered non-MHC locus (Cmv5) controlled splenic NK cell accrual, secondary lymphoid organ structure, and lymphoid follicle development during MCMV infection. We infer that Cmv5 aids host resistance to MCMV infection by expanding NK cells needed to preserve and protect essential tissue structural elements, to enhance lymphoid remodeling and to increase viral clearance in spleen. PMID:26845690

  11. Expression of Toll-like receptor 9 (TLR9) in the lungs and lymphoid tissue of pigs.

    PubMed

    Kuzemtseva, Liudmila; Pérez, Mónica; Mateu, Enric; Segalés, Joaquim; Darwich, Laila

    2015-02-01

    The pattern of distribution of Toll-like receptor 9 (TLR9) in different tissues varies between species. The aim of the present study was to describe the distribution of TLR9 expression in selected tissues and organs of healthy pigs at 3 weeks and 3 months of age. Representative formalin-fixed samples of lung, thymus and secondary lymphoid tissues were evaluated by immunohistochemistry. TLR9 positive staining was observed in epithelial cells, vascular endothelium and myoepithelial-like cells, as well as in cells of the alveolar septa of the lung. Antigen presenting cells of perifollicular zones (interdigitating, macrophage and dendritic-like cells) of the Peyer's patches, lymph nodes, spleen and thymus were also immunoreactive for TLR9. No differences were seen in TLR9 protein expression in tissues from the two age groups. PMID:25576141

  12. Chemoimmunotherapy for Mucosa-Associated Lymphoid Tissue-Type Lymphoma: A Review of the Literature

    PubMed Central

    Kiesewetter, Barbara; Ferreri, Andrés J.M.

    2015-01-01

    Background. Biological treatments, chemoimmunotherapy, and radiotherapy are associated with excellent disease control in both gastric and extragastric mucosa-associated lymphoid tissue (MALT) lymphomas. Systemic treatment approaches with both oral and i.v. agents are being increasingly studied, not only for patients with disseminated MALT lymphoma, but also for those with localized disease. To date, however, recommendations for the use of available systemic modalities have not been clearly defined. Materials and Methods. The present report reviews the current data on systemic treatment options for patients with MALT lymphoma and provides recommendations for their use in everyday practice. Results. Different chemotherapeutic agents, including anthracyclines, alkylators, and purine analogs, have been successfully tested in patients with MALT lymphoma. Reducing side effects while maintaining efficacy should be the main goal in treating these indolent lymphomas. From the data from the largest trial performed to date, the combination of chlorambucil plus rituximab (R) appears to be active as first-line treatment. Similarly, R-bendamustine also seems to be highly effective, but a longer follow-up period is needed. R-monotherapy results in lower remission rates, but seems a suitable option for less fit patients. New immunotherapeutic agents such as lenalidomide (with or without rituximab) or clarithromycin show solid activity but have not yet been validated in larger collectives. Conclusion. Patients with MALT lymphoma should be treated within prospective trials to further define optimal therapeutic strategies. Systemic treatment is a reasonable option with potentially curative intent in everyday practice. Based on the efficacy and safety data from available studies, the present review provides recommendations for the use of systemic strategies. Implications for Practice: In view of the biology of MALT lymphoma with trafficking of cells within various mucosal structures

  13. Macrophage entry mediated by HIV Envs from brain and lymphoid tissues is determined by the capacity to use low CD4 levels and overall efficiency of fusion

    SciTech Connect

    Thomas, Elaine R.; Dunfee, Rebecca L.; Stanton, Jennifer; Bogdan, Derek; Taylor, Joann; Kunstman, Kevin; Bell, Jeanne E.; Wolinsky, Steven M.; Gabuzda, Dana . E-mail: dana_gabuzda@dfci.harvard.edu

    2007-03-30

    HIV infects macrophages and microglia in the central nervous system (CNS), which express lower levels of CD4 than CD4+ T cells in peripheral blood. To investigate mechanisms of HIV neurotropism, full-length env genes were cloned from autopsy brain and lymphoid tissues from 4 AIDS patients with HIV-associated dementia (HAD). Characterization of 55 functional Env clones demonstrated that Envs with reduced dependence on CD4 for fusion and viral entry are more frequent in brain compared to lymphoid tissue. Envs that mediated efficient entry into macrophages were frequent in brain but were also present in lymphoid tissue. For most Envs, entry into macrophages correlated with overall fusion activity at all levels of CD4 and CCR5. gp160 nucleotide sequences were compartmentalized in brain versus lymphoid tissue within each patient. Proline at position 308 in the V3 loop of gp120 was associated with brain compartmentalization in 3 patients, but mutagenesis studies suggested that P308 alone does not contribute to reduced CD4 dependence or macrophage-tropism. These results suggest that HIV adaptation to replicate in the CNS selects for Envs with reduced CD4 dependence and increased fusion activity. Macrophage-tropic Envs are frequent in brain but are also present in lymphoid tissues of AIDS patients with HAD, and entry into macrophages in the CNS and other tissues is dependent on the ability to use low receptor levels and overall efficiency of fusion.

  14. Surgical Management of Pulmonary Mucosa-Associated Lymphoid Tissue Lymphoma Associated With Light-Chain Deposition Disease.

    PubMed

    Muñoz-Largacha, Juan A; O'Hara, Carl J; Sloan, J Mark; Fernando, Hiran C; Litle, Virginia R

    2016-06-01

    A 52-year-old woman presented with a right middle lobe (RML) lung nodule suspicious for malignancy. Thoracoscopic middle lobectomy was performed. The pathology report revealed a pulmonary mucosa-associated lymphoid tissue (MALT) lymphoma in association with light-chain deposition disease (LCDD). Pulmonary MALT lymphoma and LCDD are unusual disorders presenting in the lung, and the association between these 2 conditions is even more uncommon. The optimal management for these patients is controversial, although surgical resection of localized well-circumscribed lesions may represent an effective therapeutic approach. PMID:27211983

  15. [Specific clinical and immunological features of chronic diseases of the nasal-associated lymphoid tissue in the children].

    PubMed

    Beniova, S N; Taranova, S V; Babko, S V

    2014-01-01

    The objective of the present work was to study the structure, clinical, and immunological features of various etiological variants of chronic diseases of the nasal-associated lymphoid tissue in the children. A total of 142 children at the age from 3 to 7 years presenting with this pathological condition were available for the observation. The study revealed differences in the clinical course of the disease and the cytokine response (IL-6, Ril-6, TNF, sYNFR55, sTNFR75) at the local and systemic levels for different pathogens (S. aureus, S. pneumoniae, S. pyrogenes). PMID:25377675

  16. Dynamics of CCR5 Expression by CD4+ T Cells in Lymphoid Tissues during Simian Immunodeficiency Virus Infection

    PubMed Central

    Veazey, Ronald S.; Mansfield, Keith G.; Tham, Irene C.; Carville, Angela C.; Shvetz, Daniel E.; Forand, Amy E.; Lackner, Andrew A.

    2000-01-01

    Early viral replication and profound CD4+ T-cell depletion occur preferentially in intestinal tissues of macaques infected with simian immunodeficiency virus (SIV). Here we show that a much higher percentage of CD4+ T cells in the intestine express CCR5 compared with those found in the peripheral blood, spleen, or lymph nodes. In addition, the selectivity and extent of the CD4+ T-cell loss in SIV infection may depend upon these cells coexpressing CCR5 and having a “memory” phenotype (CD45RA−). Following intravenous infection with SIVmac251, memory CD4+ CCR5+ T cells were selectively eliminated within 14 days in all major lymphoid tissues (intestine, spleen, and lymph nodes). However, the effect on CD4+ T-cell numbers was most profound in the intestine, where cells of this phenotype predominate. The CD4+ T cells that remain after 14 days of infection lacked CCR5 and/or were naive (CD45RA+). Furthermore, when animals in the terminal stages of SIV infection (with AIDS) were examined, virtually no CCR5-expressing CD4+ T cells were found in lymphoid tissues, and all of the remaining CD4+ T cells were naive and coexpressed CXCR4. These findings suggest that chemokine receptor usage determines which cells are targeted for SIV infection and elimination in vivo. PMID:11069995

  17. Essential role of peripheral node addressin in lymphocyte homing to nasal-associated lymphoid tissues and allergic immune responses

    PubMed Central

    Ohmichi, Yukari; Hirakawa, Jotaro; Imai, Yasuyuki; Fukuda, Minoru

    2011-01-01

    Nasal-associated lymphoid tissue (NALT) is a mucosal immune tissue that provides immune responses against inhaled antigens. Lymphocyte homing to NALT is mediated by specific interactions between lymphocytes and high endothelial venules (HEVs) in NALT. In contrast to HEVs in other mucosal lymphoid tissues, NALT HEVs strongly express peripheral node addressins (PNAds) that bear sulfated glycans recognized by the monoclonal antibody MECA-79. We investigated the role of PNAd in lymphocyte homing to NALT using sulfotransferase N-acetylglucosamine-6-O-sulfotransferase (GlcNAc6ST) 1 and GlcNAc6ST-2 double knockout (DKO) mice. The expression of PNAd in NALT HEVs was eliminated in DKO mice. Short-term homing assays indicated that lymphocyte homing to NALT was diminished by 90% in DKO mice. Production of antigen-specific IgE and the number of sneezes in response to nasally administered ovalbumin were also substantially diminished. Consistently, the NALT of DKO mice showed reduced production of IL-4 and increased production of IL-10 together with an increase in CD4+CD25+ regulatory T cells (Treg cells). Compared with the homing of CD4+CD25− conventional T cells, the homing of CD4+CD25+ Treg cells to NALT was less dependent on the L-selectin–PNAd interaction but was partially dependent on PSGL-1 (P-selectin glycoprotein ligand 1) and CD44. These results demonstrate that PNAd is essential for lymphocyte homing to NALT and nasal allergic responses. PMID:21518796

  18. Early-life compartmentalization of human T cell differentiation and regulatory function in mucosal and lymphoid tissues.

    PubMed

    Thome, Joseph J C; Bickham, Kara L; Ohmura, Yoshiaki; Kubota, Masaru; Matsuoka, Nobuhide; Gordon, Claire; Granot, Tomer; Griesemer, Adam; Lerner, Harvey; Kato, Tomoaki; Farber, Donna L

    2016-01-01

    It is unclear how the immune response in early life becomes appropriately stimulated to provide protection while also avoiding excessive activation as a result of diverse new antigens. T cells are integral to adaptive immunity; mouse studies indicate that tissue localization of T cell subsets is important for both protective immunity and immunoregulation. In humans, however, the early development and function of T cells in tissues remain unexplored. We present here an analysis of lymphoid and mucosal tissue T cells derived from pediatric organ donors in the first two years of life, as compared to adult organ donors, revealing early compartmentalization of T cell differentiation and regulation. Whereas adult tissues contain a predominance of memory T cells, in pediatric blood and tissues the main subset consists of naive recent thymic emigrants, with effector memory T cells (T(EM)) found only in the lungs and small intestine. Additionally, regulatory T (T(reg)) cells comprise a high proportion (30-40%) of CD4(+) T cells in pediatric tissues but are present at much lower frequencies (1-10%) in adult tissues. Pediatric tissue T(reg) cells suppress endogenous T cell activation, and early T cell functionality is confined to the mucosal sites that have the lowest T(reg):T(EM) cell ratios, which suggests control in situ of immune responses in early life. PMID:26657141

  19. Elevated mutant frequencies in lymphoid tissues persist throughout plasmacytoma development in BALB/c.lambdaLIZ mice.

    PubMed

    Felix, K; Kelliher, K A; Bornkamm, G W; Janz, S

    1999-08-01

    Using the phage lambdaLIZ-based transgenic in vivo mutagenesis assay, the mean mutant frequencies in the target gene, lacI, were found to be significantly increased in lymphoid tissues of congenic BALB/c.lambdaLIZ N5 mice in the terminal stage of a plasmacytoma induction experiment, 213-280 days after the first i.p. injection of the plasmacytomagenic agent pristane (2,6,10,14-tetramethylpentadecane). In plasmacytoma-bearing mice (n = 7), mutant frequencies in the spleens and mesenteric lymph nodes were elevated 2.46-fold and 5.35-fold, respectively, when compared with age-matched controls. In plasmacytoma-negative mice (n = 11), mutant frequencies were increased 2.30-fold (spleens) and 3.48-fold (mesenteric nodes). These results, interpreted in conjunction with our previous findings (K. Felix et al., Cancer Res., 58: 1616-1619, 1998) of approximately 3-fold elevations in pristane-induced splenic mutagenesis on day 42 postpristane, indicate that increased mutant levels in lymphoid tissues persist throughout plasmacytomagenesis in genetically susceptible BALB/c mice. PMID:10446972

  20. Critical role of CD4 T cells in maintaining lymphoid tissue structure for immune cell homeostasis and reconstitution

    PubMed Central

    Zeng, Ming; Paiardini, Mirko; Engram, Jessica C.; Beilman, Greg J.; Chipman, Jeffrey G.; Schacker, Timothy W.; Silvestri, Guido

    2012-01-01

    Loss of the fibroblastic reticular cell (FRC) network in lymphoid tissues during HIV-1 infection has been shown to impair the survival of naive T cells and limit immune reconstitution after antiretroviral therapy. What causes this FRC loss is unknown. Because FRC loss correlates with loss of both naive CD4 and CD8 T-cell subsets and decreased lymphotoxin-β, a key factor for maintenance of FRC network, we hypothesized that loss of naive T cells is responsible for loss of the FRC network. To test this hypothesis, we assessed the consequences of antibody-mediated depletion of CD4 and CD8 T cells in rhesus macaques and sooty mangabeys. We found that only CD4 T-cell depletion resulted in FRC loss in both species and that this loss was caused by decreased lymphotoxin-β mainly produced by the CD4 T cells. We further found the same dependence of the FRC network on CD4 T cells in HIV-1–infected patients before and after antiretroviral therapy and in other immunodeficiency conditions, such as CD4 depletion in cancer patients induced by chemotherapy and irradiation. CD4 T cells thus play a central role in the maintenance of lymphoid tissue structure necessary for their own homeostasis and reconstitution. PMID:22613799

  1. Production of a monoclonal antibody reactive with human dendritic reticulum cells and its use in the immunohistological analysis of lymphoid tissue.

    PubMed Central

    Naiem, M; Gerdes, J; Abdulaziz, Z; Stein, H; Mason, D Y

    1983-01-01

    A murine monoclonal antibody (designated R4/23) which reacts strongly with human dendritic reticulum cells (DRC) is described. Immunoperoxidase staining of tissue cryostat sections revealed that this antibody reacts strongly with DRC in lymphoid follicles (both primary and secondary), and also weakly with marginal zone splenic B cells and with some peripheral follicular mantle B lymphocytes in lymph node cortical follicles. The value of antibody R4/23 is that it allows the distribution of DRC in reactive and neoplastic lymphoid tissue to be clearly delineated. Of particular interest is the fact that all cases of follicular lymphoma of germinal centre cell origin are consistently accompanied by a proliferation of DRC, even when the neoplasm is present in non-lymphoid tissue--for example, in the kidney. In contrast, DRC in B cell lymphomas of non-germinal centre origin are partially or totally obliterated. Images PMID:6338047

  2. Morphology and distribution of 1,2-dimethylhydrazine dihydrochloride-induced colon tumors and their relationship to gut-associated lymphoid tissue in the rat.

    PubMed

    Nauss, K M; Locniskar, M; Pavlina, T; Newberne, P M

    1984-10-01

    The histopathology and relationship of sym-dimethylhydrazine dihydrochloride [(DMH) CAS: 306-37-6; 1,2-dimethylhydrazine dihydrochloride]-induced colon tumors to colonic lymphoid aggregates were examined in outbred male Sprague-Dawley rats treated with saline or DMH and sacrificed at three intervals after treatment. The ratio of polypoid:sessile tumors was 71:29 four months after DMH treatment and 62:38 when tumors were fully developed. Colonic lymphoid aggregates were found 3-5 cm from the cecal-colonic junction, near the flexure of the ascending and transverse colon, and 3-5 cm from the rectum. There were no significant differences between saline-treated and DMH-treated rats regarding the size, cellularity, and number of lymphoid aggregates per rat. A significant association (P less than .001) was seen between tumor development and the presence of a lymphoid aggregate in a given segment of the colon. Sessile adenocarcinomas, but not polypoid tumors, were significantly associated (P less than .001) with lymphoid aggregates and usually presented as mucinous tumors adjacent to or intermixed with the lymphoid tissue. PMID:6592387

  3. Both rejection and tolerance of allografts can occur in the absence of secondary lymphoid tissues.

    PubMed

    Kant, Cavit D; Akiyama, Yoshinobu; Tanaka, Katsunori; Shea, Susan; Yamada, Yohei; Connolly, Sarah E; Marino, Jose; Tocco, Georges; Benichou, Gilles

    2015-02-01

    In this study, we showed that aly/aly mice, which are devoid of lymph nodes and Peyer's patches, acutely rejected fully allogeneic skin and heart grafts. They mounted potent inflammatory direct alloresponses but failed to develop indirect alloreactivity after transplantation. Remarkably, skin allografts also were rejected acutely by splenectomized aly/aly (aly/aly-spl(-)) mice devoid of all secondary lymphoid organs. In these recipients, the rejection was mediated by alloreactive CD8(+) T cells presumably primed in the bone marrow. In contrast, cardiac transplants were not rejected by aly/aly-spl(-) mice. Actually, aly/aly-spl(-) mice that spontaneously accepted a heart allotransplant and displayed donor-specific tolerance also accepted skin grafts from the same, but not a third-party, donor via a mechanism involving CD4(+) regulatory T cells producing IL-10 cytokine. Therefore, direct priming of alloreactive T cells, as well as rejection and regulatory tolerance of allogeneic transplants, can occur in recipient mice lacking secondary lymphoid organs. PMID:25535285

  4. Discordance in lymphoid tissue recovery following stem cell transplantation in rhesus macaques: an in vivo imaging study.

    PubMed

    Donahue, Robert E; Srinivasula, Sharat; Uchida, Naoya; Kim, Insook; St Claire, Alexis; Duralde, Gorka; DeGrange, Paula; St Claire, Marisa; Reba, Richard C; Bonifacino, Aylin C; Krouse, Allen E; Metzger, Mark E; Paik, Chang H; Lane, H Clifford; Tisdale, John F; Di Mascio, Michele

    2015-12-10

    Ionizing irradiation is used routinely to induce myeloablation and immunosuppression. However, it has not been possible to evaluate the extent of ablation without invasive biopsy. For lymphoid recovery, peripheral blood (PB) lymphocytes (PBLs) have been used for analysis, but they represent <2% of cells in lymphoid tissues (LTs). Using a combination of single-photon emission computed tomography imaging and a radiotracer ((99m)Tc-labeled rhesus immunoglobulin G1 anti-CD4R1 (Fab')2), we sequentially imaged CD4(+) cell recovery in rhesus macaques following total body irradiation (TBI) and reinfusion of vector-transduced, autologous CD34(+) cells. Our results present for the first time a sequential, real-time, noninvasive method to evaluate CD4(+) cell recovery. Importantly, despite myeloablation of circulating leukocytes following TBI, total depletion of CD4(+) lymphocytes in LTs such as the spleen is not achieved. The impact of TBI on LTs and PBLs is discordant, in which as few as 32.4% of CD4(+) cells were depleted from the spleen. In addition, despite full lymphocyte recovery in the spleen and PB, lymph nodes have suboptimal recovery. This highlights concerns about residual disease, endogenous contributions to recovery, and residual LT damage following ionizing irradiation. Such methodologies also have direct application to immunosuppressive therapy and other immunosuppressive disorders, such as those associated with viral monitoring. PMID:26492933

  5. Isolated Follicles Enriched for Centroblasts and Lacking t(14;18)/BCL2 in Lymphoid Tissue: Diagnostic and Clinical Implications

    PubMed Central

    Gratzinger, Dita; Jones, Carol D.; Zehnder, James L.; Bangs, Charles D.; Cherry, Athena; Warnke, Roger A.; Natkunam, Yasodha

    2016-01-01

    We sought to address the significance of isolated follicles that exhibit atypical morphologic features that may be mistaken for lymphoma in a background of reactive lymphoid tissue. Seven cases that demonstrated centroblast-predominant isolated follicles and absent BCL2 staining in otherwise-normal lymph nodes were studied. Four of seven cases showed clonal B-cell proliferations amid a polyclonal B cell background; all cases lacked the IGH-BCL2 translocation and BCL2 protein expression. Although three patients had invasive breast carcinoma at other sites, none were associated with systemic lymphoma up to 44 months after diagnosis. The immunoarchitectural features of these highly unusual cases raise the question of whether a predominance of centroblasts and/or absence of BCL2 expression could represent a precursor lesion or atypical reactive phenomenon. Differentiating such cases from follicular lymphoma or another mimic is critical, lest patients with indolent proliferations be exposed to unnecessarily aggressive treatment. PMID:26991267

  6. The role of miRNAs and epigenetic mechanisms in primary gastric mucosa-associated lymphoid tissue lymphoma.

    PubMed

    Vasilatou, Diamantina; Sioulas, Athanasios D; Pappa, Vasiliki; Papanikolaou, Ioannis S; Triantafyllou, Konstantinos; Dimitriadis, George D; Papageorgiou, Sotirios G

    2016-07-01

    Gastric mucosa-associated lymphoid tissue (MALT) lymphoma is a rare low-grade B-cell non-Hodgkin lymphoma associated with Helicobacter pylori infection and the subsequent chronic inflammation. Significant progress in understanding the pathogenesis of the disease has already been made. However, the exact molecular pathways of lymphomagenesis remain unclear. Furthermore, difficulties regarding accurate diagnosis of gastric MALT lymphoma and its discrimination from gastritis or other lymphoma subtypes arise. Recent studies evaluate the role of miRNAs and epigenetic alterations on MALT lymphoma pathogenesis and prognosis. This review critically summarizes the most important data on the role of miRNAs and epigenetics in MALT lymphomas pathogenesis, prognosis and treatment. PMID:27079806

  7. Novel concept of iSALT (inducible skin-associated lymphoid tissue) in the elicitation of allergic contact dermatitis

    PubMed Central

    HONDA, Tetsuya; KABASHIMA, Kenji

    2016-01-01

    Allergic contact dermatitis (ACD) is one of the most common inflammatory skin diseases, which is classified as a delayed-type hypersensitivity immune response. The development of ACD is divided into two phases: sensitization and elicitation. In the sensitization phase, antigen-specific effector T cells are induced in the draining lymph nodes by antigen-captured cutaneous dendritic cells (DCs) that migrate from the skin. In the elicitation phase, the effector T cells are activated in the skin by antigen-captured cutaneous DCs and produce various chemical mediators, which create antigen-specific inflammation. In this review, we discuss the recent advancements in the immunological mechanisms of ACD, focusing on the mechanisms in the elicitation phase. The observations of elicitation of CHS lead to the emerging novel concept of iSALT (inducible skin-associated lymphoid tissue). PMID:26755397

  8. Bilateral Bronchiectasis as a Presentation Form of Pulmonary Marginal Zone B-Cell Lymphoma of Bronchus Associated Lymphoid Tissue

    PubMed Central

    Ernst, Glenda; Torres, Carla; Borsini, Eduardo; Vigovich, Félix; Downey, Daniel; Salvado, Alajandro; Bosio, Martín

    2015-01-01

    The pulmonary marginal zone B-cell lymphoma of bronchus associated lymphoid tissue of the lung (BALT) is a rare illness that can remain without symptoms. Radiological findings of pulmonary lymphoma are heterogeneous. In literature, bronchiectasis is only described in one patient who also had besides adenomegalies. We reported on a 48-year-old female patient. She showed symptoms consistent with dyspnea with productive cough; there were crepitant sounds in the auscultation. Pulmonary functional test has shown a severe restrictive pattern with a low FVC and DLCO. CT scan showed bronchiectasis in the medium lobule without adenomegalies. Echocardiogram was normal, and the laboratory findings only showed leukocytosis. There were no findings in the bronchoscopy, but the lung biopsy showed a B-cell pulmonary lymphoma (positive to CD20 and CD79a in immunostaining). A wide variety of radiological manifestations has been previously described; however, we have presented this rare case, with bronchiectasis, as unique radiological finding. PMID:26839723

  9. Isolated Follicles Enriched for Centroblasts and Lacking t(14;18)/BCL2 in Lymphoid Tissue: Diagnostic and Clinical Implications.

    PubMed

    Nybakken, Grant E; Bala, Rajeev; Gratzinger, Dita; Jones, Carol D; Zehnder, James L; Bangs, Charles D; Cherry, Athena; Warnke, Roger A; Natkunam, Yasodha

    2016-01-01

    We sought to address the significance of isolated follicles that exhibit atypical morphologic features that may be mistaken for lymphoma in a background of reactive lymphoid tissue. Seven cases that demonstrated centroblast-predominant isolated follicles and absent BCL2 staining in otherwise-normal lymph nodes were studied. Four of seven cases showed clonal B-cell proliferations amid a polyclonal B cell background; all cases lacked the IGH-BCL2 translocation and BCL2 protein expression. Although three patients had invasive breast carcinoma at other sites, none were associated with systemic lymphoma up to 44 months after diagnosis. The immunoarchitectural features of these highly unusual cases raise the question of whether a predominance of centroblasts and/or absence of BCL2 expression could represent a precursor lesion or atypical reactive phenomenon. Differentiating such cases from follicular lymphoma or another mimic is critical, lest patients with indolent proliferations be exposed to unnecessarily aggressive treatment. PMID:26991267

  10. [A case of a collision tumor comprising mucosa-associated lymphoid tissue lymphoma and early gastric cancer].

    PubMed

    Isosaka, Mai; Adachi, Takeya; Iida, Tomoya; Mitsuhashi, Kei; Tanaka, Michihiro; Kondou, Yoshihiro; Suzuki, Takashi; Tanuma, Tokuma; Kasai, Kiyoshi

    2014-07-01

    A 60-year-old woman underwent upper gastrointestinal endoscopy for an abnormality identified during routine examination. The lower gastric corpus showed a type 0-I elevated lesion with a faded mucosa and an area of converging mucosal folds in contact with the lesion. Biopsy indicated the former to be a high-grade adenoma and the latter to be a mucosa-associated lymphoid tissue (MALT) lymphoma. At the same time, Helicobacter pylori infection was diagnosed. Eradication therapy was administered to manage the MALT lymphoma; this resulted in improvement after 3 months. Endoscopic submucosal dissection was performed for the elevated lesion, and subsequent histopathology showed contact between the MALT lymphoma and gastric cancer. Therefore, the patient was diagnosed with a collision tumor. Concurrent cancers are increasingly reported and should be considered during examination. PMID:24998730

  11. Meningeal Tertiary Lymphoid Tissues and Multiple Sclerosis: A Gathering Place for Diverse Types of Immune Cells during CNS Autoimmunity

    PubMed Central

    Pikor, Natalia B.; Prat, Alexandre; Bar-Or, Amit; Gommerman, Jennifer L.

    2016-01-01

    Collections of leukocytes in the meningeal space have been documented in Multiple Sclerosis (MS). These meningeal aggregates, which in the context of other autoimmune diseases have often been termed tertiary lymphoid tissues (TLT), have been associated with sub-pial cortical damage and disease progression. However, the key molecular and cellular signals required for their formation and maintenance remain unclear. Herein, we review TLT structures in other disease states in order to provide a framework for understanding these structures in the MS meninges. We then assess the evidence that the meningeal compartment serves as an important nexus for immune cells as well as a location for drainage of antigen into cervical lymph nodes. Extrapolating what is known about the molecular and cellular cues that initiate the formation of leukocyte aggregates in non-lymphoid tissues, we speculate on what signals lead to the formation and maintenance of meningeal TLT structures. Referring to the animal model of MS [experimental autoimmune encephalomyelitis (EAE)], we also explore what is known about these structures in supporting B cell and T cell responses during neuroinflammation. Last, we examine the evidence that connects these structures to ongoing neuropathology. Collectively, our review points to the meningeal compartment as an important player in neuroinflammatory processes. Moreover, we hypothesize that in order to gain insights into pro- and anti-inflammatory properties of lymphocytes in MS, one must understand the cellular scaffolds that support lymphocyte retention within the meninges, thus highlighting the importance of non-immune cells (stromal cells) in the neuroinflammatory process. PMID:26793195

  12. Innate lymphoid cells in secondary lymphoid organs.

    PubMed

    Bar-Ephraïm, Yotam E; Mebius, Reina E

    2016-05-01

    The family of innate lymphoid cells (ILCs) has attracted attention in recent years as its members are important regulators of immunity, while they can also cause pathology. In both mouse and man, ILCs were initially discovered in developing lymph nodes as lymphoid tissue inducer (LTi) cells. These cells form the prototypic members of the ILC family and play a central role in the formation of secondary lymphoid organs (SLOs). In the absence of LTi cells, lymph nodes (LN) and Peyer's Patches (PP) fail to form in mice, although the splenic white pulp can develop normally. Besides LTi cells, the ILC family encompasses helper-like ILCs with functional distinctions as seen by T-helper cells, as well as cytotoxic natural killer (NK) cells. ILCs are still present in adult SLOs where they have been shown to play a role in lymphoid tissue regeneration. Furthermore, ILCs were implicated to interact with adaptive lymphocytes and influence the adaptive immune response. Here, we review the recent literature on the role of ILCs in secondary lymphoid tissue from the formation of SLOs to mature SLOs in adults, during homeostasis and pathology. PMID:27088915

  13. Diagnosis of preclinical CWD in farmed white-tailed deer in Canada by the immunohistochemical examination of recto-anal mucosa- associated lymphoid tissue (RAMALT)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This report summarizes the comparative diagnostic performance of postmortem rectoanal mucosa-associated lymphoid tissue (RAMALT) sampling in two white-tailed deer farms from Saskatchewan, Canada. The apparent prevalence of disease in these two farms was 21% and 31%. None of these deer were demonstra...

  14. Mercury species in lymphoid and non-lymphoid tissues after exposure to methyl mercury: Correlation with autoimmune parameters during and after treatment in susceptible mice

    SciTech Connect

    Havarinasab, Said; Bjoern, Erik; Nielsen, Jesper B.; Hultman, Per . E-mail: perhu@imk.liu.se

    2007-05-15

    be due to demethylation of MeHg in the macrophage-rich lymphoid tissue. The major autoantibody in HgIA, anti-fibrillarin antibodies, tended to increase during the initial 6 weeks after stopping treatment, while all other HgIA features including antichromatin antibodies declined to control levels after 2-4 weeks. This indicates differences in either dose requirement or induction mechanisms for the different HgIA parameters. The selective accumulation of Hg{sup 2+} in lymph nodes following MeHg treatment should be taken into account when the effect of MeHg on the immune system is evaluated.

  15. The effect of deoxyribonucleic acid extraction methods from lymphoid tissue on the purity, content, and amplifying ability

    PubMed Central

    Ayatollahi, Hossein; Sadeghian, Mohammad Hadi; Keramati, Mohammad Reza; Ayatollahi, Ali; Shajiei, Arezoo; Sheikhi, Maryam; Bakhshi, Samane

    2016-01-01

    Background: Nowadays, definitive diagnosis of numerous diseases is based on the genetic and molecular findings. Therefore, preparation of fundamental materials for these evaluations is necessary. Deoxyribonucleic acid (DNA) is the first material for the molecular pathology and genetic analysis, and better results need more pure DNA. Furthermore, higher concentration of achieved DNA causes better results and higher amplifying ability for subsequent steps. We aim to evaluate five DNA extraction methods to compare DNA intimacy including purity, concentration, and amplifying ability with each other. Materials and Methods: The lymphoid tissue DNA was extracted from formalin-fixed, paraffin embedded (FFPE) tissue through five different methods including phenol-chloroform as the reference method, DNA isolation kit (QIAamp DNA FFPE Tissue Kit, Qiagen, Germany), proteinase K and xylol extraction and heat alkaline plus mineral oil extraction as authorship innovative method. Finally, polymerase chain reaction (PCR) and real-time PCR method were assessed to compare each following method consider to DNA purity and its concentration. Results: Among five different applied methods, the highest mean of DNA purity was related to heat alkaline method. Moreover, the highest mean of DNA concentration was related to heat alkaline plus mineral oil. Furthermore, the best result in quantitative PCR was in proteinase K method that had the lowest cycle threshold averages among the other extraction methods. Conclusion: We concluded that our innovative method for DNA extraction (heat alkaline plus mineral oil) achieved high DNA purity and concentration.

  16. Prevalence of Achromobacter xylosoxidans in pulmonary mucosa-associated lymphoid tissue lymphoma in different regions of Europe.

    PubMed

    Adam, Patrick; Czapiewski, Piotr; Colak, Seba; Kosmidis, Perikles; Tousseyn, Thomas; Sagaert, Xavier; Boudova, Ludmila; Okoń, Krzysztof; Morresi-Hauf, Alicia; Agostinelli, Claudio; Pileri, Stefano; Pruneri, Giancarlo; Martinelli, Giovanni; Du, Ming-Qing; Fend, Falko

    2014-03-01

    Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) comprises 7-8% of B-cell lymphomas and commonly originates from a background of long-standing chronic inflammation. An association with distinct bacteria species has been confirmed for several anatomical sites of MALT lymphoma. For pulmonary MALT lymphoma, however, a clear link with an infectious agent or autoimmune disorder has not yet been reported. Using a 16S rRNA gene-based approach, we have recently identified Achromobacter (Alcaligenes) xylosoxidans in eight of nine cases of pulmonary MALT lymphoma. A. xylosoxidans is a gram-negative betaproteobacterium with low virulence, but high resistance to antibiotic treatment. To further examine a potential association with A. xylosoxidans, 124 cases of pulmonary MALT lymphoma and 82 control tissues from six European countries were analysed using a specific nested PCR. Although prevalence rates for A. xylosoxidans varied significantly from country to country, they were consistently higher for MALT lymphoma as compared to controls. Overall, 57/124 (46%) pulmonary MALT lymphomas and 15/82 (18%) control tissues were positive for A. xylosoxidans (P = 0·004). Whether the significant association of A. xylosoxidans with pulmonary MALT lymphoma demonstrated in our study points to a potential causal role in the pathogenesis of this lymphoma will require further studies. PMID:24372375

  17. Immunohistochemical localization of T-lymphocyte subsets in the developing lymphoid tissues of the tammar wallaby (Macropus eugenii).

    PubMed

    Duncan, Louise G; Nair, Sham V; Deane, Elizabeth M

    2012-12-01

    Research into marsupial adaptive immunity during ontogeny has been hampered by the lack of antibodies that react to marsupial immunological cell populations. In this study, newly synthesised polyclonal antibodies to the T cell marker, CD8, have been developed and used to investigate the ontogeny and distribution of this T cell population in the tammar wallaby. Immunohistochemical analysis indicated that the distribution of the CD8 lymphocytes in the lymphoid tissues of tammar neonates during the first 144 days of pouch life was similar to that of the eutherian mammals. However, CD8α(+) lymphocytes were observed in the intestines of tammar neonates prior to their first appearance in the cervical thymus, an observation that has not been found in eutherians. A dual labelling immunohistochemical approach was used for the indirect demonstration of CD4 and enabled the simultaneous detection in the tammar wallaby tissues of the two major T-lymphocyte populations, CD4 and CD8 that are associated with adaptive immunity. As in eutherian mammals, CD4(+) cells were the predominant T cell lymphocyte subset observed in the spleen while in the nodal tissues, an age-related decrease in the CD4(+)/CD8(+) ratio was noted. These antibodies provide a new immunological tool to study the role of T cell subsets in marsupial immunity and disease pathogenesis studies. PMID:22929957

  18. Reciprocal regulation of lymphoid tissue development in the large intestine by IL-25 and IL-23

    PubMed Central

    Donaldson, D S; Bradford, B M; Artis, D; Mabbott, N A

    2015-01-01

    Isolated lymphoid follicles (ILFs) develop after birth in the small and large intestines (SI and LI) and represent a dynamic response of the gut immune system to the microbiota. Despite their similarities, ILF development in the SI and LI differs on a number of levels. We show that unlike ILF in the SI, the microbiota inhibits ILF development in the colon as conventionalization of germ-free mice reduced colonic ILFs. From this, we identified a novel mechanism regulating colonic ILF development through the action of interleukin (IL)-25 on IL-23 and its ability to modulate T regulatory cell (Treg) differentiation. Colonic ILF develop in the absence of a number of factors required for the development of their SI counterparts and can be specifically suppressed by factors other than IL-25. However, IL-23 is the only factor identified that specifically promotes colonic ILFs without affecting SI-ILF development. Both IL-23 and ILFs are associated with inflammatory bowel disease, suggesting that disruption to this pathway may have an important role in the breakdown of microbiota-immune homeostasis. PMID:25249168

  19. The aged lymphoid tissue environment fails to support naïve T cell homeostasis

    PubMed Central

    Becklund, Bryan R.; Purton, Jared F.; Ramsey, Chris; Favre, Stéphanie; Vogt, Tobias K.; Martin, Christopher E.; Spasova, Darina S.; Sarkisyan, Gor; LeRoy, Eric; Tan, Joyce T.; Wahlus, Heidi; Bondi-Boyd, Brea; Luther, Sanjiv A.; Surh, Charles D.

    2016-01-01

    Aging is associated with a gradual loss of naïve T cells and a reciprocal increase in the proportion of memory T cells. While reduced thymic output is important, age-dependent changes in factors supporting naïve T cells homeostasis may also be involved. Indeed, we noted a dramatic decrease in the ability of aged mice to support survival and homeostatic proliferation of naïve T cells. The defect was not due to a reduction in IL-7 expression, but from a combination of changes in the secondary lymphoid environment that impaired naïve T cell entry and access to key survival factors. We observed an age-related shift in the expression of homing chemokines and structural deterioration of the stromal network in T cell zones. Treatment with IL-7/mAb complexes can restore naïve T cell homeostatic proliferation in aged mice. Our data suggests that homeostatic mechanisms that support the naïve T cell pool deteriorate with age. PMID:27480406

  20. The aged lymphoid tissue environment fails to support naïve T cell homeostasis.

    PubMed

    Becklund, Bryan R; Purton, Jared F; Ramsey, Chris; Favre, Stéphanie; Vogt, Tobias K; Martin, Christopher E; Spasova, Darina S; Sarkisyan, Gor; LeRoy, Eric; Tan, Joyce T; Wahlus, Heidi; Bondi-Boyd, Brea; Luther, Sanjiv A; Surh, Charles D

    2016-01-01

    Aging is associated with a gradual loss of naïve T cells and a reciprocal increase in the proportion of memory T cells. While reduced thymic output is important, age-dependent changes in factors supporting naïve T cells homeostasis may also be involved. Indeed, we noted a dramatic decrease in the ability of aged mice to support survival and homeostatic proliferation of naïve T cells. The defect was not due to a reduction in IL-7 expression, but from a combination of changes in the secondary lymphoid environment that impaired naïve T cell entry and access to key survival factors. We observed an age-related shift in the expression of homing chemokines and structural deterioration of the stromal network in T cell zones. Treatment with IL-7/mAb complexes can restore naïve T cell homeostatic proliferation in aged mice. Our data suggests that homeostatic mechanisms that support the naïve T cell pool deteriorate with age. PMID:27480406

  1. Preparation and characterization of anti-HIV nanodrug targeted to microfold cell of gut-associated lymphoid tissue.

    PubMed

    Roy, Upal; Ding, Hong; Pilakka-Kanthikeel, Sudheesh; Raymond, Andrea D; Atluri, Venkata; Yndart, Adriana; Kaftanovskaya, Elena M; Batrakova, Elena; Agudelo, Marisela; Nair, Madhavan

    2015-01-01

    The human immunodeficiency virus 1 (HIV-1) still remains one of the leading life-threatening diseases in the world. The introduction of highly active antiretroviral therapy has significantly reduced disease morbidity and mortality. However, most of the drugs have variable penetrance into viral reservoir sites, including gut-associated lymphoid tissue (GALT). Being the largest lymphoid organ, GALT plays a key role in early HIV infection and host-pathogen interaction. Many different treatment options have been proposed to eradicate the virus from GALT. However, it becomes difficult to deliver traditional drugs to the GALT because of its complex physiology. In this regard, we developed a polymer-based Pluronic nanocarrier containing anti-HIV drug called efavirenz (EFV) targeting Microfold cells (M-cells) in the GALT. M-cells are specialized epithelial cells that are predominantly present in the GALT. In this work, we have exploited this paracellular transport property of M-cells for targeted delivery of Pluronic nanocarrier tagged EFV, bioconjugated with anti-M-cell-specific antibodies to the GALT (nanodrug). Preliminary characterization showed that the nanodrug (EFV-F12-COOH) is of 140 nm size with 0.3 polydispersion index, and the zeta potential of the particles was -19.38±2.2 mV. Further, drug dissolution study has shown a significantly improved sustained release over free drugs. Binding potential of nanodrug with M-cell was also confirmed with fluorescence microscopy and in vitro uptake and release studies. The anti-HIV activity of the nanodrug was also significantly higher compared to that of free drug. This novel formulation was able to show sustained release of EFV and inhibit the HIV-1 infection in the GALT compared to the free drug. The present study has potential for our in vivo targeted nanodrug delivery system by combining traditional enteric-coated capsule technique via oral administration. PMID:26425084

  2. Preparation and characterization of anti-HIV nanodrug targeted to microfold cell of gut-associated lymphoid tissue

    PubMed Central

    Roy, Upal; Ding, Hong; Pilakka-Kanthikeel, Sudheesh; Raymond, Andrea D; Atluri, Venkata; Yndart, Adriana; Kaftanovskaya, Elena M; Batrakova, Elena; Agudelo, Marisela; Nair, Madhavan

    2015-01-01

    The human immunodeficiency virus 1 (HIV-1) still remains one of the leading life-threatening diseases in the world. The introduction of highly active antiretroviral therapy has significantly reduced disease morbidity and mortality. However, most of the drugs have variable penetrance into viral reservoir sites, including gut-associated lymphoid tissue (GALT). Being the largest lymphoid organ, GALT plays a key role in early HIV infection and host–pathogen interaction. Many different treatment options have been proposed to eradicate the virus from GALT. However, it becomes difficult to deliver traditional drugs to the GALT because of its complex physiology. In this regard, we developed a polymer-based Pluronic nanocarrier containing anti-HIV drug called efavirenz (EFV) targeting Microfold cells (M-cells) in the GALT. M-cells are specialized epithelial cells that are predominantly present in the GALT. In this work, we have exploited this paracellular transport property of M-cells for targeted delivery of Pluronic nanocarrier tagged EFV, bioconjugated with anti-M-cell-specific antibodies to the GALT (nanodrug). Preliminary characterization showed that the nanodrug (EFV-F12-COOH) is of 140 nm size with 0.3 polydispersion index, and the zeta potential of the particles was −19.38±2.2 mV. Further, drug dissolution study has shown a significantly improved sustained release over free drugs. Binding potential of nanodrug with M-cell was also confirmed with fluorescence microscopy and in vitro uptake and release studies. The anti-HIV activity of the nanodrug was also significantly higher compared to that of free drug. This novel formulation was able to show sustained release of EFV and inhibit the HIV-1 infection in the GALT compared to the free drug. The present study has potential for our in vivo targeted nanodrug delivery system by combining traditional enteric-coated capsule technique via oral administration. PMID:26425084

  3. An investigation of the use of chromium, platinum and gold coating for scanning electron microscopy of casts of lymphoid tissues.

    PubMed

    Belz, G T; Auchterlonie, G J

    1995-01-01

    Resin casts replicate the internal structure of organs and provide a three-dimensional representation of the arrangement of vessels and intercellular spaces. Casting media are insulators and must be coated with a conductor to prevent sample charging and to allow the adequate production of secondary electrons from the specimen to generate sufficient signal to form a clear image. Visualization of surface structures depends largely on the metal coating. The use of gold or platinum, deposited on Mercox casts of lymphoid tissues using plasma-magnetron sputtering, and of chromium coating of casts by Penning ion-beam coating, was investigated. Casts were examined using a field emission scanning electron microscope at 3-3.5 kV. Thick coatings of gold were necessary to reduce cast charging but they obscured fine structural information. Charging effects were less pronounced when casts were coated with platinum, but charge lines were present at slow scan rates. The dimensions of cast impressions for both platinum and chromium coatings were similar to those described in fixed tissues. Negligible charging and maximal cast thermal stability and structural information was obtained from casts which were tumbled during chromium coating. PMID:7767633

  4. IL-17-producing innate lymphoid cells are restricted to mucosal tissues and are depleted in SIV-infected macaques

    PubMed Central

    Xu, Huanbin; Wang, Xiaolei; Liu, David X.; Moroney-Rasmussen, Terri; Lackner, Andrew A.; Veazey, Ronald S.

    2013-01-01

    SUMMARY Innate lymphoid cells (ILCs) are an emerging subset of lymphocytes involved in surveillance against virally infected cells. Here we show CD3−CD8high lymphocytes in macaque blood include major subsets of ILCs including NK cells expressing CD16, NKp46 and NKG2A, but also populations of ILCs in mucosal tissues having different properties. One ILC subset secreted IL-17 (ILC17), but these were restricted to mucosal tissues. Some mucosal ILC17 cells expressed classical NK-cell markers, but little NKG2A or NKG2D. Some ILC17 cells secreted IL-22 and TNF-α, but few produced IFN-γ or contained granzyme B. IL-17 production by ILCs was induced by IL-6, TGF-β and IL-23. Further, SIV infection resulted in a significant loss of ILC17 cells, especially in the jejunum, which persisted throughout SIV infection. These findings ILC17 cells may be involved in innate mucosal immune responses, and their loss may contribute to loss of intestinal mucosal integrity and disease progression in HIV/SIV infection. PMID:22669579

  5. Noninfectious X4 but not R5 human immunodeficiency virus type 1 virions inhibit humoral immune responses in human lymphoid tissue ex vivo

    NASA Technical Reports Server (NTRS)

    Fitzgerald, Wendy; Sylwester, Andrew W.; Grivel, Jean-Charles; Lifson, Jeffrey D.; Margolis, Leonid B.

    2004-01-01

    Ex vivo human immunodeficiency virus type 1 (HIV-1) infection of human lymphoid tissue recapitulates some aspects of in vivo HIV-1 infection, including a severe depletion of CD4(+) T cells and suppression of humoral immune responses to recall antigens or to polyclonal stimuli. These effects are induced by infection with X4 HIV-1 variants, whereas infection with R5 variants results in only mild depletion of CD4(+) T cells and no suppression of immune responses. To study the mechanisms of suppression of immune responses in this ex vivo system, we used aldrithiol-2 (AT-2)-inactivated virions that have functional envelope glycoproteins but are not infectious and do not deplete CD4(+) T cells in human lymphoid tissues ex vivo. Nevertheless, AT-2-inactivated X4 (but not R5) HIV-1 virions, even with only a brief exposure, inhibit antibody responses in human lymphoid tissue ex vivo, similarly to infectious virus. This phenomenon is mediated by soluble immunosuppressive factor(s) secreted by tissue exposed to virus.

  6. Epithelial Control of Gut-Associated Lymphoid Tissue Formation through p38α-Dependent Restraint of NF-κB Signaling.

    PubMed

    Caballero-Franco, Celia; Guma, Monica; Choo, Min-Kyung; Sano, Yasuyo; Enzler, Thomas; Karin, Michael; Mizoguchi, Atsushi; Park, Jin Mo

    2016-03-01

    The protein kinase p38α mediates cellular responses to environmental and endogenous cues that direct tissue homeostasis and immune responses. Studies of mice lacking p38α in several different cell types have demonstrated that p38α signaling is essential to maintaining the proliferation-differentiation balance in developing and steady-state tissues. The mechanisms underlying these roles involve cell-autonomous control of signaling and gene expression by p38α. In this study, we show that p38α regulates gut-associated lymphoid tissue (GALT) formation in a noncell-autonomous manner. From an investigation of mice with intestinal epithelial cell-specific deletion of the p38α gene, we find that p38α serves to limit NF-κB signaling and thereby attenuate GALT-promoting chemokine expression in the intestinal epithelium. Loss of this regulation results in GALT hyperplasia and, in some animals, mucosa-associated B cell lymphoma. These anomalies occur independently of luminal microbial stimuli and are most likely driven by direct epithelial-lymphoid interactions. Our study illustrates a novel p38α-dependent mechanism preventing excessive generation of epithelial-derived signals that drive lymphoid tissue overgrowth and malignancy. PMID:26792803

  7. DIET REGULATES THE DEVELOPMENT OF GUT-ASSOCIATED LYMPHOID TISSUE IN NEONATAL PIGLETS

    Technology Transfer Automated Retrieval System (TEKTRAN)

    During the immediate postnatal period tissue growth in the pig gastrointestinal tract increases by up to 80%. Controversy exists concerning diet-induced changes to the gut epithelial and immunocytes that occur during weaning. Comparisons of bovine milk protein digestion in 3-week-old piglets and 3-...

  8. [The role of the vascular-associated lymphoid tissue (VALT) network and neovascularization in atherosclerotic carotid plaque].

    PubMed

    Kawahara, Ichiro; Tsutsumi, Keisuke; Nagata, Izumi

    2013-01-01

    As you know, atherosclerosis is a serious public problem and is the leading cause of morbidity and mortality not only in Western countries but also in Asia. Cervical carotid disease is typical atherosclerosis, which is responsible for ischemic stroke. Recently, it has been well established that the risk of an acute event mediated by rupture is predicated by plaque components rather than by the degree of luminal narrowing. Preoperative evaluation of plaque components by some modalities such as magnetic resonance imaging is very important for a decision of the treatment strategy. Generally, vulnerable plaques are characterized by a large lipid core, a thin fibrous cap, and substantial infiltration with inflammatory cells. Recently, evidence is accumulating for a role of the immune system and neovascularization in the progression of atherosclerosis. Neovascularization may act as a conduit for the entry of immune and inflammatory cells. Dendritic cells, macrophages, and T-lymphocytes play a main role in the immune-inflammatory system of atherosclerotic lesions, in which they form the vascular-associated lymphoid tissue (VALT) network together. The immune-inflammatory system in the VALT network plays a role in determining the dynamic balance between collagen degradation and collagen synthesis. On the other hand, some of these consecutive mechanisms related with plaque vulnerability have not yet been clarified. To clarify them, we should keep on researching the formation process of atherosclerotic carotid plaque from the pathohistological viewpoint. PMID:23269250

  9. Primary Sjögren's syndrome initially presenting as submandibular mucosa-associated lymphoid tissue lymphoma: A case report

    PubMed Central

    CHEN, LIANG-YU; TSAI, MING-HSUI; TSAI, LI-TAI; LU, HSIN-MAN; JAN, CHIA-ING

    2016-01-01

    The present study reports the case of a 24-year-old female affected with primary Sjögren's syndrome (pSS), who presented with mucosa-associated lymphoid tissue (MALT) lymphoma of the submandibular gland. Reports of such cases, particularly in young patients, are very rare. The patient, who presented no oral or ocular symptoms prior to the development of the mass, underwent surgical ablation of the gland, and MALT lymphoma was diagnosed by histopathology. Since MALT lymphoma in the submandibular gland is rarely observed in otherwise healthy young females, a rheumatologist and an oncologist were consulted. Following a number of immunological tests, the results of the Schirmer's and Saxon tests were negative. However, the antinuclear antibody test revealed a speckled appearance, and there was also strong positivity for the serological markers of Sjögren's syndrome. Consequently, pSS was diagnosed, despite the fact that the patient did not fulfill all the diagnostic criteria for the disease. Therefore, MALT lymphoma in a single salivary gland should be used as a differential diagnosis for Sjögren's syndrome in young asymptomatic patients. Additionally, a multidisciplinary team is required for the treatment and management of these patients. PMID:26893669

  10. Identification of dendritic cells, B cell and T cell subsets in Tasmanian devil lymphoid tissue; evidence for poor immune cell infiltration into devil facial tumors.

    PubMed

    Howson, Lauren J; Morris, Katrina M; Kobayashi, Takumi; Tovar, Cesar; Kreiss, Alexandre; Papenfuss, Anthony T; Corcoran, Lynn; Belov, Katherine; Woods, Gregory M

    2014-05-01

    The Tasmanian devil is under threat of extinction due to the transmissible devil facial tumor disease (DFTD). This fatal tumor is an allograft that does not induce an immune response, raising questions about the activity of Tasmanian devil immune cells. T and B cell analysis has been limited by a lack of antibodies, hence the need to produce such reagents. Amino acid sequence analysis revealed that CD4, CD8, IgM, and IgG were closely related to other marsupials. Monoclonal antibodies were produced against CD4, CD8, IgM, and IgG by generating bacterial fusion proteins. These, and commercial antibodies against CD1a and CD83, identified T cells, B cells and dendritic cells by immunohistochemistry. CD4(+) and CD8(+) T cells were identified in pouch young thymus, adult lymph nodes, spleen, bronchus- and gut-associated lymphoid tissue. Their anatomical distribution was characteristic of mammalian lymphoid tissues with more CD4(+) than CD8(+) cells in lymph nodes and splenic white pulp. IgM(+) and IgG(+) B cells were identified in adult lymph nodes, spleen, bronchus-associated lymphoid tissue and gut-associated lymphoid tissue, with more IgM(+) than IgG(+) cells. Dendritic cells were identified in lymph node, spleen and skin. This distribution is consistent with eutherian mammals and other marsupials, indicating they have the immune cell subsets for an anti-tumor immunity. Devil facial tumor disease tumors contained more CD8(+) than CD4(+) cells, but in low numbers. There were also low numbers of CD1a(+) and MHC class II(+) cells, but no CD83(+) IgM(+) or IgG(+) B cells, consistent with poor immune cell infiltration. PMID:24664954

  11. Compartmentalization of Total and Virus-Specific Tissue-Resident Memory CD8+ T Cells in Human Lymphoid Organs

    PubMed Central

    Li, Jane; Smith, Corey; Edwards, Jarem; Sierro, Frederic; Feng, Carl G.; Khanna, Rajiv; Bell, Andrew; Hislop, Andrew D.; Tangye, Stuart G.; Rickinson, Alan B.; Gebhardt, Thomas; Britton, Warwick J.

    2016-01-01

    Disruption of T cell memory during severe immune suppression results in reactivation of chronic viral infections, such as Epstein Barr virus (EBV) and Cytomegalovirus (CMV). How different subsets of memory T cells contribute to the protective immunity against these viruses remains poorly defined. In this study we examined the compartmentalization of virus-specific, tissue resident memory CD8+ T cells in human lymphoid organs. This revealed two distinct populations of memory CD8+ T cells, that were CD69+CD103+ and CD69+CD103—, and were retained within the spleen and tonsils in the absence of recent T cell stimulation. These two types of memory cells were distinct not only in their phenotype and transcriptional profile, but also in their anatomical localization within tonsils and spleen. The EBV-specific, but not CMV-specific, CD8+ memory T cells preferentially accumulated in the tonsils and acquired a phenotype that ensured their retention at the epithelial sites where EBV replicates. In vitro studies revealed that the cytokine IL-15 can potentiate the retention of circulating effector memory CD8+ T cells by down-regulating the expression of sphingosine-1-phosphate receptor, required for T cell exit from tissues, and its transcriptional activator, Kruppel-like factor 2 (KLF2). Within the tonsils the expression of IL-15 was detected in regions where CD8+ T cells localized, further supporting a role for this cytokine in T cell retention. Together this study provides evidence for the compartmentalization of distinct types of resident memory T cells that could contribute to the long-term protection against persisting viral infections. PMID:27540722

  12. Compartmentalization of Total and Virus-Specific Tissue-Resident Memory CD8+ T Cells in Human Lymphoid Organs.

    PubMed

    Woon, Heng Giap; Braun, Asolina; Li, Jane; Smith, Corey; Edwards, Jarem; Sierro, Frederic; Feng, Carl G; Khanna, Rajiv; Elliot, Michael; Bell, Andrew; Hislop, Andrew D; Tangye, Stuart G; Rickinson, Alan B; Gebhardt, Thomas; Britton, Warwick J; Palendira, Umaimainthan

    2016-08-01

    Disruption of T cell memory during severe immune suppression results in reactivation of chronic viral infections, such as Epstein Barr virus (EBV) and Cytomegalovirus (CMV). How different subsets of memory T cells contribute to the protective immunity against these viruses remains poorly defined. In this study we examined the compartmentalization of virus-specific, tissue resident memory CD8+ T cells in human lymphoid organs. This revealed two distinct populations of memory CD8+ T cells, that were CD69+CD103+ and CD69+CD103-, and were retained within the spleen and tonsils in the absence of recent T cell stimulation. These two types of memory cells were distinct not only in their phenotype and transcriptional profile, but also in their anatomical localization within tonsils and spleen. The EBV-specific, but not CMV-specific, CD8+ memory T cells preferentially accumulated in the tonsils and acquired a phenotype that ensured their retention at the epithelial sites where EBV replicates. In vitro studies revealed that the cytokine IL-15 can potentiate the retention of circulating effector memory CD8+ T cells by down-regulating the expression of sphingosine-1-phosphate receptor, required for T cell exit from tissues, and its transcriptional activator, Kruppel-like factor 2 (KLF2). Within the tonsils the expression of IL-15 was detected in regions where CD8+ T cells localized, further supporting a role for this cytokine in T cell retention. Together this study provides evidence for the compartmentalization of distinct types of resident memory T cells that could contribute to the long-term protection against persisting viral infections. PMID:27540722

  13. The Innate Lymphoid Cell Precursor.

    PubMed

    Ishizuka, Isabel E; Constantinides, Michael G; Gudjonson, Herman; Bendelac, Albert

    2016-05-20

    The discovery of tissue-resident innate lymphoid cell populations effecting different forms of type 1, 2, and 3 immunity; tissue repair; and immune regulation has transformed our understanding of mucosal immunity and allergy. The emerging complexity of these populations along with compounding issues of redundancy and plasticity raise intriguing questions about their precise lineage relationship. Here we review advances in mapping the emergence of these lineages from early lymphoid precursors. We discuss the identification of a common innate lymphoid cell precursor characterized by transient expression of the transcription factor PLZF, and the lineage relationships of innate lymphoid cells with conventional natural killer cells and lymphoid tissue inducer cells. We also review the rapidly growing understanding of the network of transcription factors that direct the development of these lineages. PMID:27168240

  14. Immunoreactivity for IL-1 beta and TNF alpha in human lymphoid and nonlymphoid tissues.

    PubMed Central

    Ruco, L. P.; Stoppacciaro, A.; Pomponi, D.; Boraschi, D.; Santoni, A.; Tagliabue, A.; Uccini, S.; Baroni, C. D.

    1989-01-01

    Monoclonal antibodies (MAbs) against two non-cross-reacting antigens of human IL-1 beta (Vhp20 and BRhC3) and human TNF alpha (B154.2 and B154.7) were applied to identify cytokine-containing cells in tissue sections and in cell suspensions. IL-1 beta- or TNF alpha-positive cells were not present in immunostained cytocentrifuge smears prepared from freshly isolated peripheral blood leukocytes, spleen, and lymph node cells. After 18 hours of culture with bacterial endotoxin (LPS), 80% to 90% of blood monocytes, 30% of spleen macrophages, and 2% to 28% of lymph node macrophages were strongly positive for IL-1 beta with either of the MAbs. Furthermore, 25% to 35% of blood monocytes and 6% to 60% of lymph node macrophages were stained for TNF alpha. Cells positive for IL-1 beta or TNF alpha were extremely rare in sections of normal thymus, spleen, and lymph nodes. Immunoreactivity for IL-1 beta or TNF alpha was frequently observed in sections of granulomatous lymphadenitis (N = 11). IL-1 beta or TNF alpha staining was confined to the epithelioid macrophages forming the granuloma, and the intensity of TNF alpha reactivity was generally stronger. The high frequency of cytokine-containing cells in this pathologic condition was confirmed in a cell suspension study showing that 20% of epithelioid macrophages were weakly positive for IL-1 beta and 80% were strongly positive for TNF alpha. The presence of cytokine-containing cells was investigated in cryostat sections of several nonlymphoid organs with normal histologic appearance. IL-1 beta reactivity was not observed in any of the tissues. TNF alpha reactivity was frequently demonstrated in isolated macrophages embedded in the interstitial connective tissue. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 PMID:2683798

  15. Distribution of a macaque immunosuppressive type D retrovirus in neural, lymphoid, and salivary tissues.

    PubMed Central

    Lackner, A A; Rodriguez, M H; Bush, C E; Munn, R J; Kwang, H S; Moore, P F; Osborn, K G; Marx, P A; Gardner, M B; Lowenstine, L J

    1988-01-01

    Simian acquired immune deficiency syndrome (SAIDS) in rhesus macaques (Macaca mulatta) at the California Primate Research Center is caused by a type D retrovirus designated SAIDS retrovirus serotype 1 (SRV-1). This syndrome is characterized by profound immunosuppression and death associated with opportunistic infections. Neurologic signs and lesions have not been described as part of this syndrome. The distribution of SRV-1 in the salivary glands, lymph nodes, spleens, thymuses, and brains of eight virus-infected rhesus macaques was examined by immunohistochemistry. Electron microscopy, in situ RNA hybridization, and Southern blot hybridization were also performed on selected tissues to detect viral particles, RNA, and DNA, respectively. In seven of eight SRV-1-infected animals, the transmembrane envelope glycoprotein (gp20) of SRV-1 was present in three or more tissues, but never in the brain. In the remaining animal, no viral antigen was detected in any tissue. In this same group of animals, viral nucleic acid was detected in the lymph nodes of six of six animals by Southern blot hybridization, in the salivary glands of two of five animals by both Southern blot and in situ hybridizations, and, surprisingly, in the brains of three of three animals by Southern blot and of three of five animals by in situ hybridization, including the one animal in which viral gp20 was undetectable. None of these animals had neurologic signs or lesions. The detection of viral nucleic acid in the absence of viral antigen in the brain suggests latent SRV-1 infection of the central nervous system. Images PMID:3285033

  16. Molecular identification of interleukin-2 in the lymphoid tissues of the common brushtail possum, Trichosurus vulpecula.

    PubMed

    Young, L J; Cross, M L; Duckworth, J A; Flenady, S; Belov, K

    2012-01-01

    The common brushtail possum (Trichosurus vulpecula) is an Australian marsupial. Here we describe the identification of possum interleukin-2 in mitogen-stimulated lymph node cells. We used a strategy of Rapid amplification of cDNA ends using probes designed from recently-sequenced marsupial genomes to identify the IL2 gene and then confirmed that IL-2 expression in possum immune tissue occurs in a similar manner to that in their eutherian counterparts. The predictive possum IL-2 peptide showed 28% and 35% amino acid sequence homology with the mouse and human IL-2 molecules, respectively, consistent with the divergence found within this cytokine family. Despite this low sequence identity, possum IL-2 still possessed the characteristic hallmarks of mammalian IL-2, such as a predicted signal peptide and conserved family motifs. PMID:21683733

  17. Pathology and Virus Distribution in the Lung and Lymphoid Tissues of Pigs Experimentally Inoculated with Three Distinct Type 1 PRRS Virus Isolates of Varying Pathogenicity.

    PubMed

    Morgan, S B; Frossard, J P; Pallares, F J; Gough, J; Stadejek, T; Graham, S P; Steinbach, F; Drew, T W; Salguero, F J

    2016-06-01

    Porcine reproductive and respiratory syndrome (PRRS) continues to be the most economically important disease of swine worldwide. The appearance of highly pathogenic PRRS virus (PRRSV) strains in Europe and Asia has raised concerns about this disease and initiated increased efforts to understand the pathogenesis. In this study, we have compared the pathology and the virus distribution in tissues of pigs experimentally inoculated with three different genotype 1 PRRSV isolates. Sixty 5-week-old pigs were inoculated intranasally with a) the Lelystad virus (LV), b) a field strain from the UK causing respiratory clinical signs (UK) or c) a highly pathogenic strain from Belarus (BE). Sixteen animals were mock-infected and used as controls. The animals were euthanized at 3, 7 and 35 days post-infection (dpi), and lung and lymphoid tissues collected for histopathological examination and PRRSV detection by immunohistochemistry (IHC). Histopathological lesions consisted of interstitial pneumonia with mononuclear cell infiltrates in the lungs, lymphoid depletion, apoptosis and follicular hyperplasia in the spleen, lymph nodes and tonsil and lymphoid depletion in the thymus. Porcine reproductive and respiratory syndrome virus was detected mainly in monocytes-macrophages. BE-infected animals showed the highest pathological scores and the highest presence of virus at 3 and 7 dpi, followed by the UK field strain and then LV. Moderate lesions were observed at 35 dpi with lesser detection of PRRSV by IHC in each infected group. The highly pathogenic BE strain induced more severe pathology in both lungs and lymphoid organs of pigs compared with the classic field isolate and the prototype LV. The increased severity of pathology was in correlation with the presence of a higher number of PRRSV-infected cells in the tissues. PMID:25382098

  18. Coexistence of papillary thyroid microcarcinoma and mucosa-associated lymphoid tissue lymphoma in a context of Hashimoto's thyroiditis.

    PubMed

    Levy-Blitchtein, Saul; Plasencia-Rebata, Stefany; Morales Luna, Domingo; Del Valle Mendoza, Juana

    2016-08-01

    Papillary thyroid cancer (PTC) represents 80-85% of thyroid cancer and its prevalence has been rising in the last decades. Primary thyroid lymphoma (PTL) accounts for 3% of extranodal lymphomas and about 5% of thyroid malignancies, having a prevalence of one or two cases per million people. Mucosa-Associated Lymphoid Tissue lymphoma represents approximately 30% of PTL. Both entities have an indolent course and a very good prognosis. Diagnosis is made by ultrasound and fine needle aspiration (FNA) or surgery specimen pathology. They have also been associated with HT, but pathogenesis and its links remains to be known. Treatment remains controversial and surgery is generally accepted in cases of disease limited to thyroid, as the present. Patients with thyroid nodules should be observed and followed. If there is an enlargement by ultrasound or clinical symptoms, FNA should be performed promptly. Patients with Hashimoto's thyroiditis (HT) deserve additional surveillance, since this condition is associated with both PTC and PTL. In this case, the management with surgery and radioactive iodine ablation therapy was effective for both entities. Patients with thyroid nodules should be properly evaluated with ultrasound and thyroid function tests. If there is an enlargement of the neck, reported by symptoms or ultrasound, it requires further investigation. HT is associated to both PTC and PTL so if the enlargement of the nodules is on this context additional tests such as FNA should be performed. In this case, the patient was managed with surgery and radioactive iodine ablation therapy and it was effective for both entities. PMID:27569894

  19. Clinical value of magnetic resonance imaging and other baseline testing for conjunctival mucosa-associated lymphoid tissue lymphoma.

    PubMed

    Nasser, Qasiem J; Pfeiffer, Margaret L; Romaguera, Jorge; Fowler, Nathan; Debnam, J Matthew; Samaniego, Felipe; El-Sawy, Tarek; McLaughlin, Peter; Bakhoum, Mathieu F; Esmaeli, Bita

    2014-05-01

    Abstract The objective of this study was to assess the value of magnetic resonance imaging (MRI) of the orbit for conjunctival mucosa-associated lymphoid tissue (MALT) lymphoma. The yield of other staging tests at baseline were also evaluated. Twenty-one consecutive patients treated for conjunctival MALT lymphoma were retrospectively studied. Lymphoma was staged according to both the Ann Arbor system and the seventh edition of the AJCC [American Joint Committee on Cancer] cancer staging manual. Findings on MRI of the orbit, whole-body positron emission tomography/computed tomography (PET/CT), CT of the chest/abdomen/pelvis, bone marrow (BM) biopsy and gastrointestinal (GI) endoscopy were recorded. Seventeen patients had orbital MRI. Fourteen of 17 patients (82%) with obvious conjunctival MALT lymphoma on clinical examination had a negative MRI scan. Only three patients had subtle conjunctival enhancement on orbital MRI. Ann Arbor stage at presentation was as follows: stage IE (15 patients), stage IIE (two patients) and stage IV (four patients). Eighteen of 21 patients had total-body PET/CT; four patients (22%) had hypermetabolic activity evident on PET scan. All 21 patients had bilateral BM biopsies. Fifteen of 21 patients (71%) had GI endoscopy. None of the patients had a positive BM biopsy or findings on GI endoscopy. Our data suggest that orbital MRI has a very low yield for identification of conjunctival MALT lymphoma. Clinical examination is critical in diagnosing and assessing treatment response in conjunctival MALT lymphoma. The yield for GI endoscopy and BM biopsy may also be low in staging of conjunctival MALT lymphoma. PMID:23879202

  20. Management of Suspicious Mucosa-Associated Lymphoid Tissue Lymphoma in Gastric Biopsy Specimens Obtained during Screening Endoscopy.

    PubMed

    Yang, Hyo-Joon; Lim, Seon Hee; Lee, Changhyun; Choi, Ji Min; Yang, Jong In; Chung, Su Jin; Choi, Seung Ho; Im, Jong Pil; Kim, Sang Gyun; Kim, Joo Sung

    2016-07-01

    It is often difficult to differentiate gastric mucosa-associated lymphoid tissue (MALT) lymphoma from Helicobacter pylori-associated follicular gastritis, and thus, it becomes unclear how to manage these diseases. This study aimed to explore the management strategy for and the long-term outcomes of suspicious gastric MALT lymphoma detected by forceps biopsy during screening upper endoscopy. Between October 2003 and May 2013, consecutive subjects who were diagnosed with suspicious gastric MALT lymphomas by screening endoscopy in a health checkup program in Korea were retrospectively enrolled. Suspicious MALT lymphoma was defined as a Wotherspoon score of 3 or 4 upon pathological evaluation of the biopsy specimen. Of 105,164 subjects who underwent screening endoscopies, 49 patients with suspicious MALT lymphomas who underwent subsequent endoscopy were enrolled. Eight patients received a subsequent endoscopy without H. pylori eradication (subsequent endoscopy only group), and 41 patients received H. pylori eradication first followed by endoscopy (eradication first group). MALT lymphoma development was significantly lower in the eradication first group (2/41, 4.9%) than in the subsequent endoscopy only group (3/8, 37.5%, P = 0.026). Notably, among 35 patients with successful H. pylori eradication, there was only one MALT lymphoma patient (2.9%) in whom complete remission was achieved, and there was no recurrence during a median 45 months of endoscopic follow-up. H. pylori eradication with subsequent endoscopy would be a practical management option for suspicious MALT lymphoma detected in a forceps biopsy specimen obtained during screening upper endoscopy. PMID:27366005

  1. Bone marrow involvement is not associated with the clinical outcomes of gastric mucosa-associated lymphoid tissue lymphoma.

    PubMed

    Gong, Eun Jeong; Ahn, Ji Yong; Jung, Hwoon-Yong; Jung, Kyoungwon; Cho, Charles J; Na, Hee Kyong; Jung, Kee Wook; Kim, Do Hoon; Lee, Jeong Hoon; Choi, Kee Don; Song, Ho June; Lee, Gin Hyug; Kim, Jin-Ho; Yoon, Dok Hyun

    2016-08-01

    Objective Bone marrow (BM) examination is recommended as part of the initial staging work-up in patients with gastric mucosa-associated lymphoid tissue (MALT) lymphoma. However, the clinical significance of BM involvement in gastric MALT lymphoma patients has not been evaluated. Materials and methods From November 1995 to September 2014, 496 subjects who were diagnosed with gastric MALT lymphoma and underwent BM examination were eligible to be included in this study. BM involvement was found in 33 patients (6.7%) by retrospective review, and after exclusions, the clinical outcomes of 28 patients with BM involvement and 412 patients without BM involvement were evaluated. Results When comparing the characteristics of patients, age (median 60 vs. 53 years, p = 0.007) and Helicobacter pylori infection rate (71.0% vs. 85.5%, p = 0.040) were different between patients with and without BM involvement, while the location, macroscopic findings, and depth of invasion were similar. The overall complete remission (CR) rate was 85.2% during a median follow-up period of 42 months (interquartile range, 23-66 months) and did not differ between the two groups (78.6 and 85.7%, p = 0.280). Eradication therapy was performed as the first-line treatment in 18 of the 28 patients (64.3%) with BM involvement, and CR was achieved in 13 patients (72.2%). Logistic regression analysis showed that age and location in the upper part of the stomach were factors related to remission failure. Conclusion Gastric MALT lymphoma has a favorable outcome, and eradication therapy can be justified in selected cases even with BM involvement, when these patients are closely monitored. PMID:27149022

  2. Management of Suspicious Mucosa-Associated Lymphoid Tissue Lymphoma in Gastric Biopsy Specimens Obtained during Screening Endoscopy

    PubMed Central

    2016-01-01

    It is often difficult to differentiate gastric mucosa-associated lymphoid tissue (MALT) lymphoma from Helicobacter pylori-associated follicular gastritis, and thus, it becomes unclear how to manage these diseases. This study aimed to explore the management strategy for and the long-term outcomes of suspicious gastric MALT lymphoma detected by forceps biopsy during screening upper endoscopy. Between October 2003 and May 2013, consecutive subjects who were diagnosed with suspicious gastric MALT lymphomas by screening endoscopy in a health checkup program in Korea were retrospectively enrolled. Suspicious MALT lymphoma was defined as a Wotherspoon score of 3 or 4 upon pathological evaluation of the biopsy specimen. Of 105,164 subjects who underwent screening endoscopies, 49 patients with suspicious MALT lymphomas who underwent subsequent endoscopy were enrolled. Eight patients received a subsequent endoscopy without H. pylori eradication (subsequent endoscopy only group), and 41 patients received H. pylori eradication first followed by endoscopy (eradication first group). MALT lymphoma development was significantly lower in the eradication first group (2/41, 4.9%) than in the subsequent endoscopy only group (3/8, 37.5%, P = 0.026). Notably, among 35 patients with successful H. pylori eradication, there was only one MALT lymphoma patient (2.9%) in whom complete remission was achieved, and there was no recurrence during a median 45 months of endoscopic follow-up. H. pylori eradication with subsequent endoscopy would be a practical management option for suspicious MALT lymphoma detected in a forceps biopsy specimen obtained during screening upper endoscopy. PMID:27366005

  3. [Shengqifuzheng Injection promotes the recovery of B cells in gut-associated lymphoid tissues of mice treated with cyclophosphamide].

    PubMed

    Deng, Xiangliang; Huang, Rongrong; Wen, Ruyan; Luo, Xia; Zhou, Lian

    2016-08-01

    Objective To investigate the effect of Shengqifuzheng Injection (SQFZ) on the number recovery of B cells in gut-associated lymphoid tissues (GALTs) of mice receiving cyclophosphamide-based chemotherapy. Methods BALB/c mice were randomly divided into control group, cyclophosphamide (Cy) group and SQFZ group. Mice in Cy group and SQFZ group were injected intraperitoneally with Cy (100 mg/kg), while the control mice were injected with an equal volume of normal saline. Twenty-four hours later, mice in SQFZ group were administrated intragastricly with 1 mL SQFZ once daily for 10 consecutive days, and mice in the other groups were given the same volume of normal saline. Body mass of all the mice was measured every day. Mice were killed on day 10, and the indexes of spleen and thymus were measured. Cell cycles of bone marrow cells and the percentage of B cells in lymphocytes in mesenteric lymph node (MLN) and Peyer's patch (PP) were detected by flow cytometry. In vitro, after being treated with SQFZ, activity of lymphocytes was evaluzed by MTT assay; expression of CD86 on B cell surface was analyzed by flow cytometry; and B cell proliferation was tested by carboxyfluorescein succinimidyl ester (CFSE)-based lymphocyte proliferation assay. Results SQFZ alleviated the loss of body mass caused by Cy and promoted the recovery of thymus indexes, spleen indexes and B cell number in MLN and PP. But it did not alleviate the bone marrow suppression of mice in this condition. In vitro, SQFZ enhanced lymphocyte activity, and improved the activation and proliferation of B cells. Conclusion SQFZ could accelerate the recovery of B cells in GALTs of mice receiving chemotherapy and it might act by promoting B cell proliferation. PMID:27412939

  4. Early occurrence of apoptosis in lymphoid tissues from chickens infected with strains of Newcastle disease virus of varying virulence

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Newcastle disease virus (NDV), the causative agent of Newcastle disease, is a prevalent problem in the poultry industry and often the cause of severe economic loss. There are many strains of the virus and these have varying virulence. The most virulent strains cause systemic lesions of lymphoid ti...

  5. Evaluation of the clinical characteristics, management, and prognosis of 103 patients with gastric mucosa-associated lymphoid tissue lymphoma

    PubMed Central

    LI, XIAOWU; WANG, XIANG; ZHAN, ZHONGLI; ZHANG, LIANYU; SUN, BAOCHUN; ZHANG, YIZHUO

    2016-01-01

    The diagnosis of gastric mucosa-associated lymphoid tissue (MALT) lymphoma is difficult owing to its non-specific symptoms and various endoscopic findings. Treatments such as radiotherapy (RT) for localized and chemotherapy (CT) for advanced stages of the disease are employed. The aim of the present study was to examine the clinical characteristics and prognostic factors of Helicobacter pylori (H. pylori) eradication (HPE) in patients with gastric MALT lymphoma. The medical records of 103 patients with gastric MALT lymphoma for the period 2001–2013, were analyzed. The 103 median age of the patients was 53 years and the male to female ratio was 1:1. Serum lactate dehydrogenase and β2-microglobulin were within normal range. Macroscopically, the most commonly involved site was the antrum, followed by the corpus and fundus. A total of 97 patients (94%) tested positive for H. pylori. Forty patients (39%) had stage I, 35 patients (35%) had local or distant nodal involvement, 20 of 103 patients had stage IIIE (19%) and 8 of 103 patients had stage IV (7%) disease. Complete remission, after HPE, was achieved in 54 of the 69 patients (78%) that were H. pylori-positive and in 2 of the 4 patients (50%) that were H. pylori-negative. HPE had a superior trend in the H. pylori-positive patients although no significant difference was identified in the two groups (p=0.194). In patients with advanced disease, the 5-year progression-free survival (PFS) and overall survival (OS) estimates were significantly improoved for patients receiving HPE with CT or RT than those receiving CT or RT (p=0.046 and 0.035, respectively). The multivariate analysis revealed that, the advanced stages were independently associated with shorter PFS, and the modified-International Prognostic Index (m-IPI) (≥2) was associated with shorter OS. In conclusion, gastric MALT lymphoma had a favorable outcome with a high OS rate. HPE was an effective treatment for gastric MALT lymphoma. The patients with

  6. Primary Mucosa-Associated Lymphoid Tissue Lymphoma of the Salivary Glands: A Multicenter Rare Cancer Network Study

    SciTech Connect

    Anacak, Yavuz; Miller, Robert C.; Constantinou, Nikos; Mamusa, Angela M.; Epelbaum, Ron; Li Yexiong; Calduch, Anna Lucas; Kowalczyk, Anna; Weber, Damien C.; Kadish, Sidney P.; Poortmans, Philip; Kamer, Serra; Ozsahin, Mahmut

    2012-01-01

    Purpose: Involvement of salivary glands with mucosa-associated lymphoid tissue (MALT) lymphoma is rare. This retrospective study was performed to assess the clinical profile, treatment outcome, and prognostic factors of MALT lymphoma of the salivary glands. Methods and Materials: Thirteen member centers of the Rare Cancer Network from 10 countries participated, providing data on 63 patients. The median age was 58 years; 47 patients were female and 16 were male. The parotid glands were involved in 49 cases, submandibular in 15, and minor glands in 3. Multiple glands were involved in 9 patients. Staging was as follows: IE in 34, IIE in 12, IIIE in 2, and IV in 15 patients. Results: Surgery (S) alone was performed in 9, radiotherapy (RT) alone in 8, and chemotherapy (CT) alone in 4 patients. Forty-one patients received combined modality treatment (S + RT in 23, S + CT in 8, RT + CT in 4, and all three modalities in 6 patients). No active treatment was given in one case. After initial treatment there was no tumor in 57 patients and residual tumor in 5. Tumor progression was observed in 23 (36.5%) (local in 1, other salivary glands in 10, lymph nodes in 11, and elsewhere in 6). Five patients died of disease progression and the other 5 of other causes. The 5-year disease-free survival, disease-specific survival, and overall survival were 54.4%, 93.2%, and 81.7%, respectively. Factors influencing disease-free survival were use of RT, stage, and residual tumor (p < 0.01). Factors influencing disease-specific survival were stage, recurrence, and residual tumor (p < 0.01). Conclusions: To our knowledge, this report represents the largest series of MALT lymphomas of the salivary glands published to date. This disease may involve all salivary glands either initially or subsequently in 30% of patients. Recurrences may occur in up to 35% of patients at 5 years; however, survival is not affected. Radiotherapy is the only treatment modality that improves disease-free survival.

  7. Primary rectal mucosa-associated lymphoid tissue lymphoma in a patient with previously identified primary biliary cirrhosis and secondary Sjögren's syndrome.

    PubMed

    Kawashima, Kazumasa; Katakura, Kyoko; Takahashi, Yuta; Asama, Hiroyuki; Fujiwara, Tatsuo; Kumakawa, Hiromi; Ohira, Hiromasa

    2016-06-01

    An 83-year-old female began treatment with prednisolone and ursodeoxycholic acid at 62 years of age, following a diagnosis of primary biliary cirrhosis (PBC) and secondary Sjögren's syndrome (SjS). With persisting bloody stools, the patient underwent colonoscopy at 83 years of age. Histopathological evaluation revealed mucosa-associated lymphoid tissue (MALT) lymphoma. The elevated rectal lesion resolved with rituximab treatment. We report this case because although patients with SjS are at increased risk of malignant lymphoma, primary rectal MALT lymphoma is very uncommon in association with PBC and secondary SjS. PMID:27037914

  8. Bioengineering of Artificial Lymphoid Organs

    PubMed Central

    Nosenko, M. A.; Drutskaya, M. S.; Moisenovich, M. M.; Nedospasov, S. A.

    2016-01-01

    This review addresses the issue of bioengineering of artificial lymphoid organs.Progress in this field may help to better understand the nature of the structure-function relations that exist in immune organs. Artifical lymphoid organs may also be advantageous in the therapy or correction of immunodefficiencies, autoimmune diseases, and cancer. The structural organization, development, and function of lymphoid tissue are analyzed with a focus on the role of intercellular contacts and on the cytokine signaling pathways regulating these processes. We describe various polymeric materials, as scaffolds, for artificial tissue engineering. Finally, published studies in which artificial lymphoid organs were generated are reviewed and possible future directions in the field are discussed. PMID:27437136

  9. Nanodrug formulations to enhance HIV drug exposure in lymphoid tissues and cells: clinical significance and potential impact on treatment and eradication of HIV/AIDS.

    PubMed

    Shao, Jingwei; Kraft, John C; Li, Bowen; Yu, Jesse; Freeling, Jennifer; Koehn, Josefin; Ho, Rodney Jy

    2016-01-01

    Although oral combination antiretroviral therapy effectively clears plasma HIV, patients on oral drugs exhibit much lower drug concentrations in lymph nodes than blood. This drug insufficiency is linked to residual HIV in cells of lymph nodes. While nanoformulations improve drug solubility, safety and delivery, most HIV nanoformulations are intended to extend plasma levels. A stable nanodrug combination that transports, delivers and accumulates in lymph nodes is needed to clear HIV in lymphoid tissues. This review discusses limitations of current oral combination antiretroviral therapy and advances in anti-HIV nanoformulations. A 'systems approach' has been proposed to overcome these limitations. This concept has been used to develop nanoformulations for overcoming drug insufficiency, extending cell and tissue exposure and clearing virus for treating HIV/AIDS. PMID:26892323

  10. Compartmentalization of simian immunodeficiency virus replication within secondary lymphoid tissues of rhesus macaques is linked to disease stage and inversely related to localization of virus-specific CTL.

    PubMed

    Connick, Elizabeth; Folkvord, Joy M; Lind, Katherine T; Rakasz, Eva G; Miles, Brodie; Wilson, Nancy A; Santiago, Mario L; Schmitt, Kimberly; Stephens, Edward B; Kim, Hyeon O; Wagstaff, Reece; Li, Shengbin; Abdelaal, Hadia M; Kemp, Nathan; Watkins, David I; MaWhinney, Samantha; Skinner, Pamela J

    2014-12-01

    We previously demonstrated that HIV replication is concentrated in lymph node B cell follicles during chronic infection and that HIV-specific CTL fail to accumulate in large numbers at those sites. It is unknown whether these observations can be generalized to other secondary lymphoid tissues or whether virus compartmentalization occurs in the absence of CTL. We evaluated these questions in SIVmac239-infected rhesus macaques by quantifying SIV RNA(+) cells and SIV-specific CTL in situ in spleen, lymph nodes, and intestinal tissues obtained at several stages of infection. During chronic asymptomatic infection prior to simian AIDS, SIV-producing cells were more concentrated in follicular (F) compared with extrafollicular (EF) regions of secondary lymphoid tissues. At day 14 of infection, when CTL have minimal impact on virus replication, there was no compartmentalization of SIV-producing cells. Virus compartmentalization was diminished in animals with simian AIDS, which often have low-frequency CTL responses. SIV-specific CTL were consistently more concentrated within EF regions of lymph node and spleen in chronically infected animals regardless of epitope specificity. Frequencies of SIV-specific CTL within F and EF compartments predicted SIV RNA(+) cells within these compartments in a mixed model. Few SIV-specific CTL expressed the F homing molecule CXCR5 in the absence of the EF retention molecule CCR7, possibly accounting for the paucity of F CTL. These findings bolster the hypothesis that B cell follicles are immune privileged sites and suggest that strategies to augment CTL in B cell follicles could lead to improved viral control and possibly a functional cure for HIV infection. PMID:25362178

  11. Effect of IL-4 on the Development and Function of Memory-like CD8 T Cells in the Peripheral Lymphoid Tissues.

    PubMed

    Park, Hi-Jung; Lee, Ara; Lee, Jae-Il; Park, Seong Hoe; Ha, Sang-Jun; Jung, Kyeong Cheon

    2016-04-01

    Unlike conventional T cells, innate CD8 T cells develop a memory-like phenotype in the thymus and immediately respond upon antigen stimulation, similar to memory T cells. The development of innate CD8 T cells in the thymus is known to require IL-4, which upregulates Eomesodermin (Eomes). These features are similar to that of virtual memory CD8 T cells and IL-4-induced memory-like CD8 T cells generated in the peripheral tissues. However, the relationship between these cell types has not been clearly documented. In the present study, IL-4-induced memory-like CD8 T cells generated in the peripheral tissues were compared with innate CD8 T cells in terms of phenotype and function. When an IL-4/anti-IL-4 antibody complex (IL-4C) was injected into C57BL/6 mice daily for 7 days, the Eomes(hi)CXCR3 (+) CD8 T cell population was markedly increased in the peripheral lymphoid organs and blood. These cells were generated from naïve CD8 T cells or accumulated via the expansion of pre-existing CD44(hi)CXCR3 (+) CD8 T cells. Initially, the majority of these CXCR3 (+) CD8 T cells expressed low levels of CD44, which was followed by the conversion to the CD44(hi) phenotype. This conversion was associated with the acquisition of enhanced effector function. After discontinuation of IL-4C treatment, Eomes expression levels gradually decreased in CXCR3 (+) CD8 T cells. Taken together, the results of this study demonstrate that IL-4-induced memory-like CD8 T cells generated in the peripheral lymphoid tissues are phenotypically and functionally similar to the innate CD8 T cells generated in the thymus. PMID:27162529

  12. Effect of IL-4 on the Development and Function of Memory-like CD8 T Cells in the Peripheral Lymphoid Tissues

    PubMed Central

    Park, Hi-Jung; Lee, Ara; Lee, Jae-Il; Park, Seong Hoe

    2016-01-01

    Unlike conventional T cells, innate CD8 T cells develop a memory-like phenotype in the thymus and immediately respond upon antigen stimulation, similar to memory T cells. The development of innate CD8 T cells in the thymus is known to require IL-4, which upregulates Eomesodermin (Eomes). These features are similar to that of virtual memory CD8 T cells and IL-4-induced memory-like CD8 T cells generated in the peripheral tissues. However, the relationship between these cell types has not been clearly documented. In the present study, IL-4-induced memory-like CD8 T cells generated in the peripheral tissues were compared with innate CD8 T cells in terms of phenotype and function. When an IL-4/anti-IL-4 antibody complex (IL-4C) was injected into C57BL/6 mice daily for 7 days, the EomeshiCXCR3 + CD8 T cell population was markedly increased in the peripheral lymphoid organs and blood. These cells were generated from naïve CD8 T cells or accumulated via the expansion of pre-existing CD44hiCXCR3 + CD8 T cells. Initially, the majority of these CXCR3 + CD8 T cells expressed low levels of CD44, which was followed by the conversion to the CD44hi phenotype. This conversion was associated with the acquisition of enhanced effector function. After discontinuation of IL-4C treatment, Eomes expression levels gradually decreased in CXCR3 + CD8 T cells. Taken together, the results of this study demonstrate that IL-4-induced memory-like CD8 T cells generated in the peripheral lymphoid tissues are phenotypically and functionally similar to the innate CD8 T cells generated in the thymus. PMID:27162529

  13. Vpu serine 52 dependent counteraction of tetherin is required for HIV-1 replication in macrophages, but not in ex vivo human lymphoid tissue

    PubMed Central

    2010-01-01

    Background The human immunodeficiency virus type 1 (HIV-1) Vpu protein degrades CD4 and counteracts a restriction factor termed tetherin (CD317; Bst-2) to enhance virion release. It has been suggested that both functions can be genetically separated by mutation of a serine residue at position 52. However, recent data suggest that the S52 phosphorylation site is also important for the ability of Vpu to counteract tetherin. To clarify this issue, we performed a comprehensive analysis of HIV-1 with a mutated casein kinase-II phosphorylation site in Vpu in various cell lines, primary blood lymphocytes (PBL), monocyte-derived macrophages (MDM) and ex vivo human lymphoid tissue (HLT). Results We show that mutation of serine 52 to alanine (S52A) entirely disrupts Vpu-mediated degradation of CD4 and strongly impairs its ability to antagonize tetherin. Furthermore, casein-kinase II inhibitors blocked the ability of Vpu to degrade tetherin. Overall, Vpu S52A could only overcome low levels of tetherin, and its activity decreased in a manner dependent on the amount of transiently or endogenously expressed tetherin. As a consequence, the S52A Vpu mutant virus was unable to replicate in macrophages, which express high levels of this restriction factor. In contrast, HIV-1 Vpu S52A caused CD4+ T-cell depletion and spread efficiently in ex vivo human lymphoid tissue and PBL, most likely because these cells express comparably low levels of tetherin. Conclusion Our data explain why the effect of the S52A mutation in Vpu on virus release is cell-type dependent and suggest that a reduced ability of Vpu to counteract tetherin impairs HIV-1 replication in macrophages, but not in tissue CD4+ T cells. PMID:20078884

  14. Lymphoid follicles of the ileal Peyer's patch of lambs express low levels of PrP, as demonstrated by quantitative real-time RT-PCR on microdissected tissue compartments, in situ hybridization and immunohistochemistry.

    PubMed

    Austbø, Lars; Espenes, Arild; Olsaker, Ingrid; Press, Charles McL; Skretting, Grethe

    2006-11-01

    The expression level of normal cellular prion protein (PrP(C)) is thought to influence the transmission of transmissible spongiform encephalopathies (TSEs) from the peripheral entry site to the site of pathological changes in the central nervous system. In many TSEs, the clinical disease is preceded by a period in which the agent accumulates in lymphoid organs, particularly in association with follicular dendritic cells of lymphoid follicles. As the probable route of entry of the TSE agent is via the gut, the expression profile of PrP was examined in well-developed gut-associated lymphoid tissue of lambs, the ileal Peyer's patch, by laser microdissection and real-time RT-PCR. Lymphoid follicles were found to have very low levels of expression, whilst highest levels were detected in the outer submucosa and the muscular layer. These findings were supported by in situ hybridization and immunohistochemistry, which showed specific labelling in nerve cells in ganglia of the submucosal (Meissner's) and myenteric (Auerbach's) plexi of the enteric nervous system. Based on the assumption that potential sites for conversion to the scrapie-related prion protein (PrP(Sc)) should display high levels of expression of PrP(C), this study suggests that the accumulation of PrP(Sc) in the lymphoid follicles of the Peyer's patch is not preceded by PrP conversion in the same tissue compartment. PMID:17030883

  15. Primary colorectal lymphoma comprising both components of diffuse large B-cell lymphoma and mucosa-associated lymphoid tissue lymphoma combined with cytomegalovirus colitis.

    PubMed

    Katsumata, Ryo; Matsumoto, Hiroshi; Motoyasu, Osawa; Murao, Takahisa; Ishii, Manabu; Fujita, Minoru; Tokunaga, Hirotoshi; Akiyama, Takashi; Wada, Hideho; Sugihara, Takashi; Shiotani, Akiko; Haruma, Ken

    2016-04-01

    A 16-year-old girl presented to our hospital with diarrhea and abdominal pain. The macroscopic findings of colonoscopy revealed multiple submucosal tumors and multiple ulcers, which were localized in the sigmoid colon, and diffuse granular mucosa which extended to the total colon. The pathological diagnosis was malignant lymphoma comprising both components of diffuse large B-cell lymphoma (DLBCL) and mucosa-associated lymphoid tissue (MALT) lymphoma, because the large lymphoma cells were CD20+, CD10-, and CD5-. Furthermore, immunohistochemical analysis of colorectal biopsy samples from multiple ulcers revealed cytomegalovirus (CMV)-positive cells. The patient was diagnosed with primary colorectal lymphoma comprising both components of DLBCL and MALT lymphoma combined with CMV colitis. She received anti-viral medication and chemotherapy. PMID:27015999

  16. Localization of collagen modifying enzymes on fibroblastic reticular cells and follicular dendritic cells in non-neoplastic and neoplastic lymphoid tissues.

    PubMed

    Ohe, Rintaro; Aung, Naing Ye; Meng, Hongxue; Kabasawa, Takanobu; Suto, Aya; Tamazawa, Nobuyuki; Yang, Suran; Kato, Tomoya; Yamakawa, Mitsunori

    2016-07-01

    The aim of this study was to evaluate the localization of collagen modifying enzymes (CMEs) on fibroblastic reticular cells (FRCs) and follicular dendritic cells (FDCs) in non-neoplastic lymphoid tissues and various malignant lymphomas. The expression of prolyl 4-hydroxylase 1 (P4H1), lysyl hydroxylase 3 (LH3), and protein disulfide isomerase (PDI) was frequently observed on FRCs and FDCs in the germinal center (GC), except for the mantle zone. The expression of CMEs was lower in most lymphomas than in their respective postulated normal counterparts. The ratio of transglutaminase II(+) FRCs/CD35(+) FDCs was also lower in follicular lymphomas (FL) than in other lymphomas. The mRNAs of some CMEs (P4H1, prolyl 4-hydroxylase 3, LH3, and heat shock protein 47) were confirmed in almost all lymphomas. These results indicate that lymphoma cell proliferation suppresses/decreases the number of CMEs expressing FRCs and FDCs in most lymphomas. PMID:26700650

  17. Cell-to-cell transmission of HIV-1 is required to trigger pyroptotic death of lymphoid tissue-derived CD4 T cells

    PubMed Central

    Monroe, Kathryn M.; Yang, Zhiyuan; Muñoz-Arias, Isa; Levy, David N; Greene, Warner C.

    2015-01-01

    The progressive depletion of CD4 T cells underlies clinical progression to AIDS in untreated HIV-infected subjects. Most dying CD4 T cells correspond to resting nonpermissive cells residing in lymphoid tissues. Death is due to an innate immune response against the incomplete cytosolic viral DNA intermediates accumulating in these cells. The viral DNA is detected by the IFI16 sensor leading to inflammasome assembly, caspase 1 activation, and the induction of pyroptosis, a highly inflammatory form of programmed cell death. We now show that cell-to-cell transmission of HIV is obligatorily required for activation of this death pathway. Cell-free HIV-1 virions, even when added in large quantities, fail to activate pyroptosis. These findings underscore the infected CD4 T cells as the major killing units promoting progression to AIDS and highlight a previously unappreciated role for the virological synapse in HIV pathogenesis. PMID:26321639

  18. Diffuse large B-cell lymphoma transformed from mucosa-associated lymphoid tissue lymphoma arising in a female urethra treated with rituximab for the first time.

    PubMed

    Zahrani, A Al; Abdelsalam, M; Fiaar, A Al; Ibrahim, N; Al-Elawi, A; Muhammad, B

    2012-05-01

    A 30-year-old female patient presented to the gynecology clinic with a small (painless) swelling at the urethral orifice. She underwent surgical excision of the lesion. Pathological examination revealed non-Hodgkin's lymphoma of diffuse large B-cell type and mucosa-associated lymphoid tissue type, stage IE. The patient refused radiotherapy. Accordingly, we started CHOP-R chemotherapy. She received a total of 6 cycles of CHOP and 8 cycles of rituximab. Patient follow-up was done 3 months later through CT scan and cytoscopy confirming the complete remission. The patient has been disease-free for 4 years. We reviewed 26 cases of this rare entity reported previously. PMID:22679430

  19. Localization of collagen modifying enzymes on fibroblastic reticular cells and follicular dendritic cells in non-neoplastic and neoplastic lymphoid tissues

    PubMed Central

    Ohe, Rintaro; Aung, Naing Ye; Meng, Hongxue; Kabasawa, Takanobu; Suto, Aya; Tamazawa, Nobuyuki; Yang, Suran; Kato, Tomoya; Yamakawa, Mitsunori

    2016-01-01

    Abstract The aim of this study was to evaluate the localization of collagen modifying enzymes (CMEs) on fibroblastic reticular cells (FRCs) and follicular dendritic cells (FDCs) in non-neoplastic lymphoid tissues and various malignant lymphomas. The expression of prolyl 4-hydroxylase 1 (P4H1), lysyl hydroxylase 3 (LH3), and protein disulfide isomerase (PDI) was frequently observed on FRCs and FDCs in the germinal center (GC), except for the mantle zone. The expression of CMEs was lower in most lymphomas than in their respective postulated normal counterparts. The ratio of transglutaminase II+ FRCs/CD35+ FDCs was also lower in follicular lymphomas (FL) than in other lymphomas. The mRNAs of some CMEs (P4H1, prolyl 4-hydroxylase 3, LH3, and heat shock protein 47) were confirmed in almost all lymphomas. These results indicate that lymphoma cell proliferation suppresses/decreases the number of CMEs expressing FRCs and FDCs in most lymphomas. PMID:26700650

  20. Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue type arising in the pleura with pleural fibrous plaques in a lathe worker.

    PubMed

    Nakatsuka, Shin-ichi; Nagano, Teruaki; Kimura, Hayato; Hanada, Shoji; Inoue, Hidetoshi; Iwata, Takashi

    2012-06-01

    Our patient was an 86-year-old man who had worked as a lathe operator for 40 years. He had no history of tuberculosis, pyothorax, or autoimmune disease. He had not been exposed to asbestos. He was asymptomatic, but an imaging study showed gradually increasing pleural plaques. A biopsy specimen of a pleural lesion showed sclerosis of the pleura and diffuse infiltration of small- to medium-sized B lymphocytes. Polymerase chain reaction-based analysis detected monoclonal rearrangement of immunoglobulin heavy-chain genes. Histologic diagnosis was extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue type (MALT lymphoma). The lymphoma was negative for Epstein-Barr virus. We report a rare case of a metal worker with MALT lymphoma arising in the pleura with pleural fibrous plaques. It is speculated that MALT lymphoma might develop in the background of pneumoconiosis. Inflammatory and/or immunologic reactions to metal particles might contribute to the oncogenesis of this tumor. PMID:21546297

  1. Gamma heavy chain disease in man: synthesis of a deleted gamma3 immunoglobulin by lymphoid cells in short and long term tissue culture.

    PubMed Central

    Buxbaum, J N; Alexander, A; Olivier, O

    1978-01-01

    Bone marrow cells were obtained from a patient with gamma heavy chain disease (HCD) whose serum contained a deleted immunoglobulin heavy chain. Incubation of the marrow cells with radioactive amino acids in short term tissue culture resulted in the synthesis of the labelled HCD protein. A permanent cell line was established from the peripheral blood of the patient. Similar labelling studies with the cell line and its cloned progeny demonstrated the synthesis of a protein identical in size and antigenicity to that synthesized by the marrow cells and found in the patient's serum. These experiments clearly demonstrated that, in this case of heavy chain disease, the deleted protein was the synthetic product of a clone of malignant lymphoid cells. Images FIG. 5 FIG. 7 PMID:80297

  2. Complex expression patterns of lymphocyte-specific genes during the development of cartilaginous fish implicate unique lymphoid tissues in generating an immune repertoire

    NASA Technical Reports Server (NTRS)

    Miracle, A. L.; Anderson, M. K.; Litman, R. T.; Walsh, C. J.; Luer, C. A.; Rothenberg, E. V.; Litman, G. W.

    2001-01-01

    Cartilaginous fish express canonical B and T cell recognition genes, but their lymphoid organs and lymphocyte development have been poorly defined. Here, the expression of Ig, TCR, recombination-activating gene (Rag)-1 and terminal deoxynucleosidase (TdT) genes has been used to identify roles of various lymphoid tissues throughout development in the cartilaginous fish, Raja eglanteria (clearnose skate). In embryogenesis, Ig and TCR genes are sharply up-regulated at 8 weeks of development. At this stage TCR and TdT expression is limited to the thymus; later, TCR gene expression appears in peripheral sites in hatchlings and adults, suggesting that the thymus is a source of T cells as in mammals. B cell gene expression indicates more complex roles for the spleen and two special organs of cartilaginous fish-the Leydig and epigonal (gonad-associated) organs. In the adult, the Leydig organ is the site of the highest IgM and IgX expression. However, the spleen is the first site of IgM expression, while IgX is expressed first in gonad, liver, Leydig and even thymus. Distinctive spatiotemporal patterns of Ig light chain gene expression also are seen. A subset of Ig genes is pre-rearranged in the germline of the cartilaginous fish, making expression possible without rearrangement. To assess whether this allows differential developmental regulation, IgM and IgX heavy chain cDNA sequences from specific tissues and developmental stages have been compared with known germline-joined genomic sequences. Both non-productively rearranged genes and germline-joined genes are transcribed in the embryo and hatchling, but not in the adult.

  3. T cell engraftment in lymphoid tissues of human peripheral blood lymphocyte reconstituted SCID mice with or without prior activation of cells.

    PubMed

    Olive, C; Cheung, C; Falk, M C

    1998-12-01

    The reconstitution of severe combined immunodeficiency (SCID) mice with human PBL (Hu-PBL-SCID) was assessed using fresh unstimulated PBL and anti-CD3-stimulated PBL. Mice were reconstituted with PBL by intraperitoneal injection of 1-2.5 x 107 PBL in PBS; controls received PBS. Successful engraftment of human PBL in SCID mice was determined by measurement of human IgG in mouse sera, polymerase chain reaction (PCR) detection of human-specific HLA-DRbeta DNA in SCID periphery, and immunohistochemical staining of mouse tissues (spleen, lymph nodes, thymus, liver and lung) with antibodies specific for human CD45 and CD3. Human IgG was detected 1 week after reconstitution in sera of all animals that received at least 1 x 107 PBL and continued to increase for 8 weeks. Human-specific HLA-DRbeta DNA was detected in the majority of mice 3 weeks after reconstitution but not in controls. Moreover, immunohistochemical analysis of Hu-PBL-SCID mouse tissues revealed the presence of human CD45+ cells in all tissues examined. CD3+ T cell engraftment was observed in lymphoid tissues irrespective of whether PBL had been activated prior to transfer or not. PMID:9893029

  4. Characterization of tuberculous granulomas in different stages of progression and associated tertiary lymphoid tissue in goats experimentally infected with Mycobacterium avium subsp. hominissuis.

    PubMed

    Schinköthe, Jan; Köhler, Heike; Liebler-Tenorio, Elisabeth M

    2016-08-01

    Oral infection of goats with Mycobacterium avium subsp. hominissuis (MAH) resulted in a large variety of granulomas in organized gut-associated lymphatic tissues and intestinal lymph nodes. To characterize the cellular composition of granulomas, CD4(+), CD8(+), γδ, B lymphocytes and plasma, CD25(+), CD68(+), MHC-II(+), Ki67(+) and endothelial cells were labeled in consecutive frozen sections by immunohistochemistry and acid fast bacilli (AFB) by Kinyoun stain. Granulomas with extensive necrosis, little mineralization and variable numbers of AFB surrounded by many CD4(+) T cells, but only few epitheloid macrophages were observed in severely sick goats at 2-3mpi. They were interpreted as exuberant immune reaction. Organized granulomas with very few AFB were seen in clinically healthy goats at 13mpi. The necrotic cores were surrounded by a zone of granulomatous infiltrate with many epitheloid macrophages and few lymphocytes. This zone was initially wide and highly vascularized and became progressively smaller. It was enclosed by an increasing layer of connective tissue. All organized granulomas were surrounded by compartimentalized tertiary lymphoid tissue. The granulomas in experimental infection of goats with MAH reflect the heterogeneity of lesions seen in mycobacterial infections of humans and ruminants and are therefore valuable for comparative research. PMID:27477506

  5. The Gut-Associated Lymphoid Tissues in the Small Intestine, Not the Large Intestine, Play a Major Role in Oral Prion Disease Pathogenesis

    PubMed Central

    Donaldson, David S.; Else, Kathryn J.

    2015-01-01

    ABSTRACT Prion diseases are infectious neurodegenerative disorders characterized by accumulations of abnormally folded cellular prion protein in affected tissues. Many natural prion diseases are acquired orally, and following exposure, the early replication of some prion isolates upon follicular dendritic cells (FDC) within gut-associated lymphoid tissues (GALT) is important for the efficient spread of disease to the brain (neuroinvasion). Prion detection within large intestinal GALT biopsy specimens has been used to estimate human and animal disease prevalence. However, the relative contributions of the small and large intestinal GALT to oral prion pathogenesis were unknown. To address this issue, we created mice that specifically lacked FDC-containing GALT only in the small intestine. Our data show that oral prion disease susceptibility was dramatically reduced in mice lacking small intestinal GALT. Although these mice had FDC-containing GALT throughout their large intestines, these tissues were not early sites of prion accumulation or neuroinvasion. We also determined whether pathology specifically within the large intestine might influence prion pathogenesis. Congruent infection with the nematode parasite Trichuris muris in the large intestine around the time of oral prion exposure did not affect disease pathogenesis. Together, these data demonstrate that the small intestinal GALT are the major early sites of prion accumulation and neuroinvasion after oral exposure. This has important implications for our understanding of the factors that influence the risk of infection and the preclinical diagnosis of disease. IMPORTANCE Many natural prion diseases are acquired orally. After exposure, the accumulation of some prion diseases in the gut-associated lymphoid tissues (GALT) is important for efficient spread of disease to the brain. However, the relative contributions of GALT in the small and large intestines to oral prion pathogenesis were unknown. We show that the

  6. The immunomodulatory compound 2-acetyl-4-tetrahydroxybutyl imidazole causes sequestration of lymphocytes in non-lymphoid tissues.

    PubMed

    Bradbury, M G; Qiu, M R; Parish, C R

    1997-10-01

    2-Acetyl-4(5)-(1,2,3,4-tetrahydroxybutyl) imidazole (THI) is an immunomodulatory compound which causes a reversible lymphopenia in mice by an unknown mechanism. In this study, we investigated the whereabouts of cells lost from the blood and the spleen during THI treatment Homing studies following is injection of fluorescently labelled splenocytes into THI-pretreated recipients showed that THI increased labelled cells in the liver, lungs and kidneys of THI-treated mice. Furthermore, the sequestration in the liver occurred just 1.5 h after injection of labelled cells with the increase still being present at 24 h after injection. Microscopic examination of liver sections indicated that fluorescent lymphocytes were clustered within the liver sinusoids in THI-treated mice, possibly associated with endothelial cells. The liver retention of lymphocytes was confirmed by immunohistochemical studies which showed a significant increase of T cells in the liver of THI-treated mice. To determine the subset of lymphocytes which are lost from the spleen and sequestered in non-lymphoid organs, lymphocytes remaining in the spleen after THI treatment were characterized. Our results confirmed that THI reduced B cells, CD4+ and CD8+ T cells and cells expressing CD62L, CD44 and IL-2R in the spleen. PMID:9429899

  7. Induction of apoptotic lesions in liver and lymphoid tissues and modulation of cytokine mRNA expression by acute exposure to deoxynivalenol in piglets

    PubMed Central

    Yamaguchi, Hiroyuki; Murata, Hideo; Nakajima, Yasuyuki; Miyazaki, Shigeru

    2010-01-01

    Six 1-month-old piglets were intravenously injected with deoxynivalenol (DON) at the concentration of 1 mg/kg body weight, with three pigs each necropsied at 6 and 24 h post-injection (PI) for investigation of hepatotoxicity and immunotoxicity with special attention to apoptotic changes and cytokine mRNA expression. Histopathological examination of the DON-injected pigs revealed systemic apoptosis of lymphocytes in lymphoid tissues and hepatocytes. Apoptosis of lymphocytes and hepatocytes was confirmed by the TdT-mediated dUTP-biotin nick end-labeling (TUNEL) method and immunohistochemical staining against single-stranded DNA and cleaved caspase-3. The number of TUNEL-positive cells in the thymus and Peyer's patches of the ileum was increased at 24 h PI compared to 6 h PI, but the peak was at 6 h PI in the liver. The mRNA expression of interleukin (IL)-1β, IL-6, IL-18, and tumor necrosis factor (TNF)-α in the spleen, thymus and mesenteric lymph nodes were determined by semi-quantitative RT-PCR, and elevated expression of IL-1β mRNA at 6 h PI and a decrease of IL-18 mRNA at 24 h PI were observed in the spleen. IL-1β and IL-6 mRNA expressions increased significantly at 6 h PI in the thymus, but TNF-α decreased at 6 h PI in the mesenteric lymph nodes. These results show the apoptosis of hepatocytes suggesting the hepatotoxic potential of DON, in addition to an immunotoxic effect on the modulation of proinflammatory cytokine genes in lymphoid organs with extensive apoptosis of lymphocytes induced by acute exposure to DON in pigs. PMID:20458150

  8. Hyaluronan and Hyaluronan-Binding Proteins Accumulate in Both Human Type 1 Diabetic Islets and Lymphoid Tissues and Associate With Inflammatory Cells in Insulitis

    PubMed Central

    Bogdani, Marika; Johnson, Pamela Y.; Potter-Perigo, Susan; Nagy, Nadine; Day, Anthony J.; Bollyky, Paul L.

    2014-01-01

    Hyaluronan (HA) is an extracellular matrix glycosaminoglycan that is present in pancreatic islets, but little is known about its involvement in the development of human type 1 diabetes (T1D). We have evaluated whether pancreatic islets and lymphoid tissues of T1D and nondiabetic organ donors differ in the amount and distribution of HA and HA-binding proteins (hyaladherins), such as inter-α-inhibitor (IαI), versican, and tumor necrosis factor–stimulated gene-6 (TSG-6). HA was dramatically increased both within the islet and outside the islet endocrine cells, juxtaposed to islet microvessels in T1D. In addition, HA was prominent surrounding immune cells in areas of insulitis. IαI and versican were present in HA-rich areas of islets, and both molecules accumulated in diabetic islets and regions exhibiting insulitis. TSG-6 was observed within the islet endocrine cells and in inflammatory infiltrates. These patterns were only observed in tissues from younger donors with disease duration of <10 years. Furthermore, HA and IαI amassed in follicular germinal centers and in T-cell areas in lymph nodes and spleens in T1D patients compared with control subjects. Our observations highlight potential roles for HA and hyaladherins in the pathogenesis of diabetes. PMID:24677718

  9. Evaluation of lymphoid tissue structure in Sole (Euryglossa orientalis) and Yellowfin Seabream (Acanthopagus latus) affected by environmental contaminants in the Persian Gulf.

    PubMed

    Taheri, Rezvan; Salamat, Negin; Movahedinia, Abdolali

    2016-05-01

    This study sought to analyze structures of lymphatic tissues in two commercial fish species, e.g. Sole (Euryglossa orientalis) and Yellowfin Seabream (Acanthopagus latus), collected from five stations with varying levels of pollution in the Musa Creek near the Persian Gulf, e.g. Petro-chemical, Gaafari, Majidieh, Ghazaleh and Zangi Stations. Samples from Genaveh Station located outside Musa Creek were collected as controls. To correlate findings of changes in the studied tissues with local pollution status, levels of Hg, Pb, Zn, Cu and Cd were measured in sediments and water at each station. Fish were caught from the sampling stations; the spleen and head kidney were collected and sections prepared to permit histologic evaluation. The results indicated that, in both species, the most common changes were observed in fish collected near the Petrochemical station and included an increase in melano-macrophage aggregates, hemorrhage and damaged/dead red blood cells in the spleen; in the head kidney, the major findings were melano-macrophage aggregation, hemorrhage and lifting of the tubular basement membrane. No pathological alternations were noted in the spleen and head kidney of fish from the Zangi station. Samples of A. latus collected from Gaafari station and of E. orientalis from Majidieh station also had pathological changes. No significant differences were found in the tissue structures of fish recovered from the Zangi and Genaveh control stations. The concentrations for nearly all of the studied metals in sediment and water samples collected from the different stations followed the pattern: Petrochemical station ≈ Majidieh ≈ Gaafari > Ghazaleh > Zangi Stations. From the data, it was concluded that changes in lymphoid tissues of the fish studied here "correlated" with geographical conditions and sources of pollution at the different test stations. What these changes mean to the long-term health of both species remains to be determined in

  10. Next-Generation mRNA Sequencing Reveals Pyroptosis-Induced CD4+ T Cell Death in Early Simian Immunodeficiency Virus-Infected Lymphoid Tissues

    PubMed Central

    Lu, Wuxun; Demers, Andrew J.; Ma, Fangrui; Kang, Guobin; Yuan, Zhe; Wan, Yanmin; Li, Yue; Xu, Jianqing; Lewis, Mark

    2015-01-01

    ABSTRACT Lymphoid tissues (LTs) are the principal sites where human immunodeficiency virus type 1 (HIV-1) replicates and virus-host interactions take place, resulting in immunopathology in the form of inflammation, immune activation, and CD4+ T cell death. The HIV-1 pathogenesis in LTs has been extensively studied; however, our understanding of the virus-host interactions in the very early stages of infection remains incomplete. We investigated virus-host interactions in the rectal draining lymph nodes (dLNs) of rhesus macaques at different times after intrarectal inoculation (days postinoculation [dpi]) with simian immunodeficiency virus (SIV). At 3 dpi, 103 differentially expressed genes (DEGs) were detected using next-generation mRNA sequencing (RNA-seq). At 6 and 10 dpi, concomitant with increased SIV replication, 366 and 1,350 DEGs were detected, respectively, including upregulation of genes encoding proteins that play a role in innate antiviral immune responses, inflammation, and immune activation. Notably, genes (IFI16, caspase-1, and interleukin 1β [IL-1β]) in the canonical pyroptosis pathway were significantly upregulated in expression. We further validated increased pyroptosis using flow cytometry and found that the number of CD4+ T cells expressing activated caspase-1 protein, the hallmark of ongoing pyroptosis, were significantly increased, which is correlated with decreased CD4+ T cells in dLNs. Our results demonstrated that pyroptosis contributes to the CD4+ T cell death in vivo in early SIV infection, which suggests that pyroptosis may play a pivotal role in the pathogenesis of SIV, and by extension, that of HIV-1, since pyroptosis not only induces CD4+ T cell death but also amplifies inflammation and immune activation. Thus, blocking CD4+ T cell pyroptosis could be a complementary treatment to antiretroviral therapy. IMPORTANCE Although secondary lymphoid tissues (LTs) are principal sites of human immunodeficiency virus type 1 (HIV-1) replication

  11. Innate Lymphoid Cells in Cancer.

    PubMed

    Vallentin, Blandine; Barlogis, Vincent; Piperoglou, Christelle; Cypowyj, Sophie; Zucchini, Nicolas; Chéné, Matthieu; Navarro, Florent; Farnarier, Catherine; Vivier, Eric; Vély, Frédéric

    2015-10-01

    The world of lymphocytes has recently expanded. A group of cells, innate lymphoid cells (ILC), has been defined. It includes lymphoid cells that have been known for decades, such as natural killer (NK) cells and lymphoid tissue-inducer (LTi) cells. NK cells recognize a vast array of tumor cells, which they help to eliminate through cytotoxicity and the production of cytokines, such as IFNγ. Advances in our understanding of NK-cell biology have led to a growing interest in the clinical manipulation of these cells in cancer. The other ILCs are found mostly in the mucosae and mucosal-associated lymphoid tissues, where they rapidly initiate immune responses to pathogens without the need for specific sensitization. Here, we outline the basic features of ILCs and review the role of ILCs other than NK cells in cancer. Much of the role of these ILCs in cancer remains unknown, but several findings should lead to further efforts to dissect the contribution of different ILC subsets to the promotion, maintenance, or elimination of tumors at various anatomic sites. This will require the development of standardized reagents and protocols for monitoring the presence and function of ILCs in human blood and tissue samples. PMID:26438443

  12. Light and electron microscopic study of the eyelids, conjunctiva-associated lymphoid tissue and lacrimal gland in Bilgorajska Goose (Anser anser).

    PubMed

    Klećkowska-Nawrot, Joanna; Nowaczyk, Renata; Goździewska-Harłajczuk, Karolina; Barszcz, Karolina; Kowalczyk, Artur; Łukaszewicz, Ewa

    2016-01-01

    Normal structure of the accessory organs of the eye is essential for normal eye physiology. Among the most important accessory organs of the eye are the eyelids, the conjunctiva-associated lymphoid tissue (CALT) and the lacrimal gland (LG). The aim of this study was to demonstrate the histological structure of the eyelids and LG by histochemical and ultrastructural analysis. The study was performed on 13 adult female Bilgorajska geese. Eyelid samples were stained with the Alcian blue (AB pH 2.5) and periodic acid-Schiff (PAS) methods. Staining methods used for LG were AB pH 2.5, aldehyde fuchsin (AF), PAS and Hale's dialysed iron (HDI). Within the connective tissue of the eyelids, well-developed, diffuse, CALT follicles were observed, mostly under the conjunctival epithelium. Numerous lymphocytes were present within loose connective tissue. Staining of the eyelids with the PAS method demonstrated the presence of goblet cells of a mucous nature, and AB pH 2.5 staining indicated the presence of sulfated acid mucopolysaccharides. PAS staining of LG revealed the presence of secretory cells containing weakly PAS-positive granules. All epithelial cells of the corpus glandulae and the duct systems reacted positively to AB pH 2.5. HDI staining detected the presence of carboxylated acid mucopolysaccharides. Transmission electron microscopy investigations revealed two types of secretory epithelial cells in LG. Both types of LG cells contained drop-like secretory vesicles of different sizes with low or high electron density in cytoplasm, as well as small and large lipid vacuoles, and numerous small primary lysosomes. PMID:25673221

  13. Exploring the Feasibility of Multi-Site Flow Cytometric Processing of Gut Associated Lymphoid Tissue with Centralized Data Analysis for Multi-Site Clinical Trials

    PubMed Central

    McGowan, Ian; Anton, Peter A.; Elliott, Julie; Cranston, Ross D.; Duffill, Kathryn; Althouse, Andrew D.; Hawkins, Kevin L.; De Rosa, Stephen C.

    2015-01-01

    The purpose of this study was to determine whether the development of a standardized approach to the collection of intestinal tissue from healthy volunteers, isolation of gut associated lymphoid tissue mucosal mononuclear cells (MMC), and characterization of mucosal T cell phenotypes by flow cytometry was sufficient to minimize differences in the normative ranges of flow parameters generated at two trial sites. Forty healthy male study participants were enrolled in Pittsburgh and Los Angeles. MMC were isolated from rectal biopsies using the same biopsy acquisition and enzymatic digestion protocols. As an additional comparator, peripheral blood mononuclear cells (PBMC) were collected from the study participants. For quality control, cryopreserved PBMC from a single donor were supplied to both sites from a central repository (qPBMC). Using a jointly optimized standard operating procedure, cells were isolated from tissue and blood and stained with monoclonal antibodies targeted to T cell phenotypic markers. Site-specific flow data were analyzed by an independent center which analyzed all data from both sites. Ranges for frequencies for overall CD4+ and CD8+ T cells, derived from the qPBMC samples, were equivalent at both UCLA and MWRI. However, there were significant differences across sites for the majority of T cell activation and memory subsets in qPBMC as well as PBMC and MMC. Standardized protocols to collect, stain, and analyze MMC and PBMC, including centralized analysis, can reduce but not exclude variability in reporting flow data within multi-site studies. Based on these data, centralized processing, flow cytometry, and analysis of samples may provide more robust data across multi-site studies. Centralized processing requires either shipping of fresh samples or cryopreservation and the decision to perform centralized versus site processing needs to take into account the drawbacks and restrictions associated with each method. PMID:26010577

  14. Detection of Foot-and-mouth Disease Virus RNA and Capsid Protein in Lymphoid Tissues of Convalescent Pigs Does Not Indicate Existence of a Carrier State.

    PubMed

    Stenfeldt, C; Pacheco, J M; Smoliga, G R; Bishop, E; Pauszek, S J; Hartwig, E J; Rodriguez, L L; Arzt, J

    2016-04-01

    A systematic study was performed to investigate the potential of pigs to establish and maintain persistent foot-and-mouth disease virus (FMDV) infection. Infectious virus could not be recovered from sera, oral, nasal or oropharyngeal fluids obtained after resolution of clinical infection with any of five FMDV strains within serotypes A, O and Asia-1. Furthermore, there was no isolation of live virus from tissue samples harvested at 28-100 days post-infection from convalescent pigs recovered from clinical or subclinical FMD. Despite lack of detection of infectious FMDV, there was a high prevalence of FMDV RNA detection in lymph nodes draining lesion sites harvested at 35 days post-infection, with the most frequent detection recorded in popliteal lymph nodes (positive detection in 88% of samples obtained from non-vaccinated pigs). Likewise, at 35 dpi, FMDV capsid antigen was localized within follicles of draining lymph nodes, but without concurrent detection of FMDV non-structural protein. There was a marked decline in the detection of FMDV RNA and antigen in tissue samples by 60 dpi, and no antigen or viral RNA could be detected in samples obtained at 100 dpi. The data presented herein provide the most extensive investigation of FMDV persistence in pigs. The overall conclusion is that domestic pigs are unlikely to be competent long-term carriers of infectious FMDV; however, transient persistence of FMDV protein and RNA in lymphoid tissues is common following clinical or subclinical infection. PMID:24943477

  15. Lack of prion accumulation in lymphoid tissues of PRNP ARQ/ARR sheep intracranially inoculated with the agent of scrapie

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Sheep scrapie is a transmissible spongiform encephalopathy that can be transmitted horizontally. The prion protein gene (PRNP) profoundly influences the susceptibility of sheep to the scrapie agent and the tissue levels and distribution of PrPSc in affected sheep. The purpose of this study was to co...

  16. Analysis of Th17 and Tc17 Frequencies and Antiviral Defenses in Gut-Associated Lymphoid Tissue of Chronic HIV-1 Positive Patients.

    PubMed

    d'Ettorre, Gabriella; Ceccarelli, Giancarlo; Andreotti, Mauro; Selvaggi, Carla; Giustini, Noemi; Serafino, Sara; Schietroma, Ivan; Nunnari, Giuseppe; Antonelli, Guido; Vullo, Vincenzo; Scagnolari, Carolina

    2015-01-01

    The complex relationship between both the Th1/Th17 and Tc1/Tc17 axis and innate defences in the intestinal mucosa during HIV-1 infection has not been well characterized. This study examined the frequency, phenotype, and functional status of T cell populations in the gut-associated lymphoid tissue and peripheral blood of virologically suppressed HIV-1-infected patients on therapy, focusing on the Th1, Th17, Tc1, and Tc17 cell subsets. We found a persistent immune cell activation (CD38 and HLADR expression) into the GALT despite the higher levels of Th17 and Tc17 in respect to peripheral blood. An upregulation of type I IFN response in GALT compared to the peripheral blood compartment was also recorded. Furthermore, IFN-α/β levels were negatively related to the frequencies of Th1 naïve cells and Tc1 cell subsets (naïve, central memory, and effector memory) in the GALT. In contrast, no relationships between type I IFN response and Th1 or Tc1 cell subsets in peripheral blood compartment and between IFN-α/β and Th17/Tc17 in both GALT and peripheral blood district were recorded. These data indicate that prolonged antiretroviral treatment improves GALT immune function despite the persistence of immune activation and type I IFN response in chronic HIV-1 positive patients. PMID:26221062

  17. Analysis of Th17 and Tc17 Frequencies and Antiviral Defenses in Gut-Associated Lymphoid Tissue of Chronic HIV-1 Positive Patients

    PubMed Central

    d'Ettorre, Gabriella; Ceccarelli, Giancarlo; Andreotti, Mauro; Selvaggi, Carla; Giustini, Noemi; Serafino, Sara; Schietroma, Ivan; Nunnari, Giuseppe; Antonelli, Guido; Vullo, Vincenzo; Scagnolari, Carolina

    2015-01-01

    The complex relationship between both the Th1/Th17 and Tc1/Tc17 axis and innate defences in the intestinal mucosa during HIV-1 infection has not been well characterized. This study examined the frequency, phenotype, and functional status of T cell populations in the gut-associated lymphoid tissue and peripheral blood of virologically suppressed HIV-1-infected patients on therapy, focusing on the Th1, Th17, Tc1, and Tc17 cell subsets. We found a persistent immune cell activation (CD38 and HLADR expression) into the GALT despite the higher levels of Th17 and Tc17 in respect to peripheral blood. An upregulation of type I IFN response in GALT compared to the peripheral blood compartment was also recorded. Furthermore, IFN-α/β levels were negatively related to the frequencies of Th1 naïve cells and Tc1 cell subsets (naïve, central memory, and effector memory) in the GALT. In contrast, no relationships between type I IFN response and Th1 or Tc1 cell subsets in peripheral blood compartment and between IFN-α/β and Th17/Tc17 in both GALT and peripheral blood district were recorded. These data indicate that prolonged antiretroviral treatment improves GALT immune function despite the persistence of immune activation and type I IFN response in chronic HIV-1 positive patients. PMID:26221062

  18. A Multicenter Phase II Study of Local Radiation Therapy for Stage IEA Mucosa-Associated Lymphoid Tissue Lymphomas: A Preliminary Report From the Japan Radiation Oncology Group (JAROG)

    SciTech Connect

    Isobe, Koichi Kagami, Yoshikazu; Higuchi, Keiko; Kodaira, Takeshi; Hasegawa, Masatoshi; Shikama, Naoto; Nakazawa, Masanori; Fukuda, Ichiro; Nihei, Keiji; Ito, Kana; Teshima, Teruki; Matsuno, Yoshihiro; Oguchi, Masahiko

    2007-11-15

    Purpose: The aim of this study was to evaluate the efficacy and toxicity of moderate dose radiation therapy (RT) for mucosa-associated lymphoid tissue (MALT) lymphoma in a prospective multicenter phase II trial. Methods and Materials: The subjects in this study were 37 patients with MALT lymphoma between April 2002 and November 2004. There were 16 male and 21 female patients, ranging in age from 24 to 82 years, with a median of 56 years. The primary tumor originated in the orbit in 24 patients, in the thyroid and salivary gland in 4 patients each, and 5 in the others. The median tumor dose was 30.6 Gy (range, 30.6-39.6 Gy), depending on the primary site and maximal tumor diameter. The median follow-up was 37.3 months. Results: Complete remission (CR) or CR/unconfirmed was achieved in 34 patients (92%). The 3-year overall survival, progression-free survival, and local control probability were 100%, 91.9%, and 97.3%, respectively. Thirteen patients experienced Grade 1 acute toxicities including dermatitis, mucositis, and conjunctivitis. One patient developed Grade 2 taste loss. Regarding late toxicities, Grade 2 reactions including hypothyroidism, and radiation pneumonitis were observed in three patients, and Grade 3 cataract was seen in three patients. Conclusions: This prospective phase II study demonstrated that moderate dose RT was highly effective in achieving local control with acceptable morbidity in 37 patients with MALT lymphoma.

  19. Functional CD25- and CD25+ mucosal regulatory T cells are induced in gut-draining lymphoid tissue within 48 h after oral antigen application.

    PubMed

    Hauet-Broere, Femke; Unger, Wendy W J; Garssen, Johan; Hoijer, Maarten A; Kraal, Georg; Samsom, Janneke N

    2003-10-01

    Oral antigen application induces tolerance, leading to suppression of a subsequent systemic challenge with this antigen. The suppression is mediated by mucosal regulatory T (Tr) cells that may differentiate from naive peripheral T cells in the gut-draining lymphoid tissue. However, little is known about the initial steps of this differentiation process. In this study we show that 48 h after oral OVA treatment, antigen-specific T cells in mesenteric lymph nodes (MLN) and Peyer's Patches (PP) were activated and had divided up to four times. The first division was already seen in PP after 24 h. Analysis of surface marker expression and cytokine secretion of the dividing antigen-specific T cells revealed that they sequentially obtained an activation- and memory-like phenotype. These cells secreted IL-2 in most stages of division but only transiently IFN-gamma whereas no IL-4 or IL-10 secretion was detected. Remarkably, 48 h after antigen application, isolated dividing cells were suppressive, as they transferred tolerance to naive mice. Even though CD25 was expressed heterogeneously, both CD25(+) and CD25(-) OVA-specific T cells from MLN could transfer tolerance. Together these findings show that differentiation of functional Tr cells occurs in the MLN and PP within 2 days after antigen ingestion and involves the generation of CD25(+) and CD25(-) antigen-specific T cells. PMID:14515264

  20. Mucosa-associated lymphoid tissue lymphoma with large cell transformation on the background of Hashimoto's thyroiditis: a case report and review literature.

    PubMed

    Hengjeerajarus, Natavuth; Klaisuwan, Teerada; Norasetthada, Lalita; Kosachunhanun, Natapong

    2015-05-01

    Primary thyroid lymphoma (PTL) is a rare cause of malignancy that occurs in 0.5% of cases with Hashimoto's thyroiditis. The most common subtype is diffuse large B-cell lymphoma (DLBCL), followed by mucosa-associated lymphoid tissue (MALT) lymphoma. We described the case of a 70-year-old man who was diagnosed with MALT lymphoma in the background of autoimmune thyroiditis with focal area of DLBCL transformation. The patient was a 70-year-old man with rapidly growing mass of the thyroid gland with compressive symptom over two months. The laboratory data revealed primary hypothyroidism with positively anti-thyroid antibodies. The computerized tomography scan showed right thyroid mass extended to anterior mediastinum and compressed adjacent airway with multiple cervical and mediastinal lymphadenopathies. The pathology from incisional biopsy showed extranodal marginal zone B-cell lymphoma of MALT lymphoma with large cell transformation. The patient received four courses of systemic chemotherapy combined with involved field radiation therapy. The mass was dramatically decreased in size after treatment, leading to a complete resolution of compressive symptoms. Thyroid lymphoma is quite rare; however the incidence may be higher in patients with Hashimoto's thyroiditis. A rapidly growing thyroid gland should be considered as PTL. Chemotherapy and radiation are the mainstays of treatment. PMID:26058282

  1. Early, Isolated Duodenal Mucosa-Associated Lymphoid Tissue Lymphoma Presenting without Symptoms or Grossly Apparent Endoscopic Lesions and Diagnosed by Random Duodenal Biopsies

    PubMed Central

    Gjeorgjievski, Mihajlo; Makki, Issa; Khanal, Pradeep; Amin, Mitual B.; Blenc, Ann Marie; Desai, Tusar; Cappell, Mitchell S.

    2016-01-01

    Clinical data regarding mucosa-associated lymphoid tissue lymphoma (MALToma) solely involving the duodenum are sparse because of the relative rarity of the disease. A comprehensive literature review revealed only 17 cases reported until 2004, and only a moderate number of cases have been reported since. MALToma can be asymptomatic in its very early stages but frequently produces localized or nonspecific symptoms, including early satiety, abdominal pain, vomiting, and involuntary weight loss in later stages. While gastric MALToma is strongly associated with gastric Helicobactor pylori infection, duodenal MALToma is often unassociated with H. pylori infection. A 74-year-old female presented with only dysphagia (without symptoms referable to a duodenal lesion), without systemic ‘B’ symptoms, and with no evident duodenal lesions at esophagogastroduodenoscopy; however, she was diagnosed with duodenal MALToma by pathologic examination of random duodenal biopsies performed to exclude celiac disease. An important clinical feature of this case is that duodenal MALToma was diagnosed by pathologic analysis of duodenal biopsies despite (1) no endoscopically apparent duodenal lesions; (2) duodenal involvement without gastric involvement; (3) lack of symptoms attributable to duodenal MALToma, and (4) absence of evident H. pylori infection. This work shows that early duodenal MALToma can be difficult to diagnose because of absent symptoms, absence of gastric involvement, absence of endoscopic abnormalities, and absence of H. pylori infection; it may require random duodenal biopsies for diagnosis. PMID:27482191

  2. Acquisition of Pneumococci Specific Effector and Regulatory Cd4+ T Cells Localising within Human Upper Respiratory-Tract Mucosal Lymphoid Tissue

    PubMed Central

    Pido-Lopez, Jeffrey; Kwok, William W.; Mitchell, Timothy J.; Heyderman, Robert S.; Williams, Neil A.

    2011-01-01

    The upper respiratory tract mucosa is the location for commensal Streptococcus (S.) pneumoniae colonization and therefore represents a major site of contact between host and bacteria. The CD4+ T cell response to pneumococcus is increasingly recognised as an important mediator of immunity that protects against invasive disease, with data suggesting a critical role for Th17 cells in mucosal clearance. By assessing CD4 T cell proliferative responses we demonstrate age-related sequestration of Th1 and Th17 CD4+ T cells reactive to pneumococcal protein antigens within mucosal lymphoid tissue. CD25hi T cell depletion and utilisation of pneumococcal specific MHCII tetramers revealed the presence of antigen specific Tregs that utilised CTLA-4 and PDL-1 surface molecules to suppress these responses. The balance between mucosal effector and regulatory CD4+ T cell immunity is likely to be critical to pneumococcal commensalism and the prevention of unwanted pathology associated with carriage. However, if dysregulated, such responses may render the host more susceptible to invasive pneumococcal infection and adversely affect the successful implementation of both polysaccharide-conjugate and novel protein-based pneumococcal vaccines. PMID:22144893

  3. A case of gastric mucosa-associated lymphoid tissue lymphoma in which magnified endoscopy with narrow band imaging was useful in the diagnosis.

    PubMed

    Nonaka, Kouichi; Ishikawa, Keiko; Arai, Shin; Nakao, Masamitsu; Shimizu, Michio; Sakurai, Takaki; Nagata, Koji; Nishimura, Makoto; Togawa, Osamu; Ochiai, Yasutoshi; Sasaki, Yutaka; Kita, Hiroto

    2012-04-16

    Recently, we reported a case of gastric mucosa-associated lymphoid tissue (MALT) lymphoma presenting with unique vascular features. In the report, we defined the tree-like appearance (TLA) on the images of abnormal blood vessels which resembled branches from the trunk of a tree in the shiny mucosa, in which the glandular structure was lost. The 67-year-old female was diagnosed with gastric MALT lymphoma. The patient received eradication therapy for H. pylori. Conventional endoscopy revealed multiple ill-delineated brownish depressions in the stomach and cobblestone-like mucosa was observed at the greater curvature to the posterior wall of the upper gastric body 7 mo after successful eradication. Unsuccessful treatment of gastric MALT lymphoma was suspected on conventional endoscopy. Conventional endoscopic observations found focal depressions and cobblestone-like appearance, and these lesions were subsequently observed using magnified endoscopy combined with narrow band imaging to identify abnormal vessels presenting with a TLA within the lesions. Ten biopsies were taken from the area where abnormal vessels were present within these lesions. Ten biopsies were also taken from the lesions without abnormal vessels as a control. A total of 20 biopsy samples were evaluated to determine whether the diagnosis of MALT lymphoma could be obtained histologically from each sample. A positive diagnosis was obtained in 8/10 TLA (+) sites and in 2/10 TLA(-) sites. Target biopsies of the site with abnormal blood vessels can potentially improve diagnostic accuracy of gastric MALT lymphoma. PMID:22523617

  4. Glycoconjugate expression in follicle-associated epithelium (FAE) covering the nasal-associated lymphoid tissue (NALT) in specific pathogen-free and conventional rats.

    PubMed

    Jeong, K I; Uetsuka, K; Nakayama, H; Doi, K

    1999-01-01

    We examined lectin-histochemically the glycoconjugate expression in the follicle-associated epithelium (FAE) covering the nasal-associated lymphoid tissue (NALT) in the rat under specific pathogen-free (SPF) and conventional (CV) conditions and compared the results for SPF and CV rats as well as for membranous (M) cells and adjacent ciliated respiratory epithelial (CRE) cells in FAE. N-acetylgalactosamine-specific lectins, Dolichos biflorus (DBA), Helix pomatia (HPA), Glycine max (SBA) and Vicia villosa (VVA), and alpha-L-fucose-specific lectin, Ulex europaeus (UEA-I), preferentially bound to M cells mainly in the luminal surface compared with CRE cells in SPF rats, whereas DBA and UEA-I showed signs of preferential binding to the apical and basolateral cytoplasm as well as to the luminal surface of M cells in CV rats. In addition, HPA, SBA and VVA more frequently and extensively labeled M cells than CRE cells in CV rats with the same subcellular staining pattern as DBA and UEA-I. On the whole, the changes in lectin binding frequency and strength were more prominent in M cells than in CRE cells in both SPF and CV rats. The present results indicate that DBA and UEA-I are useful as markers of M cells in NALT. Furthermore, the pattern of expression of carbohydrate residues recognized by such lectins in SPF and CV rats suggests that M cells are highly sensitive to environmental changes. PMID:10067202

  5. Nasal-associated lymphoid tissue is a site of long-term virus-specific antibody production following respiratory virus infection of mice.

    PubMed

    Liang, B; Hyland, L; Hou, S

    2001-06-01

    Nasal immunoglobulin A provides an initial defense against inhaled respiratory pathogens. However, it is not known whether the nasal-associated lymphoid tissues (NALT) are able to mount an effective long-lasting pathogen-specific immune response, nor is it known whether functional differences exist between the organized NALT (O-NALT) and the diffuse NALT lining the nasal passages (D-NALT). Here we show that although both the O-NALT and the D-NALT are capable of producing virus-specific antibody in response to influenza virus infection, the frequency of specific antibody-forming cells in the D-NALT is much greater than the frequency observed in the O-NALT. Furthermore, we show that the D-NALT but not the O-NALT is the site of long-term virus-specific humoral immunity which lasts for the life of the animal. These results indicate that the D-NALT is not only the major effector site of the NALT but also the site of local long-term specific antibody production. PMID:11333927

  6. Adjuvanted Intranasal Norwalk Virus-Like Particle Vaccine Elicits Antibodies and Antibody-Secreting Cells That Express Homing Receptors for Mucosal and Peripheral Lymphoid Tissues

    PubMed Central

    El-Kamary, Samer S.; Pasetti, Marcela F.; Mendelman, Paul M.; Frey, Sharon E.; Bernstein, David I.; Treanor, John J.; Ferreira, Jennifer; Chen, Wilbur H.; Sublett, Richard; Richardson, Charles; Bargatze, Robert F.; Sztein, Marcelo B.; Tacket, Carol O.

    2010-01-01

    Background. Noroviruses cause significant morbidity and mortality from acute gastroenteritis in all age groups worldwide. Methods.We conducted 2 phase 1 double-blind, controlled studies of a virus-like particle (VLP) vaccine derived from norovirus GI.1 genotype adjuvanted with monophosphoryl lipid A (MPL) and the mucoadherent chitosan. Healthy subjects 18–49 years of age were randomized to 2 doses of intranasal Norwalk VLP vaccine or controls 21 days apart. Study 1 evaluated 5-, 15-, and 50-μg dosages of Norwalk antigen, and study 2 evaluated 50-and 100-μg dosages. Volunteers recorded symptoms for 7 days after dosing, and safety was followed up for 180 days. Blood samples were collected for serological profile, antibody secreting cells (ASCs), and analysis of ASC homing receptors. Results. The most common symptoms were nasal stuffiness, discharge, and sneezing. No vaccine-related serious adverse events occurred. Norwalk VLP-specific immunoglobulin G and immunoglobulin A antibodies increased 4.8-and 9.1-fold, respectively, for the 100-μg dosage level. All subjects tested who received the 50-or 100-μg vaccine dose developed immunoglobulin A ASCs. These cells expressed molecules associated with homing to mucosal and peripheral lymphoid tissues. Conclusions. The intranasal monovalent adjuvanted Norwalk VLP vaccine was well tolerated and highly immunogenic and is a candidate for additional study. Trial Registration. ClinicalTrials.gov identifier: NCT00806962. PMID:20979455

  7. Early, Isolated Duodenal Mucosa-Associated Lymphoid Tissue Lymphoma Presenting without Symptoms or Grossly Apparent Endoscopic Lesions and Diagnosed by Random Duodenal Biopsies.

    PubMed

    Gjeorgjievski, Mihajlo; Makki, Issa; Khanal, Pradeep; Amin, Mitual B; Blenc, Ann Marie; Desai, Tusar; Cappell, Mitchell S

    2016-01-01

    Clinical data regarding mucosa-associated lymphoid tissue lymphoma (MALToma) solely involving the duodenum are sparse because of the relative rarity of the disease. A comprehensive literature review revealed only 17 cases reported until 2004, and only a moderate number of cases have been reported since. MALToma can be asymptomatic in its very early stages but frequently produces localized or nonspecific symptoms, including early satiety, abdominal pain, vomiting, and involuntary weight loss in later stages. While gastric MALToma is strongly associated with gastric Helicobactor pylori infection, duodenal MALToma is often unassociated with H. pylori infection. A 74-year-old female presented with only dysphagia (without symptoms referable to a duodenal lesion), without systemic 'B' symptoms, and with no evident duodenal lesions at esophagogastroduodenoscopy; however, she was diagnosed with duodenal MALToma by pathologic examination of random duodenal biopsies performed to exclude celiac disease. An important clinical feature of this case is that duodenal MALToma was diagnosed by pathologic analysis of duodenal biopsies despite (1) no endoscopically apparent duodenal lesions; (2) duodenal involvement without gastric involvement; (3) lack of symptoms attributable to duodenal MALToma, and (4) absence of evident H. pylori infection. This work shows that early duodenal MALToma can be difficult to diagnose because of absent symptoms, absence of gastric involvement, absence of endoscopic abnormalities, and absence of H. pylori infection; it may require random duodenal biopsies for diagnosis. PMID:27482191

  8. Helicobacter pylori Eradication Therapy Is Effective as the Initial Treatment for Patients with H. pylori-Negative and Disseminated Gastric Mucosa-Associated Lymphoid Tissue Lymphoma

    PubMed Central

    Gong, Eun Jeong; Ahn, Ji Yong; Jung, Hwoon-Yong; Park, Hyungchul; Ko, Young Bo; Na, Hee Kyong; Jung, Kee Wook; Kim, Do Hoon; Lee, Jeong Hoon; Choi, Kee Don; Song, Ho June; Lee, Gin Hyug; Kim, Jin-Ho

    2016-01-01

    Background/Aims We investigated the effectiveness of Helicobacter pylori eradication therapy for gastric mucosa-associated lymphoid tissue (MALT) lymphoma regardless of the H. pylori infection status or disease stage. Methods From November 1995 to September 2014, 345 subjects who were diagnosed with gastric MALT lymphoma and had received eradication therapy as their first-line treatment were eligible for inclusion in this study. A retrospective review was performed using the medical records. Results Of the 345 patients, H. pylori infection was detected in 317 patients (91.9%). The complete remission (CR) rate after eradication therapy was 82.3%, which was higher in H. pylori-positive patients than in H. pylori-negative patients (84.5% vs 57.1%, p=0.001). CR rates after eradication did not present significant differences between stages, and the CR rate was 83.3% for stage IE1 and 74.4% for stage IE2 or above (p=0.167). The overall CR rate was 87.2% after additional treatment, and neither H. pylori infection status nor stage showed differences according to the treatment response. Conclusions Eradication therapy led to CR in 57.1% of H. pylori-negative patients and in 74.4% of patients with stage IE2 or above. Eradication therapy is worthwhile as an initial treatment for gastric MALT lymphoma regardless of the H. pylori infection status and stage. PMID:27114423

  9. Analysis of Multiply Spliced Transcripts in Lymphoid Tissue Reservoirs of Rhesus Macaques Infected with RT-SHIV during HAART

    PubMed Central

    Deere, Jesse D.; Kauffman, Robert C.; Cannavo, Elda; Higgins, Joanne; Villalobos, Andradi; Adamson, Lourdes; Schinazi, Raymond F.; Luciw, Paul A.; North, Thomas W.

    2014-01-01

    Highly active antiretroviral therapy (HAART) can reduce levels of human immunodeficiency virus type 1 (HIV-1) to undetectable levels in infected individuals, but the virus is not eradicated. The mechanisms of viral persistence during HAART are poorly defined, but some reservoirs have been identified, such as latently infected resting memory CD4+ T cells. During latency, in addition to blocks at the initiation and elongation steps of viral transcription, there is a block in the export of viral RNA (vRNA), leading to the accumulation of multiply-spliced transcripts in the nucleus. Two of the genes encoded by the multiply-spliced transcripts are Tat and Rev, which are essential early in the viral replication cycle and might indicate the state of infection in a given population of cells. Here, the levels of multiply-spliced transcripts were compared to the levels of gag-containing RNA in tissue samples from RT-SHIV-infected rhesus macaques treated with HAART. Splice site sequence variation was identified during development of a TaqMan PCR assay. Multiply-spliced transcripts were detected in gastrointestinal and lymphatic tissues, but not the thymus. Levels of multiply-spliced transcripts were lower than levels of gag RNA, and both correlated with plasma virus loads. The ratio of multiply-spliced to gag RNA was greatest in the gastrointestinal samples from macaques with plasma virus loads <50 vRNA copies per mL at necropsy. Levels of gag RNA and multiply-spliced mRNA in tissues from RT-SHIV-infected macaques correlate with plasma virus load. PMID:24505331

  10. The effect of continuous low dose-rate gamma irradiation on cell population kinetics of lymphoid tissue

    NASA Technical Reports Server (NTRS)

    Foster, B. R.

    1974-01-01

    Cellular response and cell population kinetics were studied during lymphopoiesis in the thymus of the mouse under continuous gamma irradiation using autoradiographic techniques and specific labeling with tritiated thymidine. On the basis of tissue weights, it is concluded that the response of both the thymus and spleen to continuous low dose-rate irradiation is multiphasic. That is, alternating periods of steady state growth, followed by collapse, which in turn is followed by another period of homeostasis. Since there are two populations of lymphocytes - short lived and long-lived, it may be that different phases of steady state growth are mediated by different lymphocytes. The spleen is affected to a greater extent with shorter periods of steady-state growth than exhibited by the thymus.

  11. Gastric mucosa-associated lymphoid tissue lymphoma and Helicobacter pylori infection: a review of current diagnosis and management.

    PubMed

    Hu, Qinglong; Zhang, Yizhuo; Zhang, Xiaoyan; Fu, Kai

    2016-01-01

    Helicobacter pylori (H. pylori)-associated gastritis is one of the most common infectious diseases in the United States, China and worldwide. Gastric mucosa-associated tissue lymphoma (MALT lymphoma) is a rare mature B-cell neoplasm associated with H. pylori infection that is curable by antibiotics therapy alone. The pathological diagnosis of gastric MALT lymphoma can be reached by histological examination, immunohistochemical staining and B-cell clonality analysis. H. pylori eradication is the choice of therapy for early-stage gastric MALT lymphoma. High response rates and long-term survival have been reported in refractory and localized diseases treated with low-dose radiation therapy. Systemic chemotherapy is recommended for advanced-stage gastric MALT lymphoma and cases with large B-cell lymphoma transformation. Recent advances in the pathological diagnosis and management of gastric MALT lymphoma are reviewed in this article. PMID:27468353

  12. Review article: Mucosa-associated lymphoid tissue (MALT)-type lymphoma of ocular adnexa. Biology and treatment.

    PubMed

    Annibali, Ombretta; Sabatino, Francesco; Mantelli, Flavio; Olimpieri, Odoardo Maria; Bonini, Stefano; Avvisati, Giuseppe

    2016-04-01

    Over the last decades, we have witnessed an increase in the incidence of primary ocular adnexa lymphomas (POALs) probably because advances in imaging techniques have enabled precise biopsies of the tumors. The ocular tissue biopsy, before the initiation of the appropriate treatment, is mandatory and necessary for a correct diagnosis of POALs by the use of immunophenotyping and a correct molecular classification. Only in a minority of cases the ocular adnexa are secondarily affected by a systemic disease. Among the POALs, the most common is the primary extra nodal lymphoma of MALT-type (POAML). POAML is rarely symptomatic in the early phase of the disease. As a consequence, often we see a delay in ophthalmic consultations and diagnosis. The clinical manifestations are heterogeneous and its management requires a multidisciplinary approach involving ophthalmologists, hematologists and radiotherapists. PMID:26857986

  13. Cellular composition of granulomatous lesions in gut-associated lymphoid tissues of goats during the first year after experimental infection with Mycobacterium avium subsp. paratuberculosis.

    PubMed

    Krüger, C; Köhler, H; Liebler-Tenorio, E M

    2015-01-15

    Mycobacterium avium subsp. paratuberculosis (MAP) causes lesions in naturally and experimentally infected ruminants which greatly differ in severity, cellular composition and number of mycobacteria. Morphologically distinct lesions are already found during the clinically inapparent phase of infection. The complex local host response and number of MAP were characterized at the initial sites of lesions, organized gut-associated lymphoid tissue, in experimentally infected goats. Tissues were collected at 3, 6, 9 and 12 month post-inoculation (mpi) from goat kids that had orally received 10 times 10mg of bacterial wet mass of MAP (JII-1961). The cellular composition of lesions in Peyer's patches in the jejunum and next to the ileocecal valve was evaluated in 21 MAP-inoculated goats, where lesions were compared with unaltered tissue of six control goats. CD68+, CD4+, CD8+, γδ T lymphocytes, B lymphocytes and plasma cells, MHC class II+ and CD25+ cells were demonstrated by immunohistochemistry in serial cryostat sections. At 3 mpi, extensive granulomatous infiltrates predominated, consisting of numerous epitheloid cells admixed with many CD4 and γδ T lymphocytes. Only single MAP were detected. This indicates a strong cellular immune reaction able to control MAP infection. γδ T lymphocytes were markedly increased in this type of lesion which may reflect their important role early in the pathogenesis of paratuberculosis. At 9 and 12 mpi, divergent lesions were observed which may reflect different outcomes of host-pathogen interactions. In five goats, minimal granulomatous lesions were surrounded by extensive lymphoplasmacytic infiltrates and no MAP were detected by immunohistochemistry. This was interpreted as effective host response that was able to eliminate MAP locally. In three goats, decreased numbers of lymphocytes, but extensive granulomatous infiltrates with numerous epitheloid cells containing increased numbers of mycobacteria were seen. This shift of the

  14. Long-Term Outcome and Patterns of Failure in Primary Ocular Adnexal Mucosa-Associated Lymphoid Tissue Lymphoma Treated With Radiotherapy

    SciTech Connect

    Hashimoto, Naoki; Sasaki, Ryohei; Nishimura, Hideki; Yoshida, Kenji; Miyawaki, Daisuke; Nakayama, Masao; Uehara, Kazuyuki; Okamoto, Yoshiaki; Ejima, Yasuo; Azumi, Atsushi; Matsui, Toshimitsu; Sugimura, Kazuro

    2012-03-15

    Purpose: To evaluate the long-term treatment outcome and disease behavior of primary ocular adnexal MALT (mucosa-associated lymphoid tissue) lymphoma (POAML) after treatment with radiotherapy. Methods and Materials: Seventy-eight patients (42 male, 36 female) diagnosed with stage I POAML between 1991 and 2010 at Kobe University Hospital were included. The median age was 60 years (range, 22-85 years). The median radiation dose administered was 30.6 Gy. Rituximab-based targeted therapy and/or chemotherapy was performed in 20 patients (25.6%). Local control (LC), recurrence-free survival (RFS), and overall survival (OS) rates were calculated using the Kaplan-Meier method. Results: The median follow-up duration was 66 months. Major tumor sites were conjunctiva in 37 patients (47.4%), orbita in 29 (37.2%), and lacrimal glands in 12 (15.4%). The 5- and 10-year OS rates were 98.1% and 95.3%, respectively. The 5- and 10-year LC rates were both 100%, and the 5- and 10-year RFS rates were 88.5% and 75.9%, respectively. Patients treated with a combination of radiotherapy and targeted therapy and/or chemotherapy had a trend for a better RFS compared with those treated with radiotherapy alone (p = 0.114). None developed greater than Grade 2 acute morbidity. There were 14 patients who experienced Grade 2 morbidities (cataract: 14; retinal disorders: 7; dry eye: 3), 23 patients who had Grade 3 morbidities (cataract: 23; dry eye: 1), and 1 patient who had Grade 4 glaucoma. Conclusions: Radiotherapy for POAML was shown to be highly effective and safe for LC and OS on the basis of long-term observation. The absence of systemic relapse in patients with combined-modality treatment suggests that lower doses of radiation combined with targeted therapy may be worth further study.

  15. Exopolysaccharide-producing Bifidobacterium animalis subsp. lactis strains and their polymers elicit different responses on immune cells from blood and gut associated lymphoid tissue.

    PubMed

    Hidalgo-Cantabrana, Claudio; Nikolic, Milica; López, Patricia; Suárez, Ana; Miljkovic, Marija; Kojic, Milan; Margolles, Abelardo; Golic, Natasa; Ruas-Madiedo, Patricia

    2014-04-01

    The effect of exopolysaccharide (EPS) producing bifidobacteria, and the EPS derived thereof, on the modulation of immune response was evaluated. Cells isolated from gut associated lymphoid tissue (GALT) and from peripheral blood mononuclear cells (PBMC) of naïve rats were used. The proliferation and cytokine production of these immune cells in the presence of the three isogenic Bifidobacterium animalis subsp. lactis strains (A1, A1dOx and A1dOxR), as well as their purified polymers, were in vitro analysed. The cytokine pattern produced by immune cells isolated from GALT showed that most levels remained stable in the presence of the three strains or their corresponding polymers. However, in PBMC the UV-inactivated bacteria induced higher levels of the ratios IFNγ/IL-17, TNFα/IL-10 and TNFα/TGFβ, and no variation in the ratio IFNγ/IL-4. Thus, B. animalis subsp. lactis strains were able to activate blood monocytes as well as T lymphocytes towards a mild inflammatory Th1 response. Furthermore, only the EPS-A1dOxR was able to stimulate a response in a similar way than its EPS-producing bacterium. Our work supports the notion that some bifidobacterial EPS could play a role in mediating the dialog of these microorganisms with the immune system. In addition, this study emphasizes the effect that the origin of the immune cells has in results obtained; this could explain the great amount of contradiction found in literature about the immunomodulation capability of EPS from probiotic bacteria. PMID:24445155

  16. Radiation Therapy Administration and Survival in Stage I/II Extranodal Marginal Zone B-Cell Lymphoma of Mucosa-Associated Lymphoid Tissue

    SciTech Connect

    Olszewski, Adam J. Desai, Amrita

    2014-03-01

    Purpose: To determine the factors associated with the use of radiation therapy and associated survival outcomes in early-stage marginal zone lymphoma of the mucosa-associated lymphoid tissue (MALT). Methods and Materials: We extracted data on adult patients with stage I/II MALT lymphoma diagnoses between 1998 and 2010 recorded in the Surveillance, Epidemiology, and End Results (SEER) database. We studied factors associated with radiation therapy administration in a logistic regression model and described the cumulative incidence of lymphoma-related death (LRD) according to receipt of the treatment. The association of radiation therapy with survival was explored in multivariate models with adjustment for immortal time bias. Results: Of the 7774 identified patients, 36% received radiation therapy as part of the initial course of treatment. Older patients; black or Hispanic men; white, Hispanic, and black women; and socioeconomically disadvantaged and underinsured patients had a significantly lower chance of receiving radiation therapy. Radiation therapy administration was associated with a lower chance of LRD in most sites. In cutaneous, ocular, and salivary MALT lymphomas, the 5-year estimate of LRD after radiation therapy was 0%. The association of radiation therapy with overall survival in different lymphoma sites was heterogeneous, and statistically significant in cutaneous (hazard ratio 0.45, P=.009) and ocular (hazard ratio 0.47, P<.0001) locations after multivariate adjustment. Conclusions: Demographic factors are associated with the use of radiation therapy in MALT lymphoma. Clinicians should be sensitive to those disparities because the administration of radiation therapy may be associated with improved survival, particularly in cutaneous and ocular lymphomas.

  17. Localized Ocular Adnexal Mucosa-Associated Lymphoid Tissue Lymphoma Treated With Radiation Therapy: A Long-Term Outcome in 86 Patients With 104 Treated Eyes

    SciTech Connect

    Harada, Ken; Murakami, Naoya; Kitaguchi, Mayuka; Sekii, Shuhei; Takahashi, Kana; Yoshio, Kotaro; Inaba, Koji; Morota, Madoka; Ito, Yoshinori; Sumi, Minako; Suzuki, Shigenobu; Tobinai, Kensei; Uno, Takashi; Itami, Jun

    2014-03-01

    Purpose: To evaluate the natural history, behavior of progression, prognostic factors, and treatment-related adverse effects of primary ocular adnexal mucosa-associated lymphoid tissue (MALT) lymphoma (POAML). Methods and Materials: Eighty-six patients with histologically proven stage I POAML treated with radiation therapy at National Cancer Center Hospital, Tokyo between 1990 and 2010 were retrospectively reviewed. The median age was 56 years (range, 18-85 years). The median dose administered was 30 Gy (range, 30-46 Gy). Seventy-seven patients (90%) were treated by radiation therapy alone. Results: The median follow-up duration was 9 years (range, 0.9-22 years). The 5- and 10-year overall survival (OS) rates were 97.6% and 93.5%, respectively, and no patients died of lymphoma. Patients with tumor sizes ≥4 cm showed a greater risk of contralateral relapse (P=.012). Six patients with contralateral relapse were seen and treated by radiation therapy alone, and all the lesions were controlled well, with follow-up times of 3 to 12 years. There was 1 case of local relapse after radiation therapy alone, and 3 cases of relapse occurred in a distant site. Cataracts developed in 36 of the 65 eyes treated without lens shielding and in 12 of the 39 patients with lens shielding (P=.037). Conclusions: The majority of patients with POAML showed behavior consistent with that of localized, indolent diseases. Thirty gray of local irradiation seems to be quite effective. The initial bilateral involvement and contralateral orbital relapses can be also controlled with radiation therapy alone. Lens shielding reduces the risk of cataract.

  18. Lipocalin-2 protein deficiency ameliorates experimental autoimmune encephalomyelitis: the pathogenic role of lipocalin-2 in the central nervous system and peripheral lymphoid tissues.

    PubMed

    Nam, Youngpyo; Kim, Jong-Heon; Seo, Minchul; Kim, Jae-Hong; Jin, Myungwon; Jeon, Sangmin; Seo, Jung-wan; Lee, Won-Ha; Bing, So Jin; Jee, Youngheun; Lee, Won Kee; Park, Dong Ho; Kook, Hyun; Suk, Kyoungho

    2014-06-13

    Lipocalin-2 (LCN2) plays an important role in cellular processes as diverse as cell growth, migration/invasion, differentiation, and death/survival. Furthermore, recent studies indicate that LCN2 expression and secretion by glial cells are induced by inflammatory stimuli in the central nervous system. The present study was undertaken to examine the regulation of LCN2 expression in experimental autoimmune encephalomyelitis (EAE) and to determine the role of LCN2 in the disease process. LCN2 expression was found to be strongly increased in spinal cord and secondary lymphoid tissues after EAE induction. In spinal cords astrocytes and microglia were the major cell types expressing LCN2 and its receptor 24p3R, respectively, whereas in spleens, LCN2 and 24p3R were highly expressed in neutrophils and dendritic cells, respectively. Furthermore, disease severity, inflammatory infiltration, demyelination, glial activation, the expression of inflammatory mediators, and the proliferation of MOG-specific T cells were significantly attenuated in Lcn2-deficient mice as compared with wild-type animals. Myelin oligodendrocyte glycoprotein-specific T cells in culture exhibited an increased expression of Il17a, Ifng, Rorc, and Tbet after treatment with recombinant LCN2 protein. Moreover, LCN2-treated glial cells expressed higher levels of proinflammatory cytokines, chemokines, and MMP-9. Adoptive transfer and recombinant LCN2 protein injection experiments suggested that LCN2 expression in spinal cord and peripheral immune organs contributes to EAE development. Taken together, these results imply LCN2 is a critical mediator of autoimmune inflammation and disease development in EAE and suggest that LCN2 be regarded a potential therapeutic target in multiple sclerosis. PMID:24808182

  19. Low-grade B-cell lymphoma of mucosa-associated lymphoid tissue in the thymus of a patient with pulmonary amyloid nodules.

    PubMed

    Moriyama, E; Yokose, T; Kodama, T; Matsuno, Y; Hojo, F; Takahashi, K; Nagai, K; Nishiwaki, Y; Ochiai, A

    2000-08-01

    Low-grade B-cell lymphoma of mucosa-associated lymphoid tissue (MALT-type lymphoma) is a rare thymic tumor, with only seven previous cases described worldwide to date. We describe the only case to have presented with pulmonary amyloid nodules. A 63-year-old Japanese female was found to have an anterior mediastinal tumor and multiple bilateral pulmonary nodules during a medical check-up in 1990 followed by chest radiography and computerized tomography. Because the mediastinal tumor grew larger, she was referred to the National Cancer Center Hospital East and hyperglobulinemia was pointed out. The thymus was resected through median sternotomy and pulmonary nodules were also resected through left thoracotomy. The solid and nodular tumor with several small satellite extensions and cyst formation was completely confined to within the thymus and the resected pulmonary nodules consisted of solid masses with a rough surface. Histologically, monotonous medium-sized centrocyte-like cells occupied the medulla of the thymus and infiltrated Hassall's corpuscles (lymphoepithelial lesions) and the resected pulmonary nodules consisted of eosinophilic amorphous deposits which showed birefringence on Congo Red staining. Immunohistochemically, the tumor cells were positive for CD20 and CD79a. IgG and kappa light chain restrictions were also found in plasmacytoid cells in the tumor. Clonal rearrangement of the immunoglobulin heavy chain gene was demonstrated by polymerase chain reaction. We diagnosed this case as low-grade B-cell MALT-type lymphoma in the thymus and nodular pulmonary amyloidosis. Since the patient had only localized amyloid deposits in the lung far from the thymic malignant lymphoma and had high serum immunoglobulins, the pulmonary amyloid deposits might be derived from a circulating precursor associated with hyperglobulinemia. PMID:11059340

  20. Endogenous IL-33 is highly expressed in mouse epithelial barrier tissues, lymphoid organs, brain, embryos, and inflamed tissues: in situ analysis using a novel Il-33-LacZ gene trap reporter strain.

    PubMed

    Pichery, Mélanie; Mirey, Emilie; Mercier, Pascale; Lefrancais, Emma; Dujardin, Arnaud; Ortega, Nathalie; Girard, Jean-Philippe

    2012-04-01

    IL-33 (previously known as NF from high endothelial venules) is an IL-1 family cytokine that signals through the ST2 receptor and drives cytokine production in mast cells, basophils, eosinophils, invariant NKT and NK cells, Th2 lymphocytes, and type 2 innate immune cells (natural helper cells, nuocytes, and innate helper 2 cells). Little is known about endogenous IL-33; for instance, the cellular sources of IL-33 in mouse tissues have not yet been defined. In this study, we generated an Il-33-LacZ gene trap reporter strain (Il-33(Gt/Gt)) and used this novel tool to analyze expression of endogenous IL-33 in vivo. We found that the Il-33 promoter exhibits constitutive activity in mouse lymphoid organs, epithelial barrier tissues, brain, and embryos. Immunostaining with anti-IL-33 Abs, using Il-33(Gt/Gt) (Il-33-deficient) mice as control, revealed that endogenous IL-33 protein is highly expressed in mouse epithelial barrier tissues, including stratified squamous epithelia from vagina and skin, as well as cuboidal epithelium from lung, stomach, and salivary gland. Constitutive expression of IL-33 was not detected in blood vessels, revealing the existence of species-specific differences between humans and mice. Importantly, IL-33 protein was always localized in the nucleus of producing cells with no evidence for cytoplasmic localization. Finally, strong expression of the Il-33-LacZ reporter was also observed in inflamed tissues, in the liver during LPS-induced endotoxin shock, and in the lung alveoli during papain-induced allergic airway inflammation. Together, our findings support the possibility that IL-33 may function as a nuclear alarmin to alert the innate immune system after injury or infection in epithelial barrier tissues. PMID:22371395

  1. Effect of in ovo-delivered prebiotics and synbiotics on the morphology and specific immune cell composition in the gut-associated lymphoid tissue.

    PubMed

    Madej, J P; Bednarczyk, M

    2016-01-01

    The purpose of this study was to examine how pre- and synbiotic administration in ovo into the air chamber at d 12 of egg incubation influenced the specific immune cell composition and distribution in the ileum, cecal tonsils (CT) and bursa of Fabricius of broilers. The experiment was performed on 800 hatching eggs of the meat-type chickens (Ross 308). Hatching eggs were treated with: prebiotic, consisting of inulin (Pre1) or Bi(2)tos(®) (Pre2); symbiotic, composed of inulin and Lactococcus lactis subsp. lactis IBB SL1 (Syn1) or Bi(2)tos and Lactococcus lactis subsp. cremoris IBB SC1 (Syn2); or physiological saline as a control group. Seven chickens from each treatment group were randomly selected on , 1, 7, and 21 after hatch for tissue collection. Ileum, cecal tonsil and bursa of Fabricius samples were immunohistochemically stained and the proportions of Bu-1(+), CD3(+), CD4(+), CD8α(+) and TCRγδ(+) cells were estimated. It was indicated that the pre- and synbiotics do not adversely affect the development of the GALT of the chicken. The temporary decrease in B-cell number in bursa on d 7 after hatch suggested an increased colonization rate of the peripheral lymphoid organs by these cells after Pre1, Pre2, and Syn2 treatment. In CT at d 7 after hatch more potent colonization of the GALT by T cells was observed in all pre- and synbiotic treated groups and by B cells in both synbiotic-treated groups than those in respective controls. Then, on d 21 in both synbiotic-treated groups, an increase in T-cell number in ileum was also noticed with faster colonization of the CT by B cells. In 21-day-old chickens, both synbiotics exerted stronger stimulatory effect on the GALT colonization by T cells then prebiotics respectively. Similarly, the colonization by B cells was more pronounced in the Syn2 than in the Pre2 group. The data obtained in this study indicated that prebiotics and particularly synbiotics administrated in ovo stimulated GALT development after hatch

  2. Reduced Genetic Diversity in Lymphoid and Central Nervous System Tissues and Selection-Induced Tissue-Specific Compartmentalization of Neuropathogenic SIVsmmFGb during Acute Infection

    PubMed Central

    Reeve, Aaron B.; Patel, Kalpana; Pearce, Nicholas C.; Augustus, Katherine V.; Domingues, Heber G.; O'Neil, Shawn P.

    2009-01-01

    Abstract The simian lentivirus strain SIVsmmFGb is a viral swarm population inducing neuropathology in over 90% of infected pigtailed macaques and serves as a reliable model for HIV neuropathogenesis. However, little is understood about the genetic diversity of this virus, how said diversity influences the initial seeding of the central nervous system and lymph nodes, or whether the virus forms distinct genetic compartments between tissues during acute infection. In this study, we establish that our SIVsmmFGb stock virus contains four genetically distinct envelope V1 region groups, three distinct integrase groups, and two Nef groups. We demonstrate that initial central nervous system and lymph node seeding reduces envelope V1 and integrase genetic diversity but has a variable effect on Nef diversity. SIVsmmFGb envelope V1 region genes from the basal ganglia, cerebellum, and hippocampus form distinct genetic compartments from each other, the midfrontal cortex, and the lymph nodes. Basal ganglia, cerebellum, hippocampus, and midfrontal cortex-derived nef genes all form distinct genetic compartments from each other, as well as from the lymph nodes. We also find basal ganglia, hippocampus, and midfrontal cortex-derived integrase sequences forming distinct compartments from both of the lymph nodes and that the hippocampus and midfrontal cortex form separate compartments from the cerebellum, while the axillary and mesenteric lymph nodes compartmentalize separately from each other. Compartmentalization of the envelope V1 genes resulted from positive selection, and compartmentalization of the nef and integrase genes from negative selection. These results indicate restrictions on virus genetic diversity during initial tissue seeding in neuropathogenic SIV infection. PMID:19500015

  3. Development of innate lymphoid cells.

    PubMed

    Zook, Erin C; Kee, Barbara L

    2016-06-21

    Innate lymphoid cells (ILCs) are a family of immune effector cells that have important roles in host defense, metabolic homeostasis and tissue repair but can also contribute to inflammatory diseases such as asthma and colitis. These cells can be categorized into three groups on the basis of the transcription factors that direct their function and the cytokines they produce, which parallel the effector functions of T lymphocytes. The hierarchy of cell-fate-restriction events that occur as common lymphoid progenitors become committed to each of the ILC lineages further underscores the relationship between these innate immune cells and T lymphocytes. In this Review we discuss the developmental program of ILCs and transcription factors that guide ILC lineage specification and commitment. PMID:27328007

  4. Update on lymphoid interstitial pneumonitis.

    PubMed

    Fishback, N; Koss, M

    1996-09-01

    Lymphoid interstitial pneumonitis (LIP) involves a clinicopathologic pattern of pulmonary disease characterized by diffuse interstitial reactive lymphoid infiltrates. In adults, it occurs most commonly in autoimmune diseases, such as Sjögren's syndrome (0.9% of these patients) and primary biliary cirrhosis, whereas in children it is usually seen in HIV infection. Dysproteinemias (hyper- and hypogammaglobulinemia) are found in more than 60% of patients. Children can show CD8-lymphocytosis in bronchoalveolar lavage fluid, lung tissue, peripheral blood, and salivary gland, associated with HLA-DR5 haplotype. Radiographically, most patients with LIP have reticulonodular infiltrates, with or without patchy areas of consolidation. CT scans can show both small nodular and ground glass patterns, patterns that are diagnostically nonspecific. Reduced lung volumes and diffusing capacities are consistent and sensitive indicators of disease in LIP. In an experimental model, diffusing capacity was the single most sensitive functional index of disease progression. Microscopically, LIP is part of a spectrum of pulmonary lymphoid proliferations, ranging from follicular bronchitis-bronchiolitis and pulmonary lymphoid hyperplasia (the latter in AIDS patients), proliferations largely limited to airways, to low-grade malignant lymphoma. These patterns may be difficult to differentiate from each other. It appears that LIP sometimes evolves to lymphoma; the frequency of this evolution is probably low but is difficult to assess because low-grade lymphomas may mimic LIP. A relatively high frequency of LIP patients have Epstein-Barr virus DNA in their lungs but not all patients with LIP show this finding, suggesting other possible etiologies. PMID:9363179

  5. Total lymphoid irradiation

    SciTech Connect

    Sutherland, D.E.; Ferguson, R.M.; Simmons, R.L.; Kim, T.H.; Slavin, S.; Najarian, J.S.

    1983-05-01

    Total lymphoid irradiation by itself can produce sufficient immunosuppression to prolong the survival of a variety of organ allografts in experimental animals. The degree of prolongation is dose-dependent and is limited by the toxicity that occurs with higher doses. Total lymphoid irradiation is more effective before transplantation than after, but when used after transplantation can be combined with pharmacologic immunosuppression to achieve a positive effect. In some animal models, total lymphoid irradiation induces an environment in which fully allogeneic bone marrow will engraft and induce permanent chimerism in the recipients who are then tolerant to organ allografts from the donor strain. If total lymphoid irradiation is ever to have clinical applicability on a large scale, it would seem that it would have to be under circumstances in which tolerance can be induced. However, in some animal models graft-versus-host disease occurs following bone marrow transplantation, and methods to obviate its occurrence probably will be needed if this approach is to be applied clinically. In recent years, patient and graft survival rates in renal allograft recipients treated with conventional immunosuppression have improved considerably, and thus the impetus to utilize total lymphoid irradiation for its immunosuppressive effect alone is less compelling. The future of total lymphoid irradiation probably lies in devising protocols in which maintenance immunosuppression can be eliminated, or nearly eliminated, altogether. Such protocols are effective in rodents. Whether they can be applied to clinical transplantation remains to be seen.

  6. Phosphatidylazidothymidine and phosphatidyl-ddC: assessment of uptake in mouse lymphoid tissues and antiviral activities in human immunodeficiency virus-infected cells and in Rauscher leukemia virus-infected mice.

    PubMed Central

    Hostetler, K Y; Richman, D D; Sridhar, C N; Felgner, P L; Felgner, J; Ricci, J; Gardner, M F; Selleseth, D W; Ellis, M N

    1994-01-01

    During the early stages of human immunodeficiency virus (HIV) infection, although symptoms are absent and viral replication in peripheral blood mononuclear cells is low, substantial levels of HIV replication can be documented in lymphoid tissue [G. Pantaleo, C. Graziosi, J.F. Demarest, L. Butini, M. Montroni, C.H. Fox, J.M. Orenstein, D.P. Kotler, and A.S. Fauci, Nature (London) 362:355-358, 1993, and J. Embretsen, M. Zupancic, J.L. Ribas, A. Burke, P. Racz, K. Tenner-Tacz, and A.T. Haase, Nature (London) 362:359-362, 1993]. This observation suggests that earlier treatment of HIV infection may be indicated and that strategies for enhancing drug targeting to the lymphoid tissue reservoris of HIV infection may be beneficial. To address this issue, we synthesized dioleoylphosphatidyl-ddC (DOP-ddC) and dipalmitoylphosphatidyl-3'-azido-3'-deoxythymidine (DPP-AZT), phospholipid prodrugs which form lipid bilayers and which are readily incorporated into liposomes. The anti-HIV activity of DOP-ddC was similar to that of ddC in HIV type 1-infected HT4-6C cells, but DPP-AZT was considerably less active than AZT in HT4-6C cells. Liposomes containing DOP-[3H]ddC or DPP-[3H]AZT administered intraperitoneally to mice produced greater levels of total radioactivity over time in plasma, spleen, and lymphoid tissue relative to the results with [3H]ddC and [3H]AZT, respectively. DPP-AZT administered intraperitoneally in liposomes as a single daily dose to mice infected with Rauscher leukemia virus prevented increased spleen weight and reverse transcriptase levels in serum with a dose-response roughly comparable to that of AZT given continuously in the drinking water. DOP-ddC, DPP-AZT, and lipid conjugates of other antiretroviral nucleosides may provide higher levels of drug over time in plasma and in lymph nodes and spleen, important reservoirs of HIV infection, and may represent an interesting alternative approach to antiviral nucleoside treatment of AIDS. PMID:7695264

  7. Oral administration of drugs with hypersensitivity potential induces germinal center hyperplasia in secondary lymphoid organ/tissue in Brown Norway rats, and this histological lesion is a promising candidate as a predictive biomarker for drug hypersensitivity occurrence in humans

    SciTech Connect

    Tamura, Akitoshi Miyawaki, Izuru; Yamada, Toru; Kimura, Juki; Funabashi, Hitoshi

    2013-08-15

    It is important to evaluate the potential of drug hypersensitivity as well as other adverse effects during the preclinical stage of the drug development process, but validated methods are not available yet. In the present study we examined whether it would be possible to develop a new predictive model of drug hypersensitivity using Brown Norway (BN) rats. As representative drugs with hypersensitivity potential in humans, phenytoin (PHT), carbamazepine (CBZ), amoxicillin (AMX), and sulfamethoxazole (SMX) were orally administered to BN rats for 28 days to investigate their effects on these animals by examinations including observation of clinical signs, hematology, determination of serum IgE levels, histology, and flow cytometric analysis. Skin rashes were not observed in any animals treated with these drugs. Increases in the number of circulating inflammatory cells and serum IgE level did not necessarily occur in the animals treated with these drugs. However, histological examination revealed that germinal center hyperplasia was commonly induced in secondary lymphoid organs/tissues in the animals treated with these drugs. In cytometric analysis, changes in proportions of lymphocyte subsets were noted in the spleen of the animals treated with PHT or CBZ during the early period of administration. The results indicated that the potential of drug hypersensitivity was identified in BN rat by performing histological examination of secondary lymphoid organs/tissues. Data obtained herein suggested that drugs with hypersensitivity potential in humans gained immune reactivity in BN rat, and the germinal center hyperplasia induced by administration of these drugs may serve as a predictive biomarker for drug hypersensitivity occurrence. - Highlights: • We tested Brown Norway rats as a candidate model for predicting drug hypersensitivity. • The allergic drugs did not induce skin rash, whereas D-penicillamine did so in the rats. • Some of allergic drugs increased

  8. Immunohistochemical characterization of selected cell markers for the detection of hematopoietic cells in formalin-fixed, paraffin wax-embedded lymphoid tissues of harbor seals (Phoca vitulina) and walruses (Odobenus rosmarus rosmarus).

    PubMed

    Seibel, H; Stimmer, L; Siebert, U; Beineke, A

    2010-10-15

    To facilitate a detailed investigation of pinniped lymphoid organs, 30 monoclonal antibodies (mAb) as well as eight polyclonal antibodies (pAb) of different species specificities directed against cell antigens of the hematopoietic system were tested for immunohistochemical cross-reactivity on formalin-fixed, paraffin wax-embedded tissues of harbor seals (Phoca vitulina) and a walrus (Odobenus rosmarus rosmarus). Six monoclonal and eight polyclonal antibodies showed specific immunoreactivities. Lymphocytes were immunolabeled by an anti-CD3 pAb, anti-Foxp3 mAb and anti-CD79 alpha mAb, while plasma cell subpopulations were recognized by anti-IgA pAb, anti-IgG pAb and anti-IgM pAb as well as by anti-kappa- and anti-lambda light chain pAb. Cells of the histiocytic lineage were recognized by lysozyme-, myeloid/histiocyte antigen-, and CD68-specific markers. Furthermore, dendritic cell-like cells were detected by an anti-S100 protein pAb. The MHC class II antigen was labeled on the majority of immune cells of the harbor seal and walrus using a bovine mAb. Mast cells were stained by an anti-mast cell tryptase mAb. Thus, using these antibodies from various species, it is now possible to determine phenotypical changes in lymphoid organs and detect different leukocyte subsets involved in inflammatory responses in archived tissue samples of these pinniped species. PMID:20566219

  9. Coincidence of different structures of mucosa-associated lymphoid tissue (MALT) in the respiratory tract of children: no indications for enhanced mucosal immunostimulation in sudden infant death syndrome (SIDS)

    PubMed Central

    Debertin, A S; Tschernig, T; Schürmann, A; Bajanowski, T; Brinkmann, B; Pabst, R

    2006-01-01

    Mucosa-associated lymphoid tissue (MALT) is the principal inductive site for mucosal immune responses that are capable of T and B cell responses and antigen-specific responses. In previous independent studies different structures of MALT, e.g. bronchus-, larynx- and nose-associated lymphoid tissue (BALT, LALT, NALT) have been described separately in various frequencies in the human respiratory tract over life spans. Because upper respiratory tract infections are common in infants, dysregulations of mucosal immune responses might be seriously involved in the aetiology of sudden infant death syndrome (SIDS). In the present study the coincidental occurrence of the three different MALT structures in the respiratory tract within the same patients were studied, and cases of SIDS and children who had died from different traumatic and natural causes of death (non-SIDS) were compared. First, the frequency of BALT and LALT in 46 children (35 SIDS, 11 non-SIDS) with or without NALT were examined. A tendency was found of a coincidence of respiratory MALT structures. In 50 additional cases of infant death (30 SIDS, 20 non-SIDS) from the multi-centric German Study on Sudden Infant Death Syndrome (GeSID) where death had occurred in the first year of life, the coincidence was evaluated. A coincidental occurrence of BALT, LALT and NALT or BALT and LALT (each about 30%) was found in both groups, whereby the coincidence in SIDS and the control patients did not differ. Interestingly, the children with coincidental MALT were strikingly older, supporting the hypothesis of respiratory MALT formation via environmental stimulation over time. PMID:16968398

  10. Benign Lymphoid Hyperplasia Presenting as Bilateral Scleral Nodules

    PubMed Central

    Cumba, Ricardo J.; Vazquez-Botet, Rene

    2015-01-01

    Purpose. To report a case of transient lymphoid hyperplasia presenting as bilateral nodular scleral mass in a young male patient. Design. Observational case report. Methods. Chart review. Causes of scleritis were considered and excluded based on detailed history, physical examination, and laboratory investigations. Results. Excisional biopsy of scleral lesions indicated lymphoid tissue. Immunohistochemical studies revealed a polyclonal population of T and B cells consistent with a benign reactive process. Conclusions. Chronic exposure of the ocular adnexa to many allergens and irritants may lead to activation of the inflammatory cascade. In severely allergic patients activation may be exponential and elicit an immune-mediated response resulting in a transient lymphoid reactive process. PMID:26421203

  11. In vitro Differentiation of Murine Innate Lymphoid Cells from Common Lymphoid Progenitor Cells

    PubMed Central

    Seehus, Corey; Kaye, Jonathan

    2016-01-01

    Subtypes of innate lymphoid cells (ILC), defined based on their cytokine secretion profiles and transcription factor expression, are important for host protection from pathogens and maintaining tissue homeostasis. ILCs develop from common lymphoid progenitors (CLP) in the bone marrow. Using the methods described here, we have previously shown that loss of the transcriptional regulator TOX (Thymocyte-selection associated HMG-box protein) leads to specific changes in ILC development and differentiation. Here, we describe how to obtain ILCs from in vivo isolated CLP grown in vitro. PMID:27239483

  12. Cutaneous lymphoid hyperplasias.

    PubMed

    Gilliam, A C; Wood, G S

    2000-06-01

    Benign hyperplastic lymphoid infiltrates of the skin (pseudolymphoma, older term) simulate lymphoma clinically and histologically. They can be divided into B-cell predominant (typical cutaneous lymphoid hyperplasia (CLH), angiolymphoid hyperplasia, Kimura's disease, and Castleman's disease) and T-cell predominant (T-cell CLH, lymphomatoid contact dermatitis, and lymphomatoid drug eruption). Both types may represent exaggerated reactions to diverse external antigens (insect bite, tattoo, zoster, trauma, among others). A composite assessment of clinical presentation and behavior, routine histology, immunophenotyping, and molecular studies is essential for the diagnosis of benign cutaneous lymphoid infiltrates. Treatment includes antibiotics, intralesional and systemic corticosteroids, excision, radiotherapy, and immunosuppressants. Treatment depends on the assessment and biologic behavior, which is usually benign. Molecular biologic analysis has shown that a significant proportion of cases harbor occult B- or T-cell clones (clonal CLH). Progression to overt cutaneous lymphoma has been observed in a minority of cases. Patients with clonal populations of B or T cells and persistent lesions should be closely observed for emergence of a lymphoma. PMID:10892716

  13. Vascular Microarchitecture of Murine Colitis-Associated Lymphoid Angiogenesis

    PubMed Central

    Turhan, Aslihan; Lin, Miao; Lee, Grace S.; Miele, Lino; Tsuda, Akira; Konerding, Moritz A.; Mentzer, Steven J.

    2010-01-01

    In permissive tissues, such as the gut and synovium, chronic inflammation can result in the ectopic development of anatomic structures that resemble lymph nodes. These inflammation-induced structures, termed lymphoid neogenesis or tertiary lymphoid organs, may reflect differential stromal responsiveness to the process of lymphoid neogenesis. To investigate the structural reorganization of the microcirculation involved in colonic lymphoid neogenesis, we studied a murine model of dextran sodium sulfate (DSS)-induced colitis. Standard 2-dimensional histology demonstrated both submucosal and intramucosal lymphoid structures in DSS-induced colitis. A spatial frequency analysis of serial histologic sections suggested that most intramucosal lymphoid aggregates developed de novo. Intravital microscopy of intravascular tracers confirmed that the developing intramucosal aggregates were supplied by capillaries arising from the quasi-polygonal mucosal plexus. Confocal optical sections and whole mount morphometry demonstrated capillary networks (185±46um diameter) involving 6–10 capillaries with a luminal diameter of 6.8±1.1um. Microdissection and angiogenesis PCR array analysis demonstrated enhanced expression of multiple angiogenic genes including CCL2, CXCL2, CXCL5, Il-1b, MMP9 and TNF within the mucosal plexus. Intravital microscopy of tracer particle flow velocities demonstrated a marked decrease in flow velocity from 808±901um/sec within the feeding mucosal plexus to 491±155um/sec within the capillary structures. We conclude that the development of ectopic lymphoid tissue requires significant structural remodeling of the stromal microcirculation. A feature of permissive tissues may be the capacity for lymphoid angiogenesis. PMID:19382226

  14. Different Pathogenesis of CCR5-Using Primary HIV-1 Isolates from Non-Switch and Switch Virus Patients in Human Lymphoid Tissue Ex Vivo

    NASA Technical Reports Server (NTRS)

    Iarlsson, Ingrid; Grivel, Jean-Charles; Chen. Silvia; Karlsson, Anders; Albert, Jan; Fenyol, Eva Maria; Margolis, Leonid B.

    2005-01-01

    CCR5-utilizing HIV-1 variants (R5) typically transmit infection and dominate its early stages, whereas emergence of CXCR4-using (X4 or R5X4) HIV-1 is often associated with disease progression. However, such a switch in co-receptor usage can only be detected in approximately onehalf of HIV-infected patients (switch virus patients), and progression to immunodeficiency may also occur in patients without detectable switch in co-receptor usage (non-switch virus patients). Here, we used a system of ex vivo-infected tonsillar tissue to compare the pathogenesis of sequential primary R5 HIV-1 isolates from the switch and non-switch patients. Inoculation of ex vivo tissue with these R5 isolates resulted in viral replication and CCR5(+)CD4(+) T cell depletion. The levels of such depletion by HIV-1 isolated from non-switch virus patients were significantly higher than those by R5 HIV-1 isolates from switch virus patients. T cell depletion seemed to be controlled by viral factors and did not significantly vary between tissues from different donors. In contrast, viral replication did not correlate with the switch status of the patients; in tissues fiom different donors it varied 30-fold and seemed to be controlled by a combination of viral and tissue factors. Nevertheless, replication-level hierarchy among sequential isolates remained constant in tissues from various donors. Viral load in vivo was higher in switch virus patients compared to non-switch virus patients. The high cytopathogenicity of CCR5(+)CD4(+) T cells by R5 HIV-1 isolates from non-switch virus patients may explain the steady decline of CD4(+) T cells in the absence of CXCR4 using virus; elimination of target cells by these isolates may limit their own replication in vivo.

  15. A Stromal Cell Niche for Human and Mouse Type 3 Innate Lymphoid Cells.

    PubMed

    Hoorweg, Kerim; Narang, Priyanka; Li, Zhi; Thuery, Anne; Papazian, Natalie; Withers, David R; Coles, Mark C; Cupedo, Tom

    2015-11-01

    Adaptive immunity critically depends on the functional compartmentalization of secondary lymphoid organs. Mesenchymal stromal cells create and maintain specialized niches that support survival, activation, and expansion of T and B cells, and integrated analysis of lymphocytes and their niche has been instrumental in understanding adaptive immunity. Lymphoid organs are also home to type 3 innate lymphoid cells (ILC3), innate effector cells essential for barrier immunity. However, a specialized stromal niche for ILC3 has not been identified. A novel lineage-tracing approach now identifies a subset of murine fetal lymphoid tissue organizer cells that gives rise exclusively to adult marginal reticular cells. Moreover, both cell types are conserved from mice to humans and colocalize with ILC3 in secondary lymphoid tissues throughout life. In sum, we provide evidence that fetal stromal organizers give rise to adult marginal reticular cells and form a dedicated stromal niche for innate ILC3 in adaptive lymphoid organs. PMID:26378073

  16. A stromal cell niche for human and mouse type 3 innate lymphoid cells ¶

    PubMed Central

    Li, Zhi; Thuery, Anne; Papazian, Natalie; Withers, David R.; Coles, Mark C.; Cupedo, Tom

    2015-01-01

    Adaptive immunity critically depends on the functional compartmentalization of secondary lymphoid organs. Mesenchymal stromal cells create and maintain specialized niches that support survival, activation and expansion of T and B cells, and integrated analysis of lymphocytes and their niche has been instrumental in understanding adaptive immunity. Lymphoid organs are also home to type 3 innate lymphoid cells (ILC3), innate effector cells essential for barrier immunity. However, a specialized stromal niche for ILC3 has not been identified. A novel lineage-tracing approach now identifies a subset of murine fetal lymphoid tissue organizer cells that gives rise exclusively to adult marginal reticular cells (MRC). Moreover, both cell types are conserved from mouse to human and co-localize with ILC3 in secondary lymphoid tissues throughout life. In sum, we provide evidence that fetal stromal organizers give rise to adult MRC and form a dedicated stromal niche for innate ILC3 in adaptive lymphoid organs. PMID:26378073

  17. Confirmation of immunoglobulin heavy chain rearrangement by polymerase chain reaction using surgically obtained, paraffin-embedded samples to diagnose primary palate mucosa-associated lymphoid tissue lymphoma: A case study

    PubMed Central

    Abe, Shigehiro; Yokomizo, Naoko; Kobayashi, Yutaka; Yamamoto, Kouhei

    2015-01-01

    Introduction Intraoral mucosa-associated lymphoid tissue (MALT) lymphoma is a rare lymphoma that has a good prognosis if diagnosed correctly and treated in time. Presentation of case A 64-year-old woman was referred to our department with asymptomatic swelling of the left hard palate. Computed tomography and magnetic resonance imaging revealed a mass in the left hard palate. We performed a pre-surgery biopsy; however, it was difficult to differentiate MALT lymphoma from other reactive lymphoproliferative disorders via gross or microscopic examination. Although the lesion was completely excised, histological findings did not allow a definitive diagnosis due to an absence of visible monoclonality. We then performed polymerase chain reaction (PCR) using DNA extracted from formalin-fixed, paraffin-embedded surgical samples. Capillary electrophoresis showed monoclonal peaks of immunoglobulin heavy chain gene rearrangement, thus facilitating a definitive diagnosis of MALT lymphoma. Discussion PCR technique is rapid, accurate, and enables a definitive diagnosis without relying on traditional histological or molecular diagnostic techniques, such as Southern blotting. Conclusion We suggest that, if histological examination is ambiguous or fresh material is insufficient, PCR can be performed using paraffin-embedded materials to definitively diagnose low-grade lymphomas, such as MALT lymphoma. PMID:25841155

  18. Seeded Amplification of Chronic Wasting Disease Prions in Nasal Brushings and Recto-anal Mucosa-Associated Lymphoid Tissues from Elk by Real-Time Quaking-Induced Conversion.

    PubMed

    Haley, Nicholas J; Siepker, Chris; Hoon-Hanks, Laura L; Mitchell, Gordon; Walter, W David; Manca, Matteo; Monello, Ryan J; Powers, Jenny G; Wild, Margaret A; Hoover, Edward A; Caughey, Byron; Richt, Jürgen A

    2016-04-01

    Chronic wasting disease (CWD), a transmissible spongiform encephalopathy of cervids, was first documented nearly 50 years ago in Colorado and Wyoming and has since been detected across North America and the Republic of Korea. The expansion of this disease makes the development of sensitive diagnostic assays and antemortem sampling techniques crucial for the mitigation of its spread; this is especially true in cases of relocation/reintroduction or prevalence studies of large or protected herds, where depopulation may be contraindicated. This study evaluated the sensitivity of the real-time quaking-induced conversion (RT-QuIC) assay of recto-anal mucosa-associated lymphoid tissue (RAMALT) biopsy specimens and nasal brushings collected antemortem. These findings were compared to results of immunohistochemistry (IHC) analysis of ante- and postmortem samples. RAMALT samples were collected from populations of farmed and free-ranging Rocky Mountain elk (Cervus elaphus nelsoni;n= 323), and nasal brush samples were collected from a subpopulation of these animals (n= 205). We hypothesized that the sensitivity of RT-QuIC would be comparable to that of IHC analysis of RAMALT and would correspond to that of IHC analysis of postmortem tissues. We found RAMALT sensitivity (77.3%) to be highly correlative between RT-QuIC and IHC analysis. Sensitivity was lower when testing nasal brushings (34%), though both RAMALT and nasal brush test sensitivities were dependent on both thePRNPgenotype and disease progression determined by the obex score. These data suggest that RT-QuIC, like IHC analysis, is a relatively sensitive assay for detection of CWD prions in RAMALT biopsy specimens and, with further investigation, has potential for large-scale and rapid automated testing of antemortem samples for CWD. PMID:26888899

  19. [Primary mucosa-associated lymphoid tissue (MALT) lymphoma of the urinary bladder associated with left renal pelvic carcinoma: a case report].

    PubMed

    Hatano, Koji; Sato, Mototaka; Tsujimoto, Yuichi; Takada, Tsuyoshi; Honda, Masato; Matsumiya, Kiyomi; Fujioka, Hideki; Oka, Kazuhisa; Tsujimoto, Masahiko

    2007-01-01

    We report a case of primary mucosa-associated lympoid tissue (MALT) lymphoma of the urinary bladder associated with left renal pelvic carcinoma. A 84-year-old woman showed microscopic hematuria during follow up for hypertention. Left renal pelvic tumor was found and she was referred to our hospital for further evaluation and managemant. She showed pyuria and Escherichia coli was detected by urine culture. Intravenous pyelography and computed tomography revealed the left renal pelvic tumor and solid bladder tumor. Transurethral resection of bladder tumor and left total nephroureterectomy were performed. Histologically, the left renal pelvic tumor was urothelial carcinoma > > adenocarcinoma, G2, pT2 and the bladder tumor was MALT lymphoma. Ga-scintigraphy showed no hot uptake suspicious of metastatic lesion. Then, external beam radiotherapy (36 Gy) was performed to the urinary bladder. She has been alive for 14 months with neither renal pelvic tumor nor MALT lymphoma showing any evidence of disease progression. PMID:17310771

  20. Activation of intraislet lymphoid cells causes destruction of islet cells.

    PubMed Central

    Lacy, P. E.; Finke, E. H.

    1991-01-01

    In vitro culture of rat islets at 24 degrees C for 7 days in tissue culture medium CMRL 1066 almost completely eliminated lymphoid cells from the islets. Immunostaining of the islets with monoclonal antibody OX4 for demonstration of class II major histocompatibility complex (MHC)-expressing cells revealed a decrease from 13.1 +/- 0.6 positive cells per islet on day 0 to 0.7 +/- 0.1 cells per islet on day 7. A comparable decrease was found using OX1 for demonstration of all leukocytes. In contrast, culture of rat islets at 24 degrees C for 7 days with tissue culture Roswell Park Memorial Institute (RPMI) 1640 medium was not as effective in eliminating lymphoid cells as in medium CMRL 1066 (3.0 +/- 0.2 class II MHC positive cells per islet at 7 days). Effective elimination of intraislet lymphoid cells apparently is due to the combined effect of low temperature culture and the tissue culture medium CMRL-1066. The second goal of the study was to determine whether the destructive effect of interferon gamma (IFN-gamma) on rat islets in culture was due to intraislet lymphoid cells. In vitro culture of rat islets with IFN-gamma (1000 units/ml) at 37 degrees C caused almost complete destruction of the islets at 7 days. If intraislet lymphoid cells were eliminated from the islets by in vitro culture at 24 degrees C followed by exposure to IFN-gamma (1000 units/ml) for 7 days at 37 degrees C, then IFN-gamma did not cause destruction of the islets and transplants of the treated islets produced normoglycemia in diabetic recipient mice. These findings indicate that intraislet lymphoid cells are responsible for destruction of islet cells when these cells (presumably macrophages) are activated by IFN-gamma. Intraislet lymphoid cells may play a significant role in destroying islet cells in autoimmune diabetes. Images Figure 1 Figure 2 PMID:1902627

  1. Norisoboldine ameliorates collagen-induced arthritis through regulating the balance between Th17 and regulatory T cells in gut-associated lymphoid tissues

    SciTech Connect

    Tong, Bei; Dou, Yannong; Wang, Ting; Yu, Juntao; Wu, Xin; Lu, Qian; Chou, Guixin; Wang, Zhengtao; Kong, Lingyi; Dai, Yue; Xia, Yufeng

    2015-01-01

    Norisoboldine (NOR), the main active ingredient of the dry root of Lindera aggregata, was previously proven to have substantial therapeutic effects on collagen-induced arthritis (CIA) in mice by oral administration. However, it exhibited a very poor bioavailability in normal rats. The pharmacokinetic–pharmacodynamics disconnection attracts us to explore its anti-arthritic mechanism in more detail. In this study, NOR, administered orally, markedly attenuated the pathological changes in CIA rats, which was accompanied by the down-regulation of pro-inflammatory cytokines and the up-regulation of anti-inflammatory cytokine IL-10. Pharmacokinetic studies demonstrated that the plasma concentration of NOR was moderately elevated in CIA rats compared with normal rats, but it was still far lower than the minimal effective concentration required for inhibiting the proliferation and activation of T lymphocytes in vitro. Interestingly, NOR was shown to regulate the balance between Th17 and regulatory T (Treg) cells in the intestinal lymph nodes more strikingly than in other tissues. It could increase the expression of Foxp3 mRNA in both gut and joints, and markedly up-regulate the number of integrin α4β7 (a marker of gut source)-positive Foxp3{sup +} cells in the joints of CIA rats. These results suggest that the gut might be the primary action site of NOR, and NOR exerts anti-arthritis effect through regulating the balance between Th17 and Treg cells in intestinal lymph nodes and yielding a trafficking of lymphocytes (especially Treg cells) from the gut to joint. The findings of the present study also provide a plausible explanation for the anti-arthritic effects of poorly absorbed compounds like NOR. - Highlights: • Norisoboldine, administered orally, markedly attenuates the clinical signs of CIA. • Norisoboldine regulates the balance of Th17/Treg cells in the intestinal lymph node. • Norisoboldine induces the migration of Treg cells from the gut to joint.

  2. Genetic errors of the human caspase recruitment domain-B-cell lymphoma 10-mucosa-associated lymphoid tissue lymphoma-translocation gene 1 (CBM) complex: Molecular, immunologic, and clinical heterogeneity.

    PubMed

    Pérez de Diego, Rebeca; Sánchez-Ramón, Silvia; López-Collazo, Eduardo; Martínez-Barricarte, Rubén; Cubillos-Zapata, Carolina; Ferreira Cerdán, Antonio; Casanova, Jean-Laurent; Puel, Anne

    2015-11-01

    Three members of the caspase recruitment domain (CARD) family of adaptors (CARD9, CARD10, and CARD11) are known to form heterotrimers with B-cell lymphoma 10 (BCL10) and mucosa-associated lymphoid tissue lymphoma-translocation gene 1 (MALT1). These 3 CARD-BCL10-MALT1 (CBM) complexes activate nuclear factor κB in both the innate and adaptive arms of immunity. Human inherited defects of the 3 components of the CBM complex, including the 2 adaptors CARD9 and CARD11 and the 2 core components BCL10 and MALT1, have recently been reported. Biallelic loss-of-function mutant alleles underlie several different immunologic and clinical phenotypes, which can be assigned to 2 distinct categories. Isolated invasive fungal infections of unclear cellular basis are associated with CARD9 deficiency, whereas a broad range of clinical manifestations, including those characteristic of T- and B-lymphocyte defects, are associated with CARD11, MALT1, and BCL10 deficiencies. Interestingly, human subjects with these mutations have some features in common with the corresponding knockout mice, but other features are different between human subjects and mice. Moreover, germline and somatic gain-of-function mutations of MALT1, BCL10, and CARD11 have also been found in patients with other lymphoproliferative disorders. This broad range of germline and somatic CBM lesions, including loss-of-function and gain-of-function mutations, highlights the contribution of each of the components of the CBM complex to human immunity. PMID:26277595

  3. Neuropathogenic SIVsmmFGb Genetic Diversity and Selection-Induced Tissue-Specific Compartmentalization During Chronic Infection and Temporal Evolution of Viral Genes in Lymphoid Tissues and Regions of the Central Nervous System

    PubMed Central

    Reeve, Aaron B.; Pearce, Nicholas C.; Patel, Kalpana; Augustus, Katherine V.

    2010-01-01

    Abstract SIVsmmFGb is a lentivirus swarm that induces neuropathology in over 90% of infected pigtailed macaques and reliably models central nervous system HIV infection in people. We have previously studied SIVsmmFGb genetic diversity and compartmentalization during acute infection, but little is understood about diversity and intertissue compartmentalization during chronic infection. Tissue-specific pressure appeared to affect the diversity of Nef sequences between tissues, but changes to the Env V1 region and Int diversity were similar across all tissues. At 2 months postinfection, compartmentalization of the SIVsmmFGb env V1 region, nef, and int was noted between different brain regions and between brain regions and lymph nodes. Convergent evolution of the nef and env V1 region, and divergent evolution of int, was noted between compartments and all genes demonstrated intratissue temporal segregation. For the env V1 region and nef, temporal segregation was stronger in the brain regions than the periphery, but little difference between tissues was noted for int. Positive selection of the env V1 region appeared in most tissues at 2 months postinfection, whereas nef and int faced negative selection in all tissues. Positive selection of the env V1 region sequences increased in some brain regions over time. SIVsmmFGb nef and int sequences each saw increased negative selection in brain regions, and one lymph node, over the course of infection. Functional differences between tissue compartments decreased over time for int and env V1 region sequences, but increased for nef sequences. PMID:20518690

  4. Distribution of particulate matter and tissue remodeling in the human lung.

    PubMed Central

    Pinkerton, K E; Green, F H; Saiki, C; Vallyathan, V; Plopper, C G; Gopal, V; Hung, D; Bahne, E B; Lin, S S; Ménache, M G; Schenker, M B

    2000-01-01

    We examined the relationship between intrapulmonary particle distribution of carbonaceous and mineral dusts and remodeling of the airways along anatomically distinct airway paths in the lungs of Hispanic males from the central valley of California. Lung autopsy specimens from the Fresno County Coroner's Office were prepared by intratracheal instillation of 2% glutaraldehyde at 30 cm H(2)O pressure. Two distinct airway paths into the apico-posterior and apico-anterior portions of the left upper lung lobe were followed. Tissue samples for histologic analysis were generally taken from the intrapulmonary second, fourth, sixth, and ninth airway generations. Parenchymal tissues beyond the 12th airway generation of each airway path were also analyzed. There was little evidence of visible particle accumulation in the larger conducting airways (generations 2-6), except in bronchial-associated lymphoid tissues and within peribronchial connective tissue. In contrast, terminal and respiratory bronchioles arising from each pathway revealed varying degrees of wall thickening and remodeling. Walls with marked thickening contained moderate to heavy amounts of carbonaceous and mineral dusts. Wall thickening was associated with increases in collagen and interstitial inflammatory cells, including dust-laden macrophages. These changes were significantly greater in first-generation respiratory bronchioles compared to second- and third-generation respiratory bronchioles. These findings suggest that accumulation of carbonaceous and mineral dust in the lungs is significantly affected by lung anatomy with the greatest retention in centers of lung acini. Furthermore, there is significant remodeling of this transitional zone in humans exposed to ambient particulate matter. PMID:11102298

  5. Differential distribution of calpain in human lymphoid cells.

    PubMed

    Deshpande, R V; Goust, J M; Banik, N L

    1993-07-01

    Calpain, a calcium-activated neutral proteinase, is ubiquitously present in human tissues. To determine if lymphoid cells implicated in pathogenesis of demyelination may harbor calpain in a functionally active form, we determined both muCalpain and mCalpain activities in human lymphoid cell lines. DEAE-cellulose and phenylsepharose column chromatography were used to isolate the enzyme from the natural inhibitor, calpastatin. Lymphocytic lines (CCRF-CEM, MOLT-3, MOLT-4, M.R.) showed predominance of muCalpain (55-80%) whereas the monocytic line (U-937) showed predominance of mCalpain (77%). Proportion and subcellular distribution of both isoforms varied among cell lines. Calpains isolated from U-937 cells degraded myelin basic protein. These results indicate that human lymphoid cells harbor functionally active calpain that can degrade myelin components in vitro. The study suggests a degradative role for calpain in demyelinating diseases. PMID:7690115

  6. [Rectal tonsil or lymphoid follicular hyperplasia of the rectum].

    PubMed

    Trillo Fandiño, L; Arias González, M; Iglesias Castañón, A; Fernández Eire, M P

    2014-01-01

    The rectal tonsil is a reactive proliferation of lymphoid tissue located in the rectum. The morphology of the lymphoid proliferation of the colon is usually polypoid or, less commonly, nodular. Only in exceptional cases does lymphoid proliferation of the colon present as a mass in the rectum (rectal tonsil), although this is the most common presentation in middle-aged patients. It is important to be familiar with the rectal tonsil because in cases of exuberant growth it can be difficult to distinguish it from other types of masses. We present the case of rectal tonsil in a four-year-old girl. We describe the magnetic resonance imaging findings and review the literature. PMID:22112591

  7. Survival in rectal cancer is predicted by T cell infiltration of tumour-associated lymphoid nodules

    PubMed Central

    McMullen, T P W; Lai, R; Dabbagh, L; Wallace, T M; de Gara, C J

    2010-01-01

    Lymphoid nodules are a normal component of the mucosa of the rectum, but little is known about their function and whether they contribute to the host immune response in malignancy. In rectal cancer specimens from patients with local (n = 18), regional (n = 12) and distant (n = 10) disease, we quantified T cell (CD3, CD25) and dendritic cell (CD1a, CD83) levels at the tumour margin as well as within tumour-associated lymphoid nodules. In normal tissue CD3+, but not CD25+, T cells are concentrated at high levels within lymphoid nodules, with significantly fewer cells found in surrounding normal mucosa (P = 0·001). Mature (CD83), but not immature (CD1a), dendritic cells in normal tissue are also found clustered almost exclusively within lymphoid nodules (P = < 0·0001). In rectal tumours, both CD3+ T cells (P = 0·004) and CD83+ dendritic cells (P = 0·0001) are also localized preferentially within tumour-associated lymphoid nodules. However, when comparing tumour specimens to normal rectal tissue, the average density of CD3+ T cells (P = 0·0005) and CD83+ dendritic cells (P = 0·0006) in tumour-associated lymphoid nodules was significantly less than that seen in lymphoid nodules in normal mucosa. Interestingly, regardless of where quantified, T cell and dendritic cell levels did not depend upon the stage of disease. Increased CD3+ T cell infiltration of tumour-associated lymphoid nodules predicted improved survival, independent of stage (P = 0·05). Other T cell (CD25) markers and different levels of CD1a+ or CD83+ dendritic cells did not predict survival. Tumour-associated lymphoid nodules, enriched in dendritic cells and T cells, may be an important site for antigen presentation and increased T cell infiltration may be a marker for improved survival. PMID:20408858

  8. Impaired telomerase activity hinders proliferation and in vitro transformation of Penaeus monodon lymphoid cells.

    PubMed

    Jayesh, P; Vrinda, S; Priyaja, P; Philip, Rosamma; Singh, I S Bright

    2016-08-01

    Retaining terminal transferase activity of telomerase, the ribonucleoprotein enzyme which add telomeric repeats on chromosome end is thought to be required to prevent cellular ageing. Additionally, telomerase considered as a marker for cell proliferation and immortalization in eukaryotes. We examined telomerase activity in tissues and lymphoid cell culture of Penaeus monodon. Along with telomerase activity, telomere repeats and an attempt on identification of telomerase reverse transcriptase (PmTERT) were made. Telomeric repeat amplification protocol revealed that telomerase-dependent telomeric lengthening has been taking place in P. monodon and the adult tissues were retaining this capacity throughout their lifespan with the highest activity in ovary, testis and lymphoid organ. However, telomerase activity could not be detected in lymphoid cells in culture. The canonical telomeric repeats added by telomerase of lymphoid tissue extract were identified as TTAGG, but pentameric repeats GGTTA and AGGTT were also added by the telomerase. PmTERT protein sequence (partial) shared 100 % identity with the TERT sequence of Daphnia pulex, 27 % sequence identity with Purple sea urchin and 24-25 % with Zebra fish. Undetectable telomerase activity in lymphoid cell culture supports the hypothesis that the inadequate telomerase activity or gene expression may be a reason that prevents neoplastic transformation and spontaneous immortalization of the cells in vitro. Thus, it is envisaged that telomerase activation in lymphoid cells may surmount cellular ageing for in vitro transformation and cell line establishment. PMID:26084784

  9. The cellular protein expression of Foxp3 in lymphoid and non-lymphoid organs of Nile tilapia.

    PubMed

    Jia, Cunxin; Zhou, Yujie; Huang, Xiaohuan; Peng, Xi; Liu, Linyan; Zhou, Linyan; Jin, Li; Shi, Hongjuan; Wei, Jing; Wang, Deshou

    2015-08-01

    In the present study, an antibody highly specific to the Nile tilapia (Oreochromis niloticus) Foxp3 was produced and characterized. Immunohistochemistry analysis indicates that Foxp3 was expressed in peripheral blood mononuclear cells (PBMC) and certain packed lymphocytes in particular, what's more, the percentage of Foxp3(+) cells among PBMC was 5.7 ± 2.0% (n = 5) in healthy adults and could be significantly up-regulated after phytohemagglutinin (50 μg/ml) stimulation in vitro at 6, 12 and 24 h, respectively. In the lymphoid tissues, such as the thymus, spleen and head kidney, Foxp3 expression was observed mainly in lymphocyte-like cells. Surprisingly, in the non-lymphoid organ stomach, Foxp3 was detected in epithelial-like cells within the mucosa. Our study demonstrates for the first time that Foxp3 protein expression occurs not only in hematopoietic cells of lymphoid organ systems but also non-hematopoietic cells of non-lymphoid organ in lower vertebrates such as the fish tilapia. The conserved expression pattern of Foxp3 at the protein and cellular levels implies that it might have conserved functions from fish to mammals. PMID:25804488

  10. Flt3 Ligand Regulates the Development of Innate Lymphoid Cells in Fetal and Adult Mice.

    PubMed

    Baerenwaldt, Anne; von Burg, Nicole; Kreuzaler, Matthias; Sitte, Selina; Horvath, Edit; Peter, Annick; Voehringer, David; Rolink, Antonius G; Finke, Daniela

    2016-03-15

    Flt3 ligand (Flt3L) promotes survival of lymphoid progenitors in the bone marrow and differentiation of dendritic cells (DCs), but its role in regulating innate lymphoid cells (ILCs) during fetal and adult life is not understood. By using Flt3L knockout and transgenic mice, we demonstrate that Flt3L controls ILC numbers by regulating the pool of α4β7(-) and α4β7(+) lymphoid tissue inducer cell progenitors in the fetal liver and common lymphoid progenitors in the bone marrow. Deletion of flt3l severely reduced the number of fetal liver progenitors and lymphoid tissue inducer cells in the neonatal intestine, resulting in impaired development of Peyer's patches. In the adult intestine, NK cells and group 2 and 3 ILCs were severely reduced. This effect occurred independently of DCs as ILC numbers were normal in mice in which DCs were constitutively deleted. Finally, we could show that administration of Flt3L increased the number of NKp46(-) group 3 ILCs in wild-type and even in Il7(-/-) mice, which generally have reduced numbers of ILCs. Taken together, Flt3L significantly contributes to ILC and Peyer's patches development by targeting lymphoid progenitor cells during fetal and adult life. PMID:26851220

  11. Peripheral Lymphoid Volume Expansion and Maintenance Are Controlled by Gut Microbiota via RALDH+ Dendritic Cells.

    PubMed

    Zhang, Zongde; Li, Jianjian; Zheng, Wencheng; Zhao, Guang; Zhang, Hong; Wang, Xiaofei; Guo, Yaqian; Qin, Chuan; Shi, Yan

    2016-02-16

    Lymphocyte homing to draining lymph nodes is critical for the initiation of immune responses. Secondary lymphoid organs of germ-free mice are underdeveloped. How gut commensal microbes remotely regulate cellularity and volume of secondary lymphoid organs remains unknown. We report here that, driven by commensal fungi, a wave of CD45(+)CD103(+)RALDH(+) cells migrates to the peripheral lymph nodes after birth. The arrival of these cells introduces high amounts of retinoic acid, mediates the neonatal to adult addressin switch on endothelial cells, and directs the homing of lymphocytes to both gut-associated lymphoid tissues and peripheral lymph nodes. In adult mice, a small number of these RALDH(+) cells might serve to maintain the volume of secondary lymphoid organs. Homing deficiency of these cells was associated with lymph node attrition in vitamin-A-deficient mice, suggesting a perpetual dependence on retinoic acid signaling for structural and functional maintenance of peripheral immune organs. PMID:26885858

  12. Changes in CD4+, CD8+, CD4+ CD8+, and Immunoglobulin M-Positive Peripheral Blood Mononuclear Cells of Postweaning Multisystemic Wasting Syndrome-Affected Pigs and Age-Matched Uninfected Wasted and Healthy Pigs Correlate with Lesions and Porcine Circovirus Type 2 Load in Lymphoid Tissues

    PubMed Central

    Darwich, Laila; Segalés, Joaquim; Domingo, Mariano; Mateu, Enric

    2002-01-01

    Forty-one 8- to 12-week-old wasted pigs were selected from several conventional farms with histories of postweaning multisystemic wasting syndrome (PMWS) and classified into two groups according to their porcine circovirus type 2 (PCV2) infection status, as determined by in situ hybridization (ISH). Twenty-four pigs tested positive for PCV2 (PCV2-positive group), while 17 pigs tested negative for PCV2 (PCV2-negative group). In addition, eight uninfected healthy pigs from an experimental farm were used as controls. Heparinized blood samples were taken to obtain peripheral blood mononuclear cells. The CD4+, CD8+, CD4+ CD8+ (double-positive [DP]), and immunoglobulin M-positive (IgM+) cell subsets were analyzed by flow cytometry with appropriate monoclonal antibodies. Histopathological studies were done to evaluate the apparent degrees of lymphocyte depletion in different lymphoid organs (superficial inguinal and mesenteric lymph nodes, Peyer's patches, tonsils, and spleen) and to determine the viral load of the PCV2 genome by using an ISH technique. Animals of the PCV2-positive group showed a significant downshift of the CD8+ and DP cell subsets compared to the other groups (P < 0.05). Moreover, in PCV2-positive pigs, the amount of PCV2 genome in lymphoid tissues was related to the degree of cell depletion in those tissues (P < 0.05) as well as to the relative decrease in IgM+ and CD8+ cells in peripheral blood. These data support the notion that PCV2-positive pigs might have an impaired immune response. PMID:11874858

  13. Selective lymphoid irradiation. I. An approach to transplantation.

    PubMed

    Hardy, M A; Fawwaz, R A; Oluwole, S; Todd, G; Nowygrod, R; Reemtsma, K

    1979-08-01

    The kinetics, distribution, and radiobiologic effects of palladium (Pd)-109-hematoporphyrin were determined in the rat. In addition, we studied the effect on rat heart allograft survival of Pd-109-hematoporphyrin, with and without antilymphocyte serum (ALS). A single sublethal dose of Pd-109-hematoporphyrin (up to 36 muCi/kg) resulted in the following: predominant concentration in lymphoid tissue and proximal bone marrow, complete central and proximal bone marrow ablation with preservation of distal bone marrow, massive depletion of lymphocytes from lymph nodes and spleen, an 80% reduction in peripheral blood lymphocytes which was completed by the addition of ALS, full recovery of lymphoid tissue and blood cellularity within 60 days of administration of radionuclide, and a 100% animal survival rate. This method of selective lymphoid irradiation (SLI) prolongs indefinitely Fisher cardiac allografts in Lewis recipients and significantly prolongs cardiac allograft survival across major histocompatibility barries (ACI to Lewis or to Fisher). Specific tolerance to donor strains was demonstrated by the acceptance of Fisher skin by Lewis recipients carrying 150-day-old Fisher hearts. Third party (ACI) skin allografts were rapidly rejected by the same animals. Further studies of SLI in larger animals are required to determine the optimal safe dose of SLI in man. PMID:380034

  14. Treatment of intractable rheumatoid arthritis with lymphoid irradiation

    SciTech Connect

    Strober, S.; Kotzin, B.L.; Hoppe, R.T.; Slavin, S.; Gottlieb, M.; Calin, A.; Fuks, Z.; Kaplan, H.S.

    1981-01-01

    Subdiaphragmatic lymphoid radiation was used as an alternative to cytotoxic drug therapy to treat six patients with progressive erosive rheumatoid arthritis. All were previously unresponsive to conventional therapy. Radiation (4,000 rad) was given to subdiaphragmatic lymphoid tissues in fractionated doses of 150 to 250 rad each. Three of the six patients demonstrated long-lasting clinical improvement with a decrease in synovitis and morning stiffness and an increase in joint function. All six patients showed a profound depression in the peripheral blood lymphocyte count which persisted for at least six months. The irradiation was well tolerated; there have been no serious complications due to radiotherapy with follow-up ranging from 13 to 36 months. The substantial efficacy in some patients and the lack of severe toxicity in all suggests that radiotherapy deserves further study as an alternative to cytotoxic drugs in the treatment of rheumatoid arthritis.

  15. Evidence that somatostatin is localized and synthesized in lymphoid organs

    SciTech Connect

    Aguila, M.C.; McCann, S.M. ); Dees, W.L.; Haensly, W.E. )

    1991-12-15

    Because several peptides originally found in the pituitary as within the central nervous system have been localized in lymphoid tissues and because somatostatin (somatotropin-release-inhibiting hormone, SRIH) can act on cells of the immune system, the authors searched for this peptide in lymphoid organs. The authors demonstrated that SRIH mRNA exists in lymphoid tissue, albeit in smaller levels that in the periventricular region of the hypothalamus, the brain region that contains the highest level of this mRNA. SRIH mRNA was found in the spleen and thymus of male rats and in the spleen, thymus, and bursa of Fabricius of the chicken. Its localization in the Bursa indicates that the peptide must be present in B lymphocytes since this is the site of origin of B lymphocytes in birds. The SRIH concentration in these lymphoid organs as determined by radioimmunoassay was greater in the thymus than in the spleen of the rat. Fluorescence immunocytochemistry revealed the presence of SRIH-positive cells in clusters inside the white pulp and more dispersed within the red pulp of the spleen of both the rat and the chicken. The thymus from these species also contained SRIH-positive cells within the medulla and around the corticomedullary junction. In the chicken, there were large cluster of SRIH-positive cells in the medullary portion of each nodule of the bursa of Fabricius. The results indicate that SRIH is synthesized and stored in cells of the immune system. SRIH may be secreted from these cells to exert paracrine actions that alter the function of immune cells in spleen and thymus.

  16. Maternal retinoids control type 3 innate lymphoid cells and set the offspring immunity

    NASA Astrophysics Data System (ADS)

    van de Pavert, Serge A.; Ferreira, Manuela; Domingues, Rita G.; Ribeiro, Hélder; Molenaar, Rosalie; Moreira-Santos, Lara; Almeida, Francisca F.; Ibiza, Sales; Barbosa, Inês; Goverse, Gera; Labão-Almeida, Carlos; Godinho-Silva, Cristina; Konijn, Tanja; Schooneman, Dennis; O'Toole, Tom; Mizee, Mark R.; Habani, Yasmin; Haak, Esther; Santori, Fabio R.; Littman, Dan R.; Schulte-Merker, Stefan; Dzierzak, Elaine; Simas, J. Pedro; Mebius, Reina E.; Veiga-Fernandes, Henrique

    2014-04-01

    The impact of nutritional status during fetal life on the overall health of adults has been recognized; however, dietary effects on the developing immune system are largely unknown. Development of secondary lymphoid organs occurs during embryogenesis and is considered to be developmentally programmed. Secondary lymphoid organ formation depends on a subset of type 3 innate lymphoid cells (ILC3) named lymphoid tissue inducer (LTi) cells. Here we show that mouse fetal ILC3s are controlled by cell-autonomous retinoic acid (RA) signalling in utero, which pre-sets the immune fitness in adulthood. We found that embryonic lymphoid organs contain ILC progenitors that differentiate locally into mature LTi cells. Local LTi cell differentiation was controlled by maternal retinoid intake and fetal RA signalling acting in a haematopoietic cell-autonomous manner. RA controlled LTi cell maturation upstream of the transcription factor RORγt. Accordingly, enforced expression of Rorgt restored maturation of LTi cells with impaired RA signalling, whereas RA receptors directly regulated the Rorgt locus. Finally, we established that maternal levels of dietary retinoids control the size of secondary lymphoid organs and the efficiency of immune responses in the adult offspring. Our results reveal a molecular link between maternal nutrients and the formation of immune structures required for resistance to infection in the offspring.

  17. The Role of TOX in the Development of Innate Lymphoid Cells

    PubMed Central

    Seehus, Corey R.; Kaye, Jonathan

    2015-01-01

    TOX, an evolutionarily conserved member of the HMG-box family of proteins, is essential for the development of various cells of both the innate and adaptive immune system. TOX is required for the development of CD4+ T lineage cells in the thymus, including natural killer T and T regulatory cells, as well as development of natural killer cells and fetal lymphoid tissue inducer cells, the latter required for lymph node organogenesis. Recently, we have identified a broader role for TOX in the innate immune system, demonstrating that this nuclear protein is required for generation of bone marrow progenitors that have potential to give rise to all innate lymphoid cells. Innate lymphoid cells, classified according to transcription factor expression and cytokine secretion profiles, derive from common lymphoid progenitors in the bone marrow and require Notch signals for their development. We discuss here the role of TOX in specifying CLP toward an innate lymphoid cell fate and hypothesize a possible role for TOX in regulating Notch gene targets during innate lymphoid cell development. PMID:26556952

  18. Humanized hemato-lymphoid system mice

    PubMed Central

    Theocharides, Alexandre P.A.; Rongvaux, Anthony; Fritsch, Kristin; Flavell, Richard A.; Manz, Markus G.

    2016-01-01

    Over the last decades, incrementally improved xenograft mouse models, supporting the engraftment and development of a human hemato-lymphoid system, have been developed and now represent an important research tool in the field. The most significant contributions made by means of humanized mice are the identification of normal and leukemic hematopoietic stem cells, the characterization of the human hematopoietic hierarchy, and their use as preclinical therapy models for malignant hematopoietic disorders. Successful xenotransplantation depends on three major factors: tolerance by the mouse host, correct spatial location, and appropriately cross-reactive support and interaction factors such as cytokines and major histocompatibility complex molecules. Each of these can be modified. Experimental approaches include the genetic modification of mice to faithfully express human support factors as non-cross-reactive cytokines, to create free niche space, the co-transplantation of human mesenchymal stem cells, the implantation of humanized ossicles or other stroma, and the implantation of human thymic tissue. Besides the source of hematopoietic cells, the conditioning regimen and the route of transplantation also significantly affect human hematopoietic development in vivo. We review here the achievements, most recent developments, and the remaining challenges in the generation of pre-clinically-predictive systems for human hematology and immunology, closely resembling the human situation in a xenogeneic mouse environment. PMID:26721800

  19. Nfil3 is required for the development of all innate lymphoid cell subsets

    PubMed Central

    Seillet, Cyril; Rankin, Lucille C.; Groom, Joanna R.; Mielke, Lisa A.; Tellier, Julie; Chopin, Michael; Huntington, Nicholas D.

    2014-01-01

    Innate lymphoid cell (ILC) populations protect against infection and are essential for lymphoid tissue formation and tissue remodeling after damage. Nfil3 is implicated in the function of adaptive immune lineages and NK cell development, but it is not yet known if Nfil3 regulates other innate lymphoid lineages. Here, we identify that Nfil3 is essential for the development of Peyer’s patches and ILC2 and ILC3 subsets. Loss of Nfil3 selectively reduced Peyer’s patch formation and was accompanied by impaired recruitment and distribution of lymphocytes within the patches. ILC subsets exhibited high Nfil3 expression and genetic deletion of Nfil3 severely compromised the development of all subsets. Subsequently, Nfil3−/− mice were highly susceptible to disease when challenged with inflammatory or infectious agents. Thus, we demonstrate that Nfil3 is a key regulator of the development of ILC subsets essential for immune protection in the lung and gut. PMID:25092873

  20. Total lymphoid irradiation in alloimmunity and autoimmunity

    SciTech Connect

    Strober, S.

    1987-12-01

    Total lymphoid irradiation has been used as an immunosuppressive regimen in autoimmune disease and organ transplantation. The rationale for its use originated from studies of patients with Hodgkin disease, in whom this radiotherapy regimen was noted to induce profound and long-lasting immune suppression and yet was well tolerated, with few long-term side effects. Total lymphoid irradiation is a unique immunosuppressive regimen that produces a selective (and long-lasting) reduction in the number and function of helper T cells and certain subsets of B cells. Conventional immunosuppressive drugs show little selectivity, and their effects are short-lived. The most important aspect of total lymphoid irradiation is the potential for achieving transplantation tolerance and permanent remissions in autoimmune disease in laboratory animals. Attempts are being made to achieve similar goals in humans given total lymphoid irradiation, so that immunosuppressive drugs can be ultimately withdrawn from transplant recipients and patients with lupus nephritis. 28 references.

  1. Total lymphoid irradiation and discordant cardiac xenografts

    SciTech Connect

    Kaplan, E.; Dresdale, A.R.; Diehl, J.T.; Katzen, N.A.; Aronovitz, M.J.; Konstam, M.A.; Payne, D.D.; Cleveland, R.J. )

    1990-01-01

    Total lymphoid irradiation can prolong concordant cardiac xenografts. The effects of total lymphoid irradiation in a discordant xenograft model (guinea pig to rat) were studied with and without adjuvant pharmacologic immunosuppression. Inbred Lewis rats were randomly allocated to one of four groups. Group 1 (n = 6) served as a control group and rats received no immunosuppression. Group 2 (n = 5) received triple-drug therapy that consisted of intraperitoneal azathioprine (2 mg/kg), cyclosporine (20 mg/kg), and methylprednisolone (1 mg/kg) for 1 week before transplantation. Group 3 animals (n = 5) received 15 Gy of total lymphoid irradiation in 12 divided doses over a 3-week period. Group 4 (n = 6) received both triple-drug therapy and total lymphoid irradiation as described for groups 2 and 3. Complement-dependent cytotoxicity assay was performed to determine if a correlation between complement-dependent cytotoxicity and rejection-free interval existed. Rejection was defined as cessation of graft pulsation and was confirmed by histologic test results. Only groups 1 and 2 showed a difference in survival (group 1, 6.9 +/- 1.0 minutes; group 2, 14.2 +/- 2.7 minutes, p = 0.02). Although total lymphoid irradiation did decrease complement-dependent cytotoxicity, linear regression revealed no correlation between complement-dependent cytotoxicity and graft survival (coefficient of correlation, 0.30). Unlike concordant cardiac xenografts, total lymphoid irradiation with or without triple-drug therapy does not prolong graft survival.

  2. B cell-specific S1PR1 deficiency blocks prion dissemination between secondary lymphoid organs.

    PubMed

    Mok, Simon W F; Proia, Richard L; Brinkmann, Volker; Mabbott, Neil A

    2012-05-15

    Many prion diseases are peripherally acquired (e.g., orally or via lesions to skin or mucous membranes). After peripheral exposure, prions replicate first upon follicular dendritic cells (FDC) in the draining lymphoid tissue before infecting the brain. However, after replication upon FDC within the draining lymphoid tissue, prions are subsequently propagated to most nondraining secondary lymphoid organs (SLO), including the spleen, by a previously underdetermined mechanism. The germinal centers in which FDC are situated produce a population of B cells that can recirculate between SLO. Therefore, we reasoned that B cells were ideal candidates by which prion dissemination between SLO may occur. Sphingosine 1-phosphate receptor (S1PR)1 stimulation controls the egress of T and B cells from SLO. S1PR1 signaling blockade sequesters lymphocytes within SLO, resulting in lymphopenia in the blood and lymph. We show that, in mice treated with the S1PR modulator FTY720 or with S1PR1 deficiency restricted to B cells, the dissemination of prions from the draining lymph node to nondraining SLO is blocked. These data suggest that B cells interacting with and acquiring surface proteins from FDC and recirculating between SLO via the blood and lymph mediate the initial propagation of prions from the draining lymphoid tissue to peripheral tissues. PMID:22504650

  3. Novel immunotherapies in lymphoid malignancies.

    PubMed

    Batlevi, Connie Lee; Matsuki, Eri; Brentjens, Renier J; Younes, Anas

    2016-01-01

    The success of the anti-CD20 monoclonal antibody rituximab in the treatment of lymphoid malignancies provided proof-of-principle for exploiting the immune system therapeutically. Since the FDA approval of rituximab in 1997, several novel strategies that harness the ability of T cells to target cancer cells have emerged. Reflecting on the promising clinical efficacy of these novel immunotherapy approaches, the FDA has recently granted 'breakthrough' designation to three novel treatments with distinct mechanisms. First, chimeric antigen receptor (CAR)-T-cell therapy is promising for the treatment of adult and paediatric relapsed and/or refractory acute lymphoblastic leukaemia (ALL). Second, blinatumomab, a bispecific T-cell engager (BiTE(®)) antibody, is now approved for the treatment of adults with Philadelphia-chromosome-negative relapsed and/or refractory B-precursor ALL. Finally, the monoclonal antibody nivolumab, which targets the PD-1 immune-checkpoint receptor with high affinity, is used for the treatment of Hodgkin lymphoma following treatment failure with autologous-stem-cell transplantation and brentuximab vedotin. Herein, we review the background and development of these three distinct immunotherapy platforms, address the scientific advances in understanding the mechanism of action of each therapy, and assess the current clinical knowledge of their efficacy and safety. We also discuss future strategies to improve these immunotherapies through enhanced engineering, biomarker selection, and mechanism-based combination regimens. PMID:26525683

  4. Novel immunotherapies in lymphoid malignancies

    PubMed Central

    Batlevi, Connie Lee; Matsuki, Eri; Brentjens, Renier J.; Younes, Anas

    2016-01-01

    The success of the anti-CD20 monoclonal antibody rituximab in the treatment of lymphoid malignancies provided proof-of-principle for exploiting the immune system therapeutically. Since the FDA approval of rituximab in 1997, several novel strategies that harness the ability of T cells to target cancer cells have emerged. Reflecting on the promising clinical efficacy of these novel immunotherapy approaches, the FDA has recently granted ‘breakthrough’ designation to three novel treatments with distinct mechanisms. First, chimeric antigen receptor (CAR)-T-cell therapy is promising for the treatment of adult and paediatric relapsed and/or refractory acute lymphoblastic leukaemia (ALL). Second, blinatumomab, a bispecific T-cell engager (BiTE®) antibody, is now approved for the treatment of adults with Philadelphia-chromosome-negative relapsed and/or refractory B-precursor ALL. Finally, the monoclonal antibody nivolumab, which targets the PD-1 immune-checkpoint receptor with high affinity, is used for the treatment of Hodgkin lymphoma following treatment failure with autologous-stem-cell transplantation and brentuximab vedotin. Herein, we review the background and development of these three distinct immunotherapy platforms, address the scientific advances in understanding the mechanism of action of each therapy, and assess the current clinical knowledge of their efficacy and safety. We also discuss future strategies to improve these immunotherapies through enhanced engineering, biomarker selection, and mechanism-based combination regimens. PMID:26525683

  5. Differentiation and diversity of subsets in group 1 innate lymphoid cells.

    PubMed

    Seillet, Cyril; Belz, Gabrielle T

    2016-01-01

    NK cells were first identified in 1975 and represent the prototypical group 1 innate lymphoid cell (ILC). More recently, the discovery of new members of the ILC family has highlighted the complexity of this innate lymphoid lineage. Importantly, it has been recognized that different subsets exist within the group 1 ILC, which have potential roles in mediating immune protection and immunosurveillance, and in regulating tissue homeostasis and inflammation. Here, we review the developmental relationships between the different group 1 ILC, which have been identified to date and discuss how heterogeneity within this expanding family may have arisen. PMID:26346810

  6. Circulating innate lymphoid cells are unchanged in response to DAC HYP therapy.

    PubMed

    Gillard, Geoffrey O; Saenz, Steven A; Huss, David J; Fontenot, Jason D

    2016-05-15

    Innate lymphoid cells (ILCs) play an important role in immunity, inflammation, and tissue remodeling and their dysregulation is implicated in autoimmune and inflammatory disorders. We analyzed the impact of daclizumab, a humanized monoclonal anti-CD25 antibody, on circulating natural killer (NK) cells and ILCs in a cohort of multiple sclerosis patients. An increase in CD56(bright) NK cells and CD56(hi)CD16(intermediate) transitional NK cells was observed. No significant change in total ILCs or major ILC subpopulations was observed. These results refine our understanding of the impact of daclizumab on innate lymphoid cell populations. PMID:27138097

  7. Transcription factors controlling development and function of innate lymphoid cells.

    PubMed

    Tanriver, Yakup; Diefenbach, Andreas

    2014-03-01

    Innate lymphoid cells (ILCs) are a heterogeneous group of lymphocytes, which play an important role in tissue homeostasis at epithelial surfaces. They are scarce in spleen and lymph nodes, but substantial numbers can be found in the intestinal mucosa even at steady state. There, they represent the first line of defence against invading pathogens and contribute to lymphorganogenesis, tissue repair and, when inappropriately activated, immune pathology. Lineage-specific development, function and maintenance of these cells depend on a restricted set of transcription factors that partially emerged as a result of diversification and selection during vertebrate evolution. The differential expression of transcription factors regulates unique developmental programs, which endow the different ILC subsets with specific effector functions. Despite this division of labour, ILCs are considered to share a common origin, as they all are progeny of the common lymphoid progenitor, rely on the common γ-chain (γc) used by various cytokine receptors and show a developmental requirement for the transcriptional regulator Id2 (inhibitor of DNA binding 2). Here, we review the transcriptional programs required for the development and function of ILCs and give an overview of the evolution of transcription factors and cytokines expressed by ILCs. PMID:24585669

  8. A Rare Case of Multilocular Thymic Cyst with Follicular Lymphoid Hyperplasia: Radiologic and Histopathologic Features.

    PubMed

    Kim, Jin-Suk; Cha, Eun Jung

    2016-06-01

    Multilocular thymic cysts are rare and acquired lesions induced by an inflammatory arising within the thymus. We report a rare case of multilocular thymic cyst with follicular lymphoid hyperplasia in a 59-year-old female. Chest CT and MRI revealed a large multilocular cystic mass, which contains thick septa and nodules in the thymus. F-18 FDG PET/CT showed almost no FDG uptake of the multilocular cystic mass but moderate FDG uptake of the solid nodules. Extended total thymectomy was performed. Histopathological findings revealed follicular lymphoid hyperplasia of thymic tissue but no neoplastic lesion. Based on these findings, diagnosis of multilocular thymic cyst with follicular lymphoid hyperplasia was made. This is a rare case that preoperatively was difficult to diagnose. PMID:27275366

  9. A Progenitor Cell Expressing Transcription Factor RORγt Generates All Human Innate Lymphoid Cell Subsets.

    PubMed

    Scoville, Steven D; Mundy-Bosse, Bethany L; Zhang, Michael H; Chen, Li; Zhang, Xiaoli; Keller, Karen A; Hughes, Tiffany; Chen, Luxi; Cheng, Stephanie; Bergin, Stephen M; Mao, Hsiaoyin C; McClory, Susan; Yu, Jianhua; Carson, William E; Caligiuri, Michael A; Freud, Aharon G

    2016-05-17

    The current model of murine innate lymphoid cell (ILC) development holds that mouse ILCs are derived downstream of the common lymphoid progenitor through lineage-restricted progenitors. However, corresponding lineage-restricted progenitors in humans have yet to be discovered. Here we identified a progenitor population in human secondary lymphoid tissues (SLTs) that expressed the transcription factor RORγt and was unique in its ability to generate all known ILC subsets, including natural killer (NK) cells, but not other leukocyte populations. In contrast to murine fate-mapping data, which indicate that only ILC3s express Rorγt, these human progenitor cells as well as human peripheral blood NK cells and all mature ILC populations expressed RORγt. Thus, all human ILCs can be generated through an RORγt(+) developmental pathway from a common progenitor in SLTs. These findings help establish the developmental signals and pathways involved in human ILC development. PMID:27178467

  10. Common-Lymphoid-Progenitor-Independent Pathways of Innate and T Lymphocyte Development.

    PubMed

    Ghaedi, Maryam; Steer, Catherine A; Martinez-Gonzalez, Itziar; Halim, Timotheus Y F; Abraham, Ninan; Takei, Fumio

    2016-04-19

    All lymphocytes are thought to develop from common lymphoid progenitors (CLPs). However, lymphoid-primed multipotent progenitors (LMPPs) are more efficient than CLPs in differentiating into T cells and group 2 innate lymphoid cells (ILC2s). Here, we have divided LMPPs into CD127(-) (LMPP-s) and CD127(+) (LMPP+s) subsets and compared them with Ly6D(-) and Ly6D(+) CLPs. Adult LMPP+s differentiated into T cells and ILCs more rapidly and efficiently than other progenitors in transplantation assays. The development of T cells and ILC2s is highly active in the neonatal period. Neonatal CLPs are rare and, unlike prominent neonatal LMPP+s, do not efficiently differentiate into T cells and ILC2s. ILC2s generated in the neonatal period are long lived and persist in adult tissues. These results suggest that some ILCs and T cells may develop from LMPP+s via CLP-independent pathways. PMID:27068476

  11. Maternal retinoids control type 3 innate lymphoid cells and set the offspring immunity

    PubMed Central

    van de Pavert, Serge A.; Ferreira, Manuela; Domingues, Rita G.; Ribeiro, Hélder; Molenaar, Rosalie; Moreira-Santos, Lara; Almeida, Francisca F.; Ibiza, Sales; Barbosa, Inês; Goverse, Gera; Labão-Almeida, Carlos; Godinho-Silva, Cristina; Konijn, Tanja; Schooneman, Dennis; O’Toole, Tom; Mizee, Mark R.; Habani, Yasmin; Haak, Esther; Santori, Fabio R.; Littman, Dan R.; Schulte-Merker, Stefan; Dzierzak, Elaine; Simas, J. Pedro; Mebius, Reina E.; Veiga-Fernandes, Henrique

    2016-01-01

    The impact of the nutritional status during foetal life in the overall health of adults has been recognised1. However dietary effects on the developing immune system are largely unknown. Development of secondary lymphoid organs (SLOs) occurs during embryogenesis and is considered to be developmentally programmed2,3. SLO formation dependents on a subset of type 3 innate lymphoid cells (ILC3) named lymphoid tissue inducer (LTi) cells2,3,4,5. Here we show that foetal ILC3s are controlled by cell-autonomous retinoic acid (RA) signalling in utero pre-setting the immune fitness in adulthood. We found that embryonic lymphoid organs contain ILC progenitors that differentiate locally into mature LTi cells. Local LTi differentiation was controlled by maternal retinoid intake and foetal RA signalling acting in a haematopoietic cell-autonomous manner. RA controlled LTi cell maturation upstream of the transcription factor RORγt. Accordingly, enforced expression of Rorgt restored maturation of LTi cells with impaired RA signalling, while RA receptors directly regulated the Rorc locus. Finally, we established that maternal levels of dietary retinoids control the size of secondary lymphoid organs and the efficiency of immune responses in the adult offspring. Our results reveal a molecular link between maternal nutrients and the formation of immune structures required for resistance to infection in the offspring. PMID:24670648

  12. Comparative genomics analysis of mononuclear phagocyte subsets confirms homology between lymphoid tissue-resident and dermal XCR1(+) DCs in mouse and human and distinguishes them from Langerhans cells.

    PubMed

    Carpentier, Sabrina; Vu Manh, Thien-Phong; Chelbi, Rabie; Henri, Sandrine; Malissen, Bernard; Haniffa, Muzlifah; Ginhoux, Florent; Dalod, Marc

    2016-05-01

    Dendritic cells (DC) are mononuclear phagocytes which exhibit a branching (dendritic) morphology and excel at naïve T cell activation. DC encompass several subsets initially identified by their expression of cell surface molecules and later shown to possess distinct functions. DC subset differentiation is orchestrated by transcription factors, growth factors and cytokines. Identifying DC subsets is challenging as very few cell surface molecules are uniquely expressed on any one of these cell populations. There is no standard consensus to identify mononuclear phagocyte subsets; varying antigens are employed depending on the tissue and animal species studied and between laboratories. This has led to confusion in how to accurately define and classify DCs across tissues and between species. Here we report a comparative genomics strategy that enables universal definition of DC and other mononuclear phagocyte subsets across species. We performed a meta-analysis of several public datasets of human and mouse mononuclear phagocyte subsets isolated from blood, spleen, skin or cutaneous lymph nodes, including by using a novel and user friendly software, BubbleGUM, which generates and integrates gene signatures for high throughput gene set enrichment analysis. This analysis demonstrates the equivalence between human and mouse skin XCR1(+) DCs, and between mouse and human Langerhans cells. PMID:26966045

  13. Comparative genomics analysis of mononuclear phagocyte subsets confirms homology between lymphoid tissue-resident and dermal XCR1+ DCs in mouse and human and distinguishes them from Langerhans cells

    PubMed Central

    Carpentier, Sabrina; Vu Manh, Thien-Phong; Chelbi, Rabie; Henri, Sandrine; Malissen, Bernard; Haniffa, Muzlifah; Ginhoux, Florent; Dalod, Marc

    2016-01-01

    Dendritic cells (DC) are mononuclear phagocytes which exhibit a branching (dendritic) morphology and excel at naïve T cell activation. DC encompass several subsets initially identified by their expression of cell surface molecules and later shown to possess distinct functions. DC subset differentiation is orchestrated by transcription factors, growth factors and cytokines. Identifying DC subsets is challenging as very few cell surface molecules are uniquely expressed on any one of these cell populations. There is no standard consensus to identify mononuclear phagocyte subsets; varying antigens are employed depending on the tissue and animal species studied and between laboratories. This has led to confusion in how to accurately define and classify DCs across tissues and between species. Here we report a comparative genomics strategy that enables universal definition of DC and other mononuclear phagocyte subsets across species. We performed a meta-analysis of several public datasets of human and mouse mononuclear phagocyte subsets isolated from blood, spleen, skin or cutaneous lymph nodes, including by using a novel and user friendly software, BubbleGUM, which generates and integrates gene signatures for high throughput gene set enrichment analysis. This analysis demonstrates the equivalence between human and mouse skin XCR1+ DCs, and between mouse and human Langerhans cells. PMID:26966045

  14. Aging impacts isolated lymphoid follicle development and function

    PubMed Central

    2011-01-01

    Background Immunosenescence is the age-related decline and dysfunction of protective immunity leading to a marked increase in the risk of infections, autoimmune disease, and cancer. The majority of studies have focused on immunosenescence in the systemic immune system; information concerning the effect of aging on intestinal immunity is limited. Isolated lymphoid follicles (ILFs) are newly appreciated dynamic intestinal lymphoid structures that arise from nascent lymphoid tissues, or cryptopatches (CP), in response to local inflammatory stimuli. ILFs promote "homeostatic" responses including the production of antigen-specific IgA, thus playing a key role in mucosal immune protection. ILF dysfunction with aging could contribute to immunosenescence of the mucosal system, and accordingly we examined phenotypic and functional aspects of ILFs from young (2 month old) and aged (2 year old) mice. Results We observed that aged mice have increased numbers of ILFs and increased numbers of structures corresponding to an early stage of CPs transforming into ILFs. The cellular composition of ILFs in aged mice is altered with a smaller B-lymphocyte population and an increased T-lymphocyte population. The ILF T-lymphocyte population is notable by the presence of CD4+ CD8αα+ T-lymphocytes, which are absent from the systemic compartment. The smaller B-lymphocyte population in ILFs from aged mice is directly correlated with decreased mRNA and protein expression of CCL20 and CXCL13, two chemokines that play crucial roles in recruiting B-lymphocytes into ILFs. Aged mice had elevated levels of serum and fecal immunoglobulins and despite the decreased B-lymphocyte population, ILFs from aged mice displayed increased IgA production. The immunoglobulin repertoire was skewed in aged mice, and ILFs demonstrated a repertoire usage similar to that of the systemic pool in both young and aged mice. Conclusions Here we observed that ILF development, cellular composition, and immunoglobulin

  15. Differentiation of human innate lymphoid cells (ILCs).

    PubMed

    Juelke, Kerstin; Romagnani, Chiara

    2016-02-01

    During the last years, a high complexity in innate lymphoid lineages now collectively referred to as innate lymphoid cells (ILCs) has been revealed. ILCs can be grouped according to their effector functions and transcriptional requirements into three main groups, termed group 1, 2 and 3 ILCs. The differentiation of ILC lineages from hematopoietic precursors and the molecular switches guiding their developmental fate have started to be characterized both in mice and humans. In this review, we discuss the origin, differentiation stages and plasticity of human ILC subsets as well as the signals that drive ILC lineage commitment and acquisition of their unique effector programs. PMID:26707651

  16. Tissue Tregs.

    PubMed

    Panduro, Marisella; Benoist, Christophe; Mathis, Diane

    2016-05-20

    The immune system is responsible for defending an organism against the myriad of microbial invaders it constantly confronts. It has become increasingly clear that the immune system has a second major function: the maintenance of organismal homeostasis. Foxp3(+)CD4(+) regulatory T cells (Tregs) are important contributors to both of these critical activities, defense being the primary purview of Tregs circulating through lymphoid organs, and homeostasis ensured mainly by their counterparts residing in parenchymal tissues. This review focuses on so-called tissue Tregs. We first survey existing information on the phenotype, function, sustaining factors, and human equivalents of the three best-characterized tissue-Treg populations-those operating in visceral adipose tissue, skeletal muscle, and the colonic lamina propria. We then attempt to distill general principles from this body of work-as concerns the provenance, local adaptation, molecular sustenance, and targets of action of tissue Tregs, in particular. PMID:27168246

  17. Diffuse lymphoid follicles of the colon associated with colonic carcinoma.

    PubMed

    Bronen, R A; Glick, S N; Teplick, S K

    1984-01-01

    In four patients aged 59-75 years, colonic carcinoma was associated with diffuse lymphoid follicles in the colon. In one case, the prominence and distribution of the lymphoid follicles corresponded to the progression and regression of the tumor bulk. It is extremely unusual to demonstrate lymphoid follicles, particularly diffuse, on barium enema in patients in this age range. The colonic carcinomas and lymphoid follicles are directly related, possibly representing an immune response. PMID:6606941

  18. Innate Lymphoid Cells in Graft‐Versus‐Host Disease

    PubMed Central

    Mjösberg, J.

    2015-01-01

    Innate lymphoid cells (ILC) are lymphocytes lacking rearranged antigen receptors such as those expressed by T and B cells. ILC are important effector and regulatory cells of the innate immune system, controlling lymphoid organogenesis, tissue inflammation, and homeostasis. The family of ILC consists of cytotoxic NK cells and the more recently described noncytotoxic group 1, 2, and 3 ILC. The classification of noncytotoxic ILC—in many aspects—mirrors that of T helper cells, which is based on the expression of master transcription factors and signature cytokines specific for each subset. The IL‐22 producing RORγt+ ILC3 subset was recently found to be critical in the prevention of intestinal graft‐versus‐host disease (GVHD) following allogeneic hematopoietic cell transplantation (HCT) via strengthening the intestinal mucosal barrier. In this review, we summarize the current view of the immunological functions of human noncytotoxic ILC subsets and discuss the potentially beneficial features of IL‐22 producing ILC3 in improving allo‐HCT efficacy by attenuating susceptibility to GVHD. In addition, we explore the possibility of other ILC subsets playing a role in GVHD. PMID:26228632

  19. The Cc Chemokine Thymus-Derived Chemotactic Agent 4 (Tca-4, Secondary Lymphoid Tissue Chemokine, 6ckine, Exodus-2) Triggers Lymphocyte Function–Associated Antigen 1–Mediated Arrest of Rolling T Lymphocytes in Peripheral Lymph Node High Endothelial Venules

    PubMed Central

    Stein, Jens V.; Rot, Antal; Luo, Yi; Narasimhaswamy, Manjunath; Nakano, Hideki; Gunn, Michael D.; Matsuzawa, Akio; Quackenbush, Elizabeth J.; Dorf, Martin E.; von Andrian, Ulrich H.

    2000-01-01

    T cell homing to peripheral lymph nodes (PLNs) is defined by a multistep sequence of interactions between lymphocytes and endothelial cells in high endothelial venules (HEVs). After initial tethering and rolling via L-selectin, firm adhesion of T cells requires rapid upregulation of lymphocyte function–associated antigen 1 (LFA-1) adhesiveness by a previously unknown pathway that activates a Gαi-linked receptor. Here, we used intravital microscopy of murine PLNs to study the role of thymus-derived chemotactic agent (TCA)-4 (secondary lymphoid tissue chemokine, 6Ckine, Exodus-2) in homing of adoptively transferred T cells from T-GFP mice, a transgenic strain that expresses green fluorescent protein (GFP) selectively in naive T lymphocytes (TGFP cells). TCA-4 was constitutively presented on the luminal surface of HEVs, where it was required for LFA-1 activation on rolling TGFP cells. Desensitization of the TCA-4 receptor, CC chemokine receptor 7 (CCR7), blocked TGFP cell adherence in wild-type HEVs, whereas desensitization to stromal cell–derived factor (SDF)-1α (the ligand for CXC chemokine receptor 4 [CXCR4]) did not affect TGFP cell behavior. TCA-4 protein was not detected on the luminal surface of PLN HEVs in plt/plt mice, which have a congenital defect in T cell homing to PLNs. Accordingly, TGFP cells rolled but did not arrest in plt/plt HEVs. When TCA-4 was injected intracutaneously into plt/plt mice, the chemokine entered afferent lymph vessels and accumulated in draining PLNs. 2 h after intracutaneous injection, luminal presentation of TCA-4 was detectable in a subset of HEVs, and LFA-1–mediated TGFP cell adhesion was restored in these vessels. We conclude that TCA-4 is both required and sufficient for LFA-1 activation on rolling T cells in PLN HEVs. This study also highlights a hitherto undocumented role for chemokines contained in afferent lymph, which may modulate leukocyte recruitment in draining PLNs. PMID:10620605

  20. The evolution of innate lymphoid cells.

    PubMed

    Vivier, Eric; van de Pavert, Serge A; Cooper, Max D; Belz, Gabrielle T

    2016-06-21

    Innate lymphoid cells (ILCs) are the most recently discovered group of immune cells. Understanding their biology poses many challenges. We discuss here the current knowledge on the appearance of ILC subsets during evolution and propose how the connection between ILCs and T cells contributes to the robustness of immunity and hence to the fitness of the hosts. PMID:27328009

  1. High beta-chemokine expression levels in lymphoid tissues of simian/human immunodeficiency virus 89.6-vaccinated rhesus macaques are associated with uncontrolled replication of simian immunodeficiency virus challenge inoculum.

    PubMed

    LaFranco-Scheuch, Lisa; Abel, Kristina; Makori, Norbert; Rothaeusler, Kristina; Miller, Christopher J

    2004-06-01

    Viral suppression by noncytolytic CD8+ T cells, in addition to that by classic antiviral CD8+ cytotoxic T lymphocytes, has been described for human immunodeficiency virus and simian immunodeficiency virus (SIV) infections. However, the role of soluble effector molecules, especially beta-chemokines, in antiviral immunity is still controversial. In an attenuated vaccine model, approximately 60% of animals immunized with simian/human immunodeficiency virus (SHIV) 89.6 and then challenged intravaginally with SIVmac239 controlled viral replication (viral RNA level in plasma, <10(4) copies/ml) and were considered protected (K. Abel, L. Compton, T. Rourke, D. Montefiori, D. Lu, K. Rothaeusler, L. Fritts, K. Bost, and C. J. Miller, J. Virol. 77:3099-3118, 2003). To determine the in vivo importance of beta-chemokine secretion and CD8+-T-cell proliferation in the control of viral replication in this vaccine model, we examined the relationship between viral RNA levels in the axillary and genital lymph nodes of vaccinated, protected (n = 20) and vaccinated, unprotected (n = 11) monkeys by measuring beta-chemokine mRNA levels and protein expression, the frequency of CD8+ T cells expressing beta-chemokines, and the extent of CD8+-T-cell proliferation. Tissues from uninfected (n = 3) and unvaccinated, SIVmac239-infected (n = 9) monkeys served as controls. Axillary and genital lymph nodes from unvaccinated and vaccinated, unprotected monkeys had significantly higher beta-chemokine mRNA expression levels and increased numbers of beta-chemokine-positive cells than did vaccinated, protected animals. Furthermore, the lymph nodes of vaccinated, unprotected monkeys had significantly higher numbers of beta-chemokine(+) CD8+ T cells than did vaccinated, protected monkeys. Lymph nodes from vaccinated, unprotected animals also had significantly more CD8+-T-cell proliferation and marked lymph node hyperplasia than the lymph nodes of vaccinated, protected monkeys. Thus, higher levels of virus

  2. Evidence of a true pharyngeal tonsil in birds: a novel lymphoid organ in Dromaius novaehollandiae and Struthio camelus (Palaeognathae)

    PubMed Central

    2012-01-01

    Background Tonsils are secondary lymphoid organs located in the naso- and oropharynx of most mammalian species. Most tonsils are characterised by crypts surrounded by dense lymphoid tissue. However, tonsils without crypts have also been recognised. Gut-associated lymphoid tissue (GALT), although not well-organised and lacking tonsillar crypts, is abundant in the avian oropharynx and has been referred to as the “pharyngeal tonsil”. In this context the pharyngeal folds present in the oropharynx of ratites have erroneously been named the pharyngeal tonsils. This study distinguishes between the different types and arrangements of lymphoid tissue in the pharyngeal region of D. novaehollandiae and S. camelus and demonstrates that both species possess a true pharyngeal tonsil which fits the classical definition of tonsils in mammals. Results The pharyngeal tonsil (Tonsilla pharyngea) of D. novaehollandiae was located on the dorsal free surface of the pharyngeal folds and covered by a small caudo-lateral extension of the folds whereas in S. camelus the tonsil was similarly located on the dorsal surface of the pharyngeal folds but was positioned retropharyngeally and encapsulated by loose connective tissue. The pharyngeal tonsil in both species was composed of lymph nodules, inter-nodular lymphoid tissue, mucus glands, crypts and intervening connective tissue septa. In S. camelus a shallow tonsillar sinus was present. Aggregated lymph nodules and inter-nodular lymphoid tissue was associated with the mucus glands on the ventral surface of the pharyngeal folds in both species and represented the Lymphonoduli pharyngeales. Similar lymphoid tissue, but more densely packed and situated directly below the epithelium, was present on the dorsal, free surface of the pharyngeal folds and represented a small, non-follicular tonsil. Conclusions The follicular pharyngeal tonsils in D. novaehollandiae and S. camelus are distinct from the pharyngeal folds in these species and

  3. Follicular dendritic cells, conduits, lymphatic vessels, and high endothelial venules in tertiary lymphoid organs: Parallels with lymph node stroma

    PubMed Central

    Stranford, Sharon; Ruddle, Nancy H.

    2012-01-01

    In this communication, the contribution of stromal, or non-hematopoietic, cells to the structure and function of lymph nodes (LNs), as canonical secondary lymphoid organs (SLOs), is compared to that of tertiary lymphoid tissue or organs (TLOs), also known as ectopic lymphoid tissues. TLOs can arise in non-lymphoid organs during chronic inflammation, as a result of autoimmune responses, graft rejection, atherosclerosis, microbial infection, and cancer. The stromal components found in SLOs including follicular dendritic cells, fibroblast reticular cells, lymphatic vessels, and high endothelial venules and possibly conduits are present in TLOs; their molecular regulation mimics that of LNs. Advances in visualization techniques and the development of transgenic mice that permit in vivo real time imaging of these structures will facilitate elucidation of their precise functions in the context of chronic inflammation. A clearer understanding of the inflammatory signals that drive non-lymphoid stromal cells to reorganize into TLO should allow the design of therapeutic interventions to impede the progression of autoimmune activity, or alternatively, to enhance anti-tumor responses. PMID:23230435

  4. Differentiation and function of group 3 innate lymphoid cells, from embryo to adult.

    PubMed

    van de Pavert, Serge A; Vivier, Eric

    2016-01-01

    Group 3 innate lymphoid cells (ILC3) represent a heterogeneous population of cells that share the nuclear hormone receptor RORγt (retinoic acid receptor-related orphan receptor γt) as a master regulator for differentiation and function. ILC3 can be divided into two major subsets based on the cell surface expression of the natural cytotoxicity receptor (NCR), NKp46. A subset of NCR(-) ILC3 includes the previously known lymphoid-tissue inducer cells that are essential for the embryonic formation of peripheral lymph nodes and Peyer's patches. After birth, the NCR(-) and NCR(+) ILC3 contribute to the maintenance of health but also to inflammation in mucosal tissues. This review will describe the differentiation pathways of ILC3, their involvement in the development of the adaptive immune system and their role in the establishment and maintenance of gut immunity. PMID:26374472

  5. Lymphoid cell kinetics under continuous low dose-rate gamma irradiation: A comparison study

    NASA Technical Reports Server (NTRS)

    Foster, B. R.

    1975-01-01

    A comparison study was conducted of the effects of continuous low dose-rate gamma irradiation on cell population kinetics of lymphoid tissue (white pulp) of the mouse spleen with findings as they relate to the mouse thymus. Experimental techniques employed included autoradiography and specific labeling with tritiated thymidine (TdR-(h-3)). The problem studied involved the mechanism of cell proliferation of lymphoid tissue of the mouse spleen and thymus under the stress of continuous irradiation at a dose rate of 10 roentgens (R) per day for 105 days (15 weeks). The aim was to determine whether or not a steady state or near-steady state of cell population could be established for this period of time, and what compensatory mechanisms of cell population were involved.

  6. Effect of selenium and vitamin E dietary deficiencies on chick lymphoid organ development (42361)

    SciTech Connect

    Marsh, J.A.; Combs, G.F. Jr.; Whitacre, M.E.; Dietert, R.R.

    1986-09-01

    Diets specifically deficient in selenium (Se) and/or vitamin E or adequate in both nutrients were fed to chicks from the time of hatching. Lymphoid organs (bursa, thymus, and in some instances, spleen) were collected from chicks 7-35 days of age. Growth of the chicks fed these diets was monitored over the experimental period as was lymphoid organ growth. The development of the primary lymphoid organs was further assessed by histological techniques and the organ contents of vitamin E (..cap alpha..-tocopherol) and Se were determined. Specific deficiencies of either Se or vitamin E were found to significantly impair bursal growth as did a combined deficiency. Thymic growth was impaired only by the combined deficiency diet. Severe histopathological changes in the bursa resulted from the combined deficiency and these were detectable by 10-14 days after hatching. These changes were characterized by a gradual degeneration of the epithelium and an accompanying depletion of lymphocytes. Similar changes, although slower to develop and less severe, were observed in the thymus as a result of the combined deficiency. When both serum and tissue levels of vitamin E and Se were monitored, it was observed that these were rapidly and independently depleted by the specific deficiency diets. These data suggest that the primary lymphoid organs are major targets of Se and vitamin E dietary deficiencies and provide a possible mechanism by which immune function may be impaired.

  7. Innate lymphoid cells in the airways.

    PubMed

    Walker, Jennifer A; McKenzie, Andrew

    2012-06-01

    The airways, similar to other mucosal surfaces, are continuously exposed to the outside environment and a barrage of antigens, allergens, and microorganisms. Of critical importance therefore is the ability to mount rapid and effective immune responses to control commensal and pathogenic microbes, while simultaneously limiting the extent of these responses to prevent immune pathology and chronic inflammation. The function of the adaptive immune response in controlling these processes at mucosal surfaces has been well documented but the important role of the innate immune system, particularly the recently identified family of innate lymphoid cells, has only lately become apparent. In this review, we give an overview of the innate lymphoid cells that exist in the airways and examine the evidence pertaining to their emerging roles in airways immunity, inflammation, and homeostasis. PMID:22678892

  8. The mucosa-associated lymphoid tissue structure, function, and derangements.

    PubMed

    Zarzaur, B L; Kudsk, K A

    2001-06-01

    Nearly 50% of the immune cells in the body lie just beneath the moist mucosal surfaces at intestinal and extra-intestinal sites. The study of this mucosal immune system in response to shock and to route and type of nutrition provides a cogent explanation for the reduced incidence of pneumonia with enteral feeding. Changes in immune cell mass and function are associated with deterioration of previously established immunity at mucosal surfaces, especially the respiratory tract. By understanding the mechanisms involved in this breakdown, therapeutic strategies can be developed to reduce septic complications in critical illness. PMID:11386611

  9. NK Cells and Other Innate Lymphoid Cells in Hematopoietic Stem Cell Transplantation.

    PubMed

    Vacca, Paola; Montaldo, Elisa; Croxatto, Daniele; Moretta, Francesca; Bertaina, Alice; Vitale, Chiara; Locatelli, Franco; Mingari, Maria Cristina; Moretta, Lorenzo

    2016-01-01

    Natural killer (NK) cells play a major role in the T-cell depleted haploidentical hematopoietic stem cell transplantation (haplo-HSCT) to cure high-risk leukemias. NK cells belong to the expanding family of innate lymphoid cells (ILCs). At variance with NK cells, the other ILC populations (ILC1/2/3) are non-cytolytic, while they secrete different patterns of cytokines. ILCs provide host defenses against viruses, bacteria, and parasites, drive lymphoid organogenesis, and contribute to tissue remodeling. In haplo-HSCT patients, the extensive T-cell depletion is required to prevent graft-versus-host disease (GvHD) but increases risks of developing a wide range of life-threatening infections. However, these patients may rely on innate defenses that are reconstituted more rapidly than the adaptive ones. In this context, ILCs may represent important players in the early phases following transplantation. They may contribute to tissue homeostasis/remodeling and lymphoid tissue reconstitution. While the reconstitution of NK cell repertoire and its role in haplo-HSCT have been largely investigated, little information is available on ILCs. Of note, CD34(+) cells isolated from different sources of HSC may differentiate in vitro toward various ILC subsets. Moreover, cytokines released from leukemia blasts (e.g., IL-1β) may alter the proportions of NK cells and ILC3, suggesting the possibility that leukemia may skew the ILC repertoire. Further studies are required to define the timing of ILC development and their potential protective role after HSCT. PMID:27242795

  10. NK Cells and Other Innate Lymphoid Cells in Hematopoietic Stem Cell Transplantation

    PubMed Central

    Vacca, Paola; Montaldo, Elisa; Croxatto, Daniele; Moretta, Francesca; Bertaina, Alice; Vitale, Chiara; Locatelli, Franco; Mingari, Maria Cristina; Moretta, Lorenzo

    2016-01-01

    Natural killer (NK) cells play a major role in the T-cell depleted haploidentical hematopoietic stem cell transplantation (haplo-HSCT) to cure high-risk leukemias. NK cells belong to the expanding family of innate lymphoid cells (ILCs). At variance with NK cells, the other ILC populations (ILC1/2/3) are non-cytolytic, while they secrete different patterns of cytokines. ILCs provide host defenses against viruses, bacteria, and parasites, drive lymphoid organogenesis, and contribute to tissue remodeling. In haplo-HSCT patients, the extensive T-cell depletion is required to prevent graft-versus-host disease (GvHD) but increases risks of developing a wide range of life-threatening infections. However, these patients may rely on innate defenses that are reconstituted more rapidly than the adaptive ones. In this context, ILCs may represent important players in the early phases following transplantation. They may contribute to tissue homeostasis/remodeling and lymphoid tissue reconstitution. While the reconstitution of NK cell repertoire and its role in haplo-HSCT have been largely investigated, little information is available on ILCs. Of note, CD34+ cells isolated from different sources of HSC may differentiate in vitro toward various ILC subsets. Moreover, cytokines released from leukemia blasts (e.g., IL-1β) may alter the proportions of NK cells and ILC3, suggesting the possibility that leukemia may skew the ILC repertoire. Further studies are required to define the timing of ILC development and their potential protective role after HSCT. PMID:27242795

  11. Retinoic acid differentially regulates the migration of innate lymphoid cell subsets to the gut

    PubMed Central

    Kim, Myung H.; Taparowsky, Elizabeth J.; Kim, Chang H.

    2015-01-01

    Summary Distinct groups of innate lymphoid cells (ILCs) such as ILC1, ILC2 and ILC3 populate the intestine, but how these ILCs develop tissue tropism for this organ is unclear. We report that prior to migration to the intestine ILCs first undergo a `switch' in their expression of homing receptors from lymphoid to gut homing receptors. This process is regulated by mucosal dendritic cells and the gut-specific tissue factor retinoic acid (RA). This change in homing receptors is required for long-term population and effector function of ILCs in the intestine. Only ILC1 and ILC3, but not ILC2, undergo the RA-dependent homing receptor switch in gut-associated lymphoid tissues. In contrast, ILC2 acquire gut homing receptors in a largely RA-independent manner during their development in the bone marrow and can migrate directly to the intestine. Thus, distinct programs regulate the migration of ILC subsets to the intestine for regulation of innate immunity. PMID:26141583

  12. Crop Isolated Lymphoid Follicles and Ileal Peyer’s patches in Egg-Layer Hens Challenged with Salmonella enterica Enteritidis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The enteric pathogen Salmonella enterica Enteritidis (SE) can be harbored within the upper and lower gastrointestinal (GI) tract of chickens. Induction of immune response by SE at various alimentary tract regions may perhaps be attributable to local gut-associated lymphoid tissue (GALT). The study...

  13. Composition, Development, and Function of Uterine Innate Lymphoid Cells

    PubMed Central

    Balmas, Elisa; Boulenouar, Selma; Gaynor, Louise M.; Kieckbusch, Jens; Gardner, Lucy; Hawkes, Delia A.; Barbara, Cynthia F.; Sharkey, Andrew M.; Brady, Hugh J. M.; Brosens, Jan J.; Moffett, Ashley; Colucci, Francesco

    2015-01-01

    Innate lymphoid cells (ILCs), including NK cells, contribute to barrier immunity and tissue homeostasis. In addition to the role of uterine NK cells in placentation and fetal growth, other uterine ILCs (uILCs) are likely to play roles in uterine physiology and pathology. In this article, we report on the composition of uILCs in the endometrium during the luteal phase and in the decidua during early pregnancy. Whereas nonkiller uILC1s and uILC2s are barely detectable in mouse and not detected in humans, a sizeable population of uILC3s is found in human endometrium and decidua, which are mostly NCR+ and partially overlap with previously described IL-22–producing uterine NK cells. Development of mouse uILC3 is Nfil3 independent, suggesting unique features of uILCs. Indeed, although the cytokine production profile of mouse uILCs recapitulates that described in other tissues, IL-5, IL-17, and IL-22 are constitutively produced by uILC2s and uILC3s. This study lays the foundation to understand how ILCs function in the specialized uterine mucosa, both in tissue homeostasis and barrier immunity and during pregnancy. PMID:26371244

  14. The proto-oncogene c-ets is preferentially expressed in lymphoid cells.

    PubMed Central

    Chen, J H

    1985-01-01

    The transforming sequences of the avian acute leukemia virus, E26, contain two distinct oncogenes, v-mybE and v-ets, fused together. By using a probe containing v-ets sequences, polyadenylated transcripts of the c-ets proto-oncogene were detected in avian tissues; they included a major 7.0-kilobase and a minor 2.0-kilobase species. These c-ets mRNAs were detected at high levels only in lymphoid organs and in avian T and B lymphoid cell lines. A similar pattern of c-ets transcription was observed in human hematopoietic cell lines, with transcripts detected in lymphoid B and T cells but not in erythroid or myeloid cells. The E26 oncogene was inserted into an inducible expression vector, and a 90-kilodalton protein (bp90) was produced in bacteria. Rabbit antisera raised to purified bp90 precipitated P135gag-mybE-ets, the v-mybE-ets polyprotein expressed in E26-transformed cells, and also reacted with p50v-mybA, the transforming protein of the avian myeloblastosis virus. Antiserum to bp90 was absorbed with a bacterially synthesized v-mybA protein to remove anti-myb activity. The absorbed anti-bp90 serum retained the ability to immunoprecipitate P135gag-mybE-ets from E26-transformed cells and specifically reacted with a 56-kilodalton polypeptide (p56) detected in chicken lymphoid organs and in T and B lymphocytes of both avian and human origin. The data suggest that p56 is a translational product of the c-ets proto-oncogene and imply that p56 may be involved in regulating the growth of lymphoid cells. Images PMID:3018492

  15. Tertiary lymphoid structures are confined to patients presenting with unifocal Langerhans Cell Histiocytosis.

    PubMed

    Quispel, Willemijn T; Steenwijk, Eline C; van Unen, Vincent; Santos, Susy J; Koens, Lianne; Mebius, Reina; Egeler, R Maarten; van Halteren, Astrid G S

    2016-08-01

    Langerhans cell histiocytosis (LCH) is a neoplastic myeloid disorder with a thus far poorly understood immune component. Tertiary lymphoid structures (TLS) are lymph node-like entities which create an immune-promoting microenvironment at tumor sites. We analyzed the presence and clinical relevance of TLS in n = 104 H&E-stained, therapy-naive LCH lesions of non-lymphoid origin and applied immunohistochemistry to a smaller series. Lymphoid-follicular aggregates were detected in 34/104 (33%) lesions. In line with the lymphocyte recruitment capacity of MECA-79(+) high endothelial venules (HEVs), MECA-79(+)-expressing-LCH lesions (37/77, 48%) contained the most CD3(+) T-lymphocytes (p = 0.003). TLS were identified in 8/15 lesions and contained T-and B-lymphocytes, Follicular Dendritic Cells (FDC), HEVs and the chemokines CXCL13 and CCL21 representing key cellular components and TLS-inducing factors in conventional lymph nodes (LN). Lymphoid-follicular aggregates were most frequently detected in patients presenting with unifocal LCH (24/70, 34%) as compared to patients with poly-ostotic or multi-system LCH (7/30, 23%, p = 0.03). In addition, patients with lymphoid-follicular aggregates-containing lesions had the lowest risk to develop new LCH lesions (p = 0.04). The identification of various stages of TLS formation within LCH lesions may indicate a key role for the immune system in controlling aberrant histiocytes which arise in peripheral tissues. PMID:27622056

  16. Effects of homozygosity of the nude (rnu) gene in an inbred strain of rats: studies of lymphoid and non--lymphoid organs in different age groups of nude rats of LEW background at a stage in the gene transfer.

    PubMed

    Hougen, H P; Klausen, B

    1984-01-01

    Several age groups of nude homozygous rnu/rnu and heterozygous rnu/+ rats of the same genetic background at an early stage of back-crossing (LEW/Mol) were compared as to body and organ weights, histological appearance and cell density of lymphoid organs, haematological values and differential counts of bone marrow and peripheral blood. No thymic tissue was found in the nude animals. 7-week-old nudes were smaller than control animals and had relatively larger non-lymphoid organs and cell-depleted peripheral lymphoid organs. Other age groups showed little difference. Peripheral blood of nude rats showed no signs of lymphopaenia in contrast with the findings in nude mice. The number of thoracic duct lymphocytes was, however, significantly smaller in all age groups of the nude rats, and the bone marrow tended to contain fewer lymphocytes. PMID:10628778

  17. Diffuse nodular lymphoid hyperplasia of the small bowel associated with common variable immunodeficiency and giardiasis: a rare case report.

    PubMed

    Olmez, Sehmus; Aslan, Mehmet; Yavuz, Alpaslan; Bulut, Gulay; Dulger, Ahmet Cumhur

    2014-05-01

    Diffuse nodular lymphoid hyperplasia (DNLH) of the intestine is an extremely rare lymphoproliferative disorder of uncertain etiology. Typically, numerous polypoid nodules composed of hyperplastic benign lymphoid tissue are present in the small and/or large intestinal mucosa. DNLH has been observed in association with common variable immunodeficiency (CVID). A 38-years-old man was admitted to our clinic due to dyspeptic complaints. An upper gastrointestinal system endoscopic examination revealed DNLH in the duodenum. A biopsy specimen showed the presence of nodular lymphoid hyperplasia and a Giardia lamblia infection in the duodenum. CVID was suspected, and the diagnosis was established by demonstrating a significant reduction in the serum gamma-globulin levels. DNLH is a rare benign condition with regards to diagnosis and treatment of unknown etiology. In patients with DNLH, screening for the immune deficiencies is being important in addition to histopathological examinations. PMID:24647448

  18. Thy-1 antigen: selective association in lymphoid organs with the vascular basement membrane involved in lymphocyte recirculation.

    PubMed Central

    Ritter, M A; Morris, R J

    1980-01-01

    The cell surface differentiation antigen, Thy-1, was demonstrated by immunofluorescence to be associated with collagen-based connective tissue (mainly basement membrane) around some blood vessels in rat lymphoid organs. This association is highly selective: only certain types of blood vessel within a given lymphoid organ were found to be Thy-1+; and different lymphoid organs (thymus, bone marrow, lymph node and spleen) had characteristic differences in the types of blood vessel that bear Thy-1. In lymph node and spleen the vessels that were Thy-1+ were those involved in lymphocyte recirculation and homing (post-capillary venules and arterioles of white pulp); the possibility that Thy-1 may function in mediating selective adhesion of small lymphocytes to extracellular substrates during recirculation is discussed. Images Figure 2 Figure 3 Figure 1 Figure 4 PMID:6991398

  19. Inducible lymphoid clusters, iSALTs, in contact dermatitis: a new concept of acquired cutaneous immune responses.

    PubMed

    Natsuaki, Yohei; Kabashima, Kenji

    2016-09-01

    Antigen presentation to peripheral memory T cells is a key step in the prompt elicitation of acquired immune responses. In the mucosa, specific sentinel lymphoid tissues called mucosa-associated lymphoid tissue serve as antigen presentation sites. Correspondingly, the concept of skin-associated lymphoid tissue (SALT) has been proposed in the 1980s. However, the details of SALT have not been clarified so far. Recently, the live imaging analysis using two photon microscopes are developed. Here, we have identified inducible lymphoid clusters in the skin, we called it inducible SALTs (iSALTs), using a murine contact hypersensitivity model. In the elicitation phase, dendritic cells (DCs) formed clusters and interacted for several hours with effector memory T cells in the dermis. This interaction was essential for proliferation and activation of effector memory T cells in situ in an antigen dependent manner. Interestingly, DC clusters were abrogated by depletion of skin macrophages. Furthermore, IL-1 treatment induced CXCL2 production from macrophages and DC clusters were suppressed with the blockade of IL-1R or CXCR2. Taken together, this sustained conjugation between DCs and memory T cells, iSALTs, is essential for establishment of the effector phase in acquired cutaneous immunity. PMID:26941109

  20. Gastric LTi cells promote lymphoid follicle formation but are limited by IRAK-M and do not alter microbial growth.

    PubMed

    Shiu, J; Piazuelo, M B; Ding, H; Czinn, S J; Drakes, M L; Banerjee, A; Basappa, N; Kobayashi, K S; Fricke, W F; Blanchard, T G

    2015-09-01

    Lymphoid tissue inducer (LTi) cells are activated by accessory cell IL-23, and promote lymphoid tissue genesis and antibacterial peptide production by the mucosal epithelium. We investigated the role of LTi cells in the gastric mucosa in the context of microbial infection. Mice deficient in IRAK-M, a negative regulator of TLR signaling, were investigated for increased LTi cell activity, and antibody mediated LTi cell depletion was used to analyze LTi cell dependent antimicrobial activity. H. pylori infected IRAK-M deficient mice developed increased gastric IL-17 and lymphoid follicles compared to wild type mice. LTi cells were present in naive and infected mice, with increased numbers in IRAK-M deficient mice by two weeks. Helicobacter and Candida infection of LTi cell depleted rag1(-/-) mice demonstrated LTi-dependent increases in calprotectin but not RegIII proteins. However, pathogen and commensal microbiota populations remained unchanged in the presence or absence of LTi cell function. These data demonstrate LTi cells are present in the stomach and promote lymphoid follicle formation in response to infection, but are limited by IRAK-M expression. Additionally, LTi cell mediated antimicrobial peptide production at the gastric epithelium is less efficacious at protecting against microbial pathogens than has been reported for other tissues. PMID:25603827

  1. CollagenVI-Cre mice: A new tool to target stromal cells in secondary lymphoid organs.

    PubMed

    Prados, Alejandro; Kollias, George; Koliaraki, Vasiliki

    2016-01-01

    Stromal cells in secondary lymphoid organs (SLOs) are non-hematopoietic cells involved in the regulation of adaptive immune responses. Three major stromal populations have been identified in adult SLOs: fibroblastic reticular cells (FRCs), follicular dendritic cells (FDCs) and marginal reticular cells (MRCs). The properties of these individual populations are not clearly defined, mainly due to the lack of appropriate genetic tools, especially for MRCs. Here, we analyzed stromal cell targeting in SLOs from a transgenic mouse strain that expresses Cre recombinase under the CollagenVI promoter, using lineage tracing approaches. We show that these mice target specifically MRCs and FDCs, but not FRCs in Peyer's patches and isolated lymphoid follicles in the intestine. In contrast, stromal cells in lymph nodes and the spleen do not express the transgene, which renders ColVI-cre mice ideal for the specific targeting of stromal cells in the gut-associated lymphoid tissue (GALT). This funding further supports the hypothesis of organ-specific stromal precursors in SLOs. Interestingly, in all tissues analyzed, there was also high specificity for perivascular cells, which have been proposed to act as FDC precursors. Taken together, ColVI-Cre mice are a useful new tool for the dissection of MRC- and FDC-specific functions and plasticity in the GALT. PMID:27604178

  2. CollagenVI-Cre mice: A new tool to target stromal cells in secondary lymphoid organs

    PubMed Central

    Prados, Alejandro; Kollias, George; Koliaraki, Vasiliki

    2016-01-01

    Stromal cells in secondary lymphoid organs (SLOs) are non-hematopoietic cells involved in the regulation of adaptive immune responses. Three major stromal populations have been identified in adult SLOs: fibroblastic reticular cells (FRCs), follicular dendritic cells (FDCs) and marginal reticular cells (MRCs). The properties of these individual populations are not clearly defined, mainly due to the lack of appropriate genetic tools, especially for MRCs. Here, we analyzed stromal cell targeting in SLOs from a transgenic mouse strain that expresses Cre recombinase under the CollagenVI promoter, using lineage tracing approaches. We show that these mice target specifically MRCs and FDCs, but not FRCs in Peyer’s patches and isolated lymphoid follicles in the intestine. In contrast, stromal cells in lymph nodes and the spleen do not express the transgene, which renders ColVI-cre mice ideal for the specific targeting of stromal cells in the gut-associated lymphoid tissue (GALT). This funding further supports the hypothesis of organ-specific stromal precursors in SLOs. Interestingly, in all tissues analyzed, there was also high specificity for perivascular cells, which have been proposed to act as FDC precursors. Taken together, ColVI-Cre mice are a useful new tool for the dissection of MRC- and FDC-specific functions and plasticity in the GALT. PMID:27604178

  3. Transmembrane adaptor molecules: a new category of lymphoid-cell markers.

    PubMed

    Tedoldi, Sara; Paterson, Jennifer C; Hansmann, Martin-Leo; Natkunam, Yasodha; Rüdiger, Thomas; Angelisova, Pavla; Du, Ming Q; Roberton, Helen; Roncador, Giovanna; Sanchez, Lydia; Pozzobon, Michela; Masir, Noraidah; Barry, Richard; Pileri, Stefano; Mason, David Y; Marafioti, Teresa; Horejsí, Václav

    2006-01-01

    Transmembrane adaptor proteins (of which 7 have been identified so far) are involved in receptor signaling in immune cells. They have only a short extracellular region, with most of the molecule comprising a substantial intracytoplasmic region carrying multiple tyrosine residues that can be phosphorylated by Src- or Syk-family kinases. In this paper, we report an immunohistologic study of 6 of these molecules in normal and neoplastic human tissue sections and show that they are restricted to subpopulations of lymphoid cells, being present in either T cells (LAT, LIME, and TRIM), B cells (NTAL), or subsets of both cell types (PAG and SIT). Their expression in neoplastic lymphoid cells broadly reflects that of normal lymphoid tissue, including the positivity of plasma cells and myeloma/plasmacytoma for LIME, NTAL, PAG, and SIT. However, this study also revealed some reactions that may be of diagnostic/prognostic value. For example, lymphocytic lymphoma and mantle-cell lymphoma showed similar profiles but differed clearly from follicle-center lymphoma, whereas PAG tended to be selectively expressed in germinal center-derived subsets of diffuse large B-cell lymphoma. These molecules represent a potentially important addition to the panel of immunophenotypic markers detectable in routine biopsies that can be used in hematopathologic studies. PMID:16160011

  4. Oxysterol gradient generation by lymphoid stromal cells guides activated B cell movement during humoral responses

    PubMed Central

    Yi, Tangsheng; Wang, Xiaoming; Kelly, Lisa M.; An, Jinping; Xu, Ying; Sailer, Andreas W.; Gustafsson, Jan-Ake; Russel, David W.; Cyster, Jason G.

    2012-01-01

    Summary 7α,25-dihydroxycholesterol (7α,25-OHC) is a ligand for the G-protein coupled receptor EBI2 (GPR183); however, the cellular sources of this oxysterol are undefined. 7α,25-OHC is synthesized from cholesterol by the stepwise actions of two enzymes, CH25H and CYP7B1, and is metabolized to a 3-oxo derivative by HSD3B7. We show that all three enzymes control EBI2-ligand concentration in lymphoid tissues. Lymphoid stromal cells are the main CH25H and CYP7B1-expressing cells required for positioning of B cells and they also mediate 7α,25-OHC inactivation. CH25H and CYP7B1 are abundant at the follicle perimeter whereas CH25H expression by follicular dendritic cells is repressed. CYP7B1-, CH25H- and HSD3B7-deficiencies each result in defective T-cell dependent plasma cell responses. These findings establish that CYP7B1 and HSD3B7, as well as CH25H, have essential roles in controlling oxysterol production in lymphoid tissues and they suggest that differential enzyme expression in stromal cell subsets establishes 7α,25-OHC gradients required for B cell responses. PMID:22999953

  5. Transcription Factor Networks Directing the Development, Function, and Evolution of Innate Lymphoid Effectors

    PubMed Central

    Kang, Joonsoo; Malhotra, Nidhi

    2015-01-01

    Mammalian lymphoid immunity is mediated by fast and slow responders to pathogens. Fast innate lymphocytes are active within hours after infections in mucosal tissues. Slow adaptive lymphocytes are conventional T and B cells with clonal antigen receptors that function days after pathogen exposure. A transcription factor (TF) regulatory network guiding early T cell development is at the core of effector function diversification in all innate lymphocytes, and the kinetics of immune responses is set by developmental programming. Operational units within the innate lymphoid system are not classified by the types of pathogen-sensing machineries but rather by discrete effector functions programmed by regulatory TF networks. Based on the evolutionary history of TFs of the regulatory networks, fast effectors likely arose earlier in the evolution of animals to fortify body barriers, and in mammals they often develop in fetal ontogeny prior to the establishment of fully competent adaptive immunity. PMID:25650177

  6. Activated Type 2 Innate Lymphoid Cells regulate Beige Fat Biogenesis

    PubMed Central

    Lee, Min-Woo; Odegaard, Justin I.; Mukundan, Lata; Qiu, Yifu; Molofsky, Ari B.; Nussbaum, Jesse C.; Yun, Karen; Locksley, Richard M.; Chawla, Ajay

    2014-01-01

    SUMMARY Type 2 innate lymphoid cells (ILC2s), an innate source of the type 2 cytokines interleukin (IL)-5 and -13, participate in the maintenance of tissue homeostasis. Although type 2 immunity is critically important for mediating metabolic adaptations to environmental cold, the functions of ILC2s in beige or brown fat development are poorly defined. We report here that activation of ILC2s by IL-33 is sufficient to promote the growth of functional beige fat in thermoneutral mice. Mechanistically, ILC2 activation results in the proliferation of bipotential adipocyte precursors (APs) and their subsequent commitment to the beige fat lineage. Loss- and gain-of-function studies reveal that ILC2-and eosinophil-derived type 2 cytokines stimulate signaling via the IL-4Rα in PDGFRα+ APs to promote beige fat biogenesis. Together, our results highlight a critical role for ILC2s and type 2 cytokines in the regulation of adipocyte precursor numbers and fate, and as a consequence, adipose tissue homeostasis. PMID:25543153

  7. Expansion of inflammatory innate lymphoid cells in patients with common variable immune deficiency

    PubMed Central

    Cols, Montserrat; Rahman, Adeeb; Maglione, Paul J.; Garcia-Carmona, Yolanda; Simchoni, Noa; Ko, Huai-Bin M.; Radigan, Lin; Cerutti, Andrea; Blankenship, Derek; Pascual, Virginia; Cunningham-Rundles, Charlotte

    2016-01-01

    Background Common variable immunodeficiency (CVID) is an antibody deficiency treated with immunoglobulin; however, patients can have noninfectious inflammatory conditions that lead to heightened morbidity and mortality. Objectives Modular analyses of RNA transcripts in whole blood previously identified an upregulation of many interferon-responsive genes. In this study we sought the cell populations leading to this signature. Methods Lymphoid cells were measured in peripheral blood of 55 patients with CVID (31 with and 24 without inflammatory/autoimmune complications) by using mass cytometry and flow cytometry. Surface markers, cytokines, and transcriptional characteristics of sorted innate lymphoid cells (ILCs) were defined by using quantitative PCR. Gastrointestinal and lung biopsy specimens of subjects with inflammatory disease were stained to seek ILCs in tissues. Results The linage-negative, CD127+, CD161+ lymphoid population containing T-box transcription factor, retinoic acid–related orphan receptor (ROR) γt, IFN-γ, IL-17A, and IL-22, all hallmarks of type 3 innate lymphoid cells, were expanded in the blood of patients with CVID with inflammatory conditions (mean, 3.7% of PBMCs). ILCs contained detectable amounts of the transcription factors inhibitor of DNA binding 2, T-box transcription factor, and RORγt and increased mRNA transcripts for IL-23 receptor (IL-23R) and IL-26, demonstrating inflammatory potential. In gastrointestinal and lung biopsy tissues of patients with CVID, numerous IFN-γ+RORγt+CD3− cells were identified, suggesting a role in these mucosal inflammatory states. Conclusions An expansion of this highly inflammatory ILC population is a characteristic of patients with CVID with inflammatory disease; ILCs and the interferon signature are markers for the uncontrolled inflammatory state in these patients. PMID:26542033

  8. Therapeutic Lymphoid Organogenesis in the Tumor Microenvironment

    PubMed Central

    Weinstein, Aliyah M.; Storkus, Walter J.

    2016-01-01

    The inflammatory status of the tumor microenvironment (TME) has been heavily investigated in recent years. Chemokine and cytokine signaling pathways such as CCR7, CXCR5, lymphotoxin, and IL-36, which are involved in the generation of secondary lymphoid organs and effector immune responses, are now recognized as having value both as prognostic factors and as immunomodulatory therapeutics in the context of cancer. Furthermore, when produced in the TME, these mediators have been shown to promote the recruitment of immune cells, including T cells, B cells, dendritic cells (DC), and other specialized immune cell subsets such as follicular dendritic cells (FDC) and T follicular helper (Tfh) cells, in association with the formation of “tertiary” lymphoid structures (TLS) within or adjacent to sites of disease. Although TLS are composed of a heterogeneous collection of immune cell types, whose composition differs based on cancer subtype, the qualitative presence of TLS has been shown to represent a biomarker of good prognosis for cancer patients. A comprehensive understanding of the role each of these pathways plays within the TME may support the rational design of future immunotherapies to selectively promote/bolster TLS formation and function, leading to improved clinical outcomes across the vast range of solid cancer types. PMID:26216634

  9. Innate Lymphoid Cells Are Depleted Irreversibly during Acute HIV-1 Infection in the Absence of Viral Suppression.

    PubMed

    Kløverpris, Henrik N; Kazer, Samuel W; Mjösberg, Jenny; Mabuka, Jenniffer M; Wellmann, Amanda; Ndhlovu, Zaza; Yadon, Marisa C; Nhamoyebonde, Shepherd; Muenchhoff, Maximilian; Simoni, Yannick; Andersson, Frank; Kuhn, Warren; Garrett, Nigel; Burgers, Wendy A; Kamya, Philomena; Pretorius, Karyn; Dong, Krista; Moodley, Amber; Newell, Evan W; Kasprowicz, Victoria; Abdool Karim, Salim S; Goulder, Philip; Shalek, Alex K; Walker, Bruce D; Ndung'u, Thumbi; Leslie, Alasdair

    2016-02-16

    Innate lymphoid cells (ILCs) play a central role in the response to infection by secreting cytokines crucial for immune regulation, tissue homeostasis, and repair. Although dysregulation of these systems is central to pathology, the impact of HIV-1 on ILCs remains unknown. We found that human blood ILCs were severely depleted during acute viremic HIV-1 infection and that ILC numbers did not recover after resolution of peak viremia. ILC numbers were preserved by antiretroviral therapy (ART), but only if initiated during acute infection. Transcriptional profiling during the acute phase revealed upregulation of genes associated with cell death, temporally linked with a strong IFN acute-phase response and evidence of gut barrier breakdown. We found no evidence of tissue redistribution in chronic disease and remaining circulating ILCs were activated but not apoptotic. These data provide a potential mechanistic link between acute HIV-1 infection, lymphoid tissue breakdown, and persistent immune dysfunction. PMID:26850658

  10. Chinese Box turtle (Cuora flavomarginata) with lymphoid leukemia characterized by immunohistochemical and cytochemical phenotyping.

    PubMed

    Bezjian, Marisa; Diep, Anh N; de Matos, Ricardo; Schaefer, Deanna

    2013-09-01

    Lymphoid leukemia of T-cell origin was diagnosed in a male Chinese Box turtle, Cuora flavomarginata, of approximately 25 years of age. The turtle presented with a history of anorexia, open-mouth breathing, and lethargy for one week. The CBC findings included a mildly increased PCV, and severe leukocytosis due to high numbers of atypical cells interpreted to be blasts. The blasts were medium-sized cells with round to pleomorphic nuclei, slightly clumped chromatin, indistinct nucleoli, and scant moderate-to-dark blue cytoplasm with occasional red-to-purple cytoplasmic granulation. Cytochemical and immunohistochemical staining indicated that the neoplastic cells were positive for CD3 and α-naphthyl butyrate esterase (ANBE), leading to the diagnosis of T-cell lymphoid leukemia. Histology of tissues collected at necropsy showed multifocal infiltrations of neoplastic round cells in the liver, spleen, kidneys, testicles, pancreas, thyroid, duodenum, bone marrow, epicardium, and myocardium. Transmission electron microscopy failed to identify viral particles within the neoplastic cells. This article describes the hematologic, histologic, and ultrastructural abnormalities associated with lymphoid leukemia in this turtle, and advanced diagnostic methods used for phenotyping the T-cell origin. PMID:23889118

  11. Ontogeny of the lymphoid organs in an Antarctic teleost, Harpagifer antarcticus (Notothenioidei: Perciformes).

    PubMed

    O'Neill, J G

    1989-01-01

    The effect of an evolutionary adaptation to low environmental temperature on the development of lymphoid organs was examined in Harpagifer antarcticus from Signy Island (South Orkney Islands; 60 degrees 43'S, 45 degrees 38'W). Thymus, pronephric kidney and spleen were typical, both in position and structural development, of those observed in warmer-water teleosts. The pronephric kidney was the first organ to be infiltrated by leucocytes, at 1 h post-hatch, though the infiltration of the thymic epithelia and the development of the splenic anlage were not observed until 4 weeks post-hatch. Full development of the lymphoid organs was not achieved until the juvenile stage. Although an increased infiltration of the thymus, by subepithelial connective tissues and epithelial mucous cells, occurred in the juvenile and adult stages, there was no evidence of an advanced stage of thymic regression or involution in the adult Harpagifer. Thus, a suppressive influence of the low temperature environment, on the onset and degree of lymphoid organ development and thymic involution, was indicated in this species. PMID:2767306

  12. [Lymphoid myelofibrosis or hairy cell leukemia].

    PubMed

    Lovisetto, P; Pellegrino, P; Tallone, M V; Biarese, V; La Rosa, G F

    1977-05-26

    By lymphoid myelofibrosis or hairy cell leukaemia or tricholeukaemia is meant an unusual haemopathic condition known only for the past few years. It is characterized pathognomonically by the presence of lymphocyte type cells with villous extroflexions, hence the name "hairy cell". Clinically the disease presents as an involutive myelopathy associated with splenomegaly, generally without any particular lymph gland involvement. The attention of students today is concentrated on the nature of the hairy cells; while some are inclined to admit their monocyte or histiocyte derivation, others consider that they derive from B lymphocytes. Therapeutically, almost everybody agrees that splenectomy is the only valid step. A case of H.C.L., which was typical from the clinical and laboratory viewpoints is reported. It is probable that certain haemopathic pictures once classified among atypical leucoses and lymphomas, would today be more correctly classed as hairy cell leukaemia. PMID:327348

  13. Treatment of experimental myasthenia gravis with total lymphoid irradiation

    SciTech Connect

    de Silva, S.; Blum, J.E.; McIntosh, K.R.; Order, S.; Drachman, D.B.

    1988-07-01

    Total lymphoid irradiation (TLI) has been reported to be effective in the immunosuppressive treatment of certain human and experimental autoimmune disorders. We have investigated the effects of TLI in Lewis rats with experimental autoimmune myasthenia gravis (EAMG) produced by immunization with purified torpedo acetylcholine receptor (AChR). The radiation is given in 17 divided fractions of 200 rad each, and nonlymphoid tissues are protected by lead shielding. This technique suppresses the immune system, while minimizing side effects, and permits the repopulation of the immune system by the patient's own bone marrow cells. Our results show that TLI treatment completely prevented the primary antibody response to immunization with torpedo AChR, it rapidly abolished the ongoing antibody response in established EAMG, and it suppressed the secondary (anamnestic) response to a boost of AChR. No EAMG animals died during TLI treatment, compared with six control animals that died of EAMG. TLI produces powerful and prompt immunosuppression and may eventually prove useful in the treatment of refractory human myasthenia gravis.

  14. Role of Innate Lymphoid Cells in Lung Disease.

    PubMed

    Marashian, Sayed Mehran; Mortaz, Esmaeil; Jamaati, Hamid Reza; Alavi-Moghaddam, Mostafa; Kiani, Arda; Abedini, Atefeh; Garssen, Johan; Adcock, Ian M; Velayati, Ali Akbar

    2015-08-01

    Innate lymphoid cells (ILCs) are identified as novel population of hematopoietic cells which protect the body by coordinating the innate immune response against a wide range of threats including infections, tissue damages and homeostatic disturbances. ILCs, particularly ILC2 cells, are found throughout the body including the brain. ILCs are morphologically similar to lymphocytes, express and release high levels of T-helper (Th)1, Th2 and Th17 cytokines but do not express classical cell-surface markers that are associated with other immune cell lineages. Three types of ILCs (ILC1, 2 & 3) have been reported depending upon the cytokines produced. ILC1 cells encompass natural killer (NK) cells and interferon (IFN)-g releasing cells; ILC2 cells release the Th2 cytokines, IL-5, IL-9 and IL-13 in response to IL-25 and IL-33; and ILC3 cells which release IL-17 and IL-22. ILC2 cells have been implicated inmucosal reactions occurring in animal models of allergic asthma and virus-induced lung disorders resulting in the regulation of airway remodeling and tissue homeostasis. There is evidence for increased ILC2 cell numbers in allergic responses in man but little is known about the role of ILCs in chronic obstructive pulmonary disease (COPD). Further understanding of the characteristics of ILCs such as their origin, location and phenotypes and function would help to clarify the role of these cells in the pathogenesis of various lung diseases. In this review we will focus on the role of ILC2 cells and consider their origin, function,location and possible role in the pathogenesis of the chronic inflammatory disorders such as asthma and COPD. PMID:26547702

  15. Total lymphoid irradiation for treatment of intractable cardiac allograft rejection

    SciTech Connect

    Hunt, S.A.; Strober, S.; Hoppe, R.T.; Stinson, E.B. )

    1991-03-01

    The ability of postoperative total lymphoid irradiation to reverse otherwise intractable cardiac allograft rejection was examined in a group of 10 patients in whom conventional rejection therapy (including pulsed steroids and monoclonal or polyclonal anti-T-cell antibody therapy) had failed to provide sustained freedom from rejection. Follow-up periods range from 73 to 1119 days since the start of total lymphoid irradiation. No patient died or sustained serious morbidity because of the irradiation. Three patients have had no further rejection (follow-up periods, 105 to 365 days). Two patients died--one in cardiogenic shock during the course of total lymphoid irradiation, the other with recurrent rejection caused by noncompliance with his medical regimen. Total lymphoid irradiation appears to be a safe and a moderately effective immunosuppressive modality for 'salvage' therapy of cardiac allograft rejection unresponsive to conventional therapy.

  16. Nucleotide Analog Prodrug, Tenofovir Disoproxil, Enhances Lymphoid Cell Loading Following Oral Administration in Monkeys

    PubMed Central

    Durand-Gasselin, Lucie; Van Rompay, Koen K.A.; Vela, Jennifer E.; Henne, Ilana N.; Lee, William A.; Rhodes, Gerry R.; Ray, Adrian S.

    2009-01-01

    The antiviral drug tenofovir (TFV) is orally administered as the fumarate salt of its disoproxil prodrug (TFV disoproxil fumarate (TDF)). TFV is a di-anion at physiological pH and, as a result, has poor lipid membrane permeability. Administration of the lipophilic and cell permeable prodrug, TFV disoproxil, enhances the oral absorption of TFV. In order to determine if oral administration of TDF also increases distribution to sites of viral infection, the plasma and circulating lymphoid cell pharmacokinetics of TFV and its phosphorylated metabolites were assessed following a single oral TDF or subcutaneous TFV administration at doses yielding equivalent plasma exposures to TFV in macaques. Despite TFV disoproxil’s lack of plasma stability and undetectable levels in the first plasma samples taken, oral administration of TDF resulted in 7.9-fold higher peripheral blood mononuclear cell exposures to the active metabolite, TFV-diphosphate. The apparent plasma terminal half-life (t1/2) of TFV was also longer following oral TDF relative to subcutaneous TFV administration (median t1/2 of 15.3 and 3.9 h, respectively), suggesting broader distribution to cells and tissues outside of the central plasma compartment. In conclusion, the disoproxil pro-moiety not only enhances the oral absorption of TFV but also tissue and lymphoid cell loading. These results illustrate that administration of even a fleeting prodrug can increase target tissue loading and gives valuable insight for future prodrug development. PMID:19545170

  17. Prion pathogenesis and secondary lymphoid organs (SLO): tracking the SLO spread of prions to the brain.

    PubMed

    Mabbott, Neil A

    2012-01-01

    Prion diseases are subacute neurodegenerative diseases that affect humans and a range of domestic and free-ranging animal species. These diseases are characterized by the accumulation of PrP (Sc), an abnormally folded isoform of the cellular prion protein (PrP (C)), in affected tissues. The pathology during prion disease appears to occur almost exclusively within the central nervous system. The extensive neurodegeneration which occurs ultimately leads to the death of the host. An intriguing feature of the prion diseases, when compared with other protein-misfolding diseases, is their transmissibility. Following peripheral exposure, some prion diseases accumulate to high levels within lymphoid tissues. The replication of prions within lymphoid tissue has been shown to be important for the efficient spread of disease to the brain. This article describes recent progress in our understanding of the cellular mechanisms that influence the propagation of prions from peripheral sites of exposure (such as the lumen of the intestine) to the brain. A thorough understanding of these events will lead to the identification of important targets for therapeutic intervention, or alternatively, reveal additional processes that influence disease susceptibility to peripherally-acquired prion diseases. PMID:22895090

  18. Nfil3 is crucial for development of innate lymphoid cells and host protection against intestinal pathogens.

    PubMed

    Geiger, Theresa L; Abt, Michael C; Gasteiger, Georg; Firth, Matthew A; O'Connor, Margaret H; Geary, Clair D; O'Sullivan, Timothy E; van den Brink, Marcel R; Pamer, Eric G; Hanash, Alan M; Sun, Joseph C

    2014-08-25

    The bZIP transcription factor Nfil3 (also known as E4BP4) is required for the development of natural killer (NK) cells and type 1 innate lymphoid cells (ILC1s). We find that Nfil3 plays a critical role in the development of other mucosal tissue-associated innate lymphocytes. Type 3 ILCs (ILC3s), including lymphoid tissue inducer (LTi)-like cells, are severely diminished in both numbers and function in Nfil3-deficient mice. Using mixed bone marrow chimeric mice, we demonstrate that Nfil3 is critical for normal development of gut-associated ILC3s in a cell-intrinsic manner. Furthermore, Nfil3 deficiency severely compromises intestinal innate immune defense against acute bacterial infection with Citrobacter rodentium and Clostridium difficile. Nfil3 deficiency resulted in a loss of the recently identified ILC precursor, yet conditional ablation of Nfil3 in the NKp46(+) ILC3 subset did not perturb ILC3 numbers, suggesting that Nfil3 is required early during ILC3 development but not for lineage maintenance. Lastly, a marked defect in type 2 ILCs (ILC2s) was also observed in the lungs and visceral adipose tissue of Nfil3-deficient mice, revealing a general requirement for Nfil3 in the development of all ILC lineages. PMID:25113970

  19. Cell-based laboratory evaluation of coagulation activation by antineoplastic drugs for the treatment of lymphoid tumors

    PubMed Central

    Tsunaka, Misae; Arai, Reina; Ohashi, Ayaka; Koyama, Takatoshi

    2016-01-01

    Objectives: Combining vorinostat, L-asparaginase, and doxorubicin (Dox) led to improved response rates in the treatment of lymphoid tumors. However, deep-vein thrombosis has been noted as one of the most serious side effects with these drugs, and how these regimens cause deep-vein thrombosis is unclear. Methods: We investigated the procoagulant effects of vorinostat, L-asparaginase, and doxorubicin in lymphoid tumors, focusing on tissue factor, phosphatidylserine, and antithrombin. The human vascular endothelial cell line EAhy926 as well as the lymphoid neoplastic cell lines HUT78 (cutaneous T-cell lymphoma), Molt4 (acute T-lymphoblastic leukemia), and Ramos (Burkitt lymphoma) were employed to investigate these procoagulant effects. Results: Vorinostat, L-asparaginase, and doxorubicin induced exposure of phosphatidylserine and procoagulant activity on the surface of lymphoid tumor cells. Vorinostat and doxorubicin also induced phosphatidylserine exposure and increased procoagulant activity on EAhy926 cells. Expression of tissue factor antigen was induced by doxorubicin on the surface of each type of cells, whereas expression of tissue factor mRNA was unchanged. Secretion of antithrombin from HepG2 cells was reduced only by L-asparaginase. Conclusion: These data suggest that vorinostat and doxorubicin may induce procoagulant activity in vessels through apoptosis of tumor cells and through phosphatidylserine exposure and/or tissue factor expression on vascular endothelial cells. L-asparaginase may induce a thrombophilic state by reducing the secretion of anticoagulant proteins such as antithrombin. The laboratory methods described here could be useful to evaluate the procoagulant effects of antineoplastic drugs. PMID:27504186

  20. Lymphoid reconstitution after transplantation of congenic hematopoietic cells in busulfan-treated mice.

    PubMed

    Yeager, A M; Shinn, C; Pardoll, D M

    1991-12-15

    The effects of pretransplant conditioning with high-dose busulfan, a myeloablative but nonimmunosuppressive alkylating agent, on reconstitution of lymphoid tissues by donor cells after bone marrow transplantation (BMT) has not been extensively examined. We used flow cytometric analyses to study the kinetics and extent of lymphocyte repopulation in C57BL/6 mice (immunophenotype Ly-5.2) given graded doses of busulfan (10 to 100 mg/kg) or total body irradiation (TBI; 900 rad) and hematopoietic cell transplantation (HCT; transplantation of bone marrow and spleen cells) from congenic Ly-5.1 donors. Mice transplanted after 10 mg/kg of busulfan had slow and incomplete lymphoid engraftment; only 6% to 11% of lymphocytes in the peripheral blood, lymph nodes, and spleen were positive for Ly-5.1 at 30 days after transplant, slightly increased to 13% to 20% at 60 days, and stabilized at 40% to 46% by 180 days after HCT. Higher doses of busulfan (20 to 100 mg/kg) provided dose-dependent congenic lymphoid reconstitution. Thirty days after HCT, the range of Ly-5.1 cells in blood, lymph nodes, and spleen of Ly-5.2 recipient mice was 43% to 54% after 20 mg/kg of busulfan, 66% to 71% after 50 to 80 mg/kg, and 77% to 85% after 100 mg/kg. Sixty days after transplant, lymphoid chimerism increased to 57% to 68% in 20 mg/kg recipients, 72% to 79% after 35 mg/kg, and 75% to 90% in animals given 50 mg/kg or greater, as seen in radiation chimeras. Despite slower early reconstitution after lower doses of busulfan, donor lymphocytes exceeded 90% to 95% by 90 to 120 days after HCT in all mice given at least 20 mg/kg. Even though busulfan lacks directly immunosuppressive properties, virtually complete sustained lymphoid reconstitution by transplanted congenic donor stem cells occurs after its administration. These observations suggest that pretreatment with busulfan may be effective in gene therapy strategies that involve infusion of autologous marrow cells into which functional genes have been

  1. Immune checkpoint inhibition in lymphoid disease.

    PubMed

    Eyre, Toby A; Collins, Graham P

    2015-08-01

    It has long been understood that the immune system has intrinsic anti-tumour activity in humans, and that a key mechanism of tumour progression is the ability of a tumour to escape this immune surveillance. A number of attempts have been made to harness this anti-tumour immunity in both solid tumour oncology and haematological malignancies with variable success. Examples include the use of allogeneic stem cell transplantation and donor lymphocyte infusion in haematological cancer and vaccine studies in solid tumours. Enhanced signalling of the Programmed cell death-1 (PDCD1, PD-1)/cytotoxic T-lymphocyte-associated protein 4 (CTLA4) 'immune checkpoint' pathway has emerged recently as a critical mechanism by which tumours can escape the natural anti-tumour immune response. As such, novel therapies have been developed to help enhance this natural immunity by switching off the PDCD1/CTLA4 immune checkpoint pathway. The following review will discuss the pathobiology of these pathways and the exciting new data now available in lymphoid malignancies. PMID:25824455

  2. Therapeutic Potential of Resveratrol in Lymphoid Malignancies.

    PubMed

    Khan, Omar S; Bhat, Ajaz A; Krishnankutty, Roopesh; Mohammad, Ramzi M; Uddin, Shahab

    2016-01-01

    Natural products have always been sought as a dependable source for the cure of many fatal diseases including cancer. Resveratrol (RSV), a naturally occurring plant polyphenol, has been of recent research interest and is being investigated for its beneficial biological properties that include antioxidant, anti-inflammatory, proapoptotic, and growth inhibitory activities. These effects are mainly mediated by cell cycle arrest, upregulation of proapoptotic proteins, loss of mitochondrial potential, and generation of reactive oxygen species. Among the beneficial properties of RSV, the anticancer property has been of the prime focus and extensively explored during the last few years. Although reports exist on the chemopreventive role of RSV in many solid tumors, limited information is available on the antiproliferative activity of RSV in human lymphoma cells and experimental models. Potential mechanisms for its antiproliferative effect include induction of cell differentiation, apoptosis, and inhibition of DNA synthesis. In this review, the different kinds of lymphoid malignancies and the main mechanisms of cell death induced by resveratrol are discussed. The challenges are limiting in vivo experimental studies involving resveratrol. An attempt for the translation of this compound into a clinical drug also forms a part of this review. PMID:27028800

  3. Group 2 innate lymphoid cells and asthma.

    PubMed

    Kabata, Hiroki; Moro, Kazuyo; Koyasu, Shigeo; Asano, Koichiro

    2015-07-01

    Group 2 innate lymphoid cells (ILC2s) are recently identified cell populations that produce type 2 cytokines such as IL-5 and IL-13 in response to epithelial cell-derived cytokines. Although ILC2s were initially reported to play a key role in the anti-helminth innate immunity, we now have greater interest in their role in asthma and other allergic diseases. In various asthma mouse models, ILC2s provoke eosinophilic inflammation accompanied by airway hyperresponsiveness independent of acquired immunity. Moreover, recent mouse studies show that ILC2s also promote acquired immunity and Th2 polarization, and various cytokines and lipid mediators influence the functions of ILC2s. Although ILC2s have also been identified in humans, studies on the role of human ILC2s in asthma are very limited. Thus far, human studies have shown that there is a slight difference in responsiveness and production of cytokines between mouse and human ILC2s, and it has been suggested that ILC2s are involved in allergic-type asthma and the exacerbation of asthma. In this review, we focus on mouse and human ILC2s, and discuss their role in asthma. PMID:26117253

  4. Innate lymphoid cells as novel regulators of obesity and its-associated metabolic dysfunction.

    PubMed

    Yang, D; Yang, W; Tian, Z; van Velkinburgh, J C; Song, J; Wu, Y; Ni, B

    2016-06-01

    The increased prevalence of obesity worldwide has been accompanied by increases in risk and rates of obesity-associated metabolic dysfunctions, such as insulin resistance. The chronic, low-grade inflammatory condition of obesity highlights the pathophysiological link between the immune system and the metabolic system, which has yet to be fully understood. Recent studies of obesity have started to uncover potential regulatory roles for the innate lymphoid cells (ILCs), which under normal conditions serve to regulate development of lymphoid tissue and function of the mucosal immune system. The ILCs are a newly identified immune cell population with complicated composition and subsequently diverse and dynamic functions. Studies to determine the distribution profile of the various ILCs in adipose tissue provide intriguing clues as to their regulatory capacity in obesity and its associated metabolic dysfunctions. Here, we review the recent findings supporting a role for ILCs as regulators of obesity or its associated insulin resistance, and discuss the potential underlying molecular mechanism as well as its promise as a therapeutic target for clinical applications. © 2016 World Obesity. PMID:26948388

  5. Total lymphoid irradiation for multiple sclerosis

    SciTech Connect

    Devereux, C.K.; Vidaver, R.; Hafstein, M.P.; Zito, G.; Troiano, R.; Dowling, P.C.; Cook, S.D.

    1988-01-01

    Although chemical immunosuppression has been shown to benefit patients with chronic progressive multiple sclerosis (MS), it appears that chemotherapy has an appreciable oncogenic potential in patients with multiple sclerosis. Accordingly, we developed a modified total lymphoid irradiation (TLI) regimen designed to reduce toxicity and applied it to a randomized double blind trial of TLI or sham irradiation in MS. Standard TLI regimens were modified to reduce dose to 1,980 rad, lowering the superior mantle margin to midway between the thyroid cartilage and angle of the mandible (to avert xerostomia) and the lower margin of the mantle field to the inferior margin of L1 (to reduce gastrointestinal toxicity by dividing abdominal radiation between mantle and inverted Y), limiting spinal cord dose to 1,000 rad by custom-made spine blocks in the mantle and upper 2 cm of inverted Y fields, and also protecting the left kidney even if part of the spleen were shielded. Clinical efficacy was documented by the less frequent functional scale deterioration of 20 TLI treated patients with chronic progressive MS compared to to 20 sham-irradiated progressive MS patients after 12 months (16% versus 55%, p less than 0.03), 18 months (28% versus 63%, p less than 0.03), and 24 months (44% versus 74%, N.S.). Therapeutic benefit during 3 years follow-up was related to the reduction in lymphocyte count 3 months post-irradiation (p less than 0.02). Toxicity was generally mild and transient, with no instance of xerostomia, pericarditis, herpes zoster, or need to terminate treatment in TLI patients. However, menopause was induced in 2 patients and staphylococcal pneumonia in one.

  6. Ikaros Inhibits Group 3 Innate Lymphoid Cell Development and Function by Suppressing the Aryl Hydrocarbon Receptor Pathway.

    PubMed

    Li, Shiyang; Heller, Jennifer J; Bostick, John W; Lee, Aileen; Schjerven, Hilde; Kastner, Philippe; Chan, Susan; Chen, Zongming E; Zhou, Liang

    2016-07-19

    Group 3 innate lymphoid cells (ILC3s) expressing the transcription factor (TF) RORγt are important for the defense and homeostasis of host intestinal tissues. The zinc finger TF Ikaros, encoded by Ikzf1, is essential for the development of RORγt(+) fetal lymphoid tissue inducer (LTi) cells and lymphoid organogenesis, but its role in postnatal ILC3s is unknown. Here, we show that small-intestinal ILC3s had lower Ikaros expression than ILC precursors and other ILC subsets. Ikaros inhibited ILC3s in a cell-intrinsic manner through zinc-finger-dependent inhibition of transcriptional activity of the aryl hydrocarbon receptor, a key regulator of ILC3 maintenance and function. Ablation of Ikzf1 in RORγt(+) ILC3s resulted in increased expansion and cytokine production of intestinal ILC3s and protection against infection and colitis. Therefore, in contrast to being required for LTi development, Ikaros inhibits postnatal ILC3 development and function to regulate gut immune responses at steady state and in disease. PMID:27438771

  7. In-vitro evaluation of three lasers for the potential treatment of equine pharyngeal lymphoid hyperplasia

    NASA Astrophysics Data System (ADS)

    Tate, Lloyd P.; Weddle, Diann L.; Correa, Maria T.

    1993-07-01

    Three medical lasers, Argon, CO2, and Nd:YAG, were studied at power outputs of 5 watts, 5 watts, and 40 watts respectively. Laser irradiation was directed at the pharyngeal mucosa of sagittally split horses heads in a randomized fashion. Areas irradiated were measured immediately using hand held calipers, and after being prepared for microscopic examination to determine width and depth of penetration into the mucosa. The results indicated that tissue destruction produced by the CO2 laser was predictable compared to the Nd:YAG laser. The Argon laser, between 1 and 6 seconds of exposure, produced only superficial photoablation of mucosal tissue which did not extend into the muscular layer. The conclusion of this in vitro investigation was that the Argon laser irradiation applied transendoscopically may be a reasonable substitute for surgery and electrocautery commonly used to treat follicular lymphoid hyperplasia, a respiratory disease of young horses.

  8. Distinct Gene Regulatory Pathways for Human Innate versus Adaptive Lymphoid Cells.

    PubMed

    Koues, Olivia I; Collins, Patrick L; Cella, Marina; Robinette, Michelle L; Porter, Sofia I; Pyfrom, Sarah C; Payton, Jacqueline E; Colonna, Marco; Oltz, Eugene M

    2016-05-19

    Innate lymphoid cells (ILCs) serve as sentinels in mucosal tissues, sensing release of soluble inflammatory mediators, rapidly communicating danger via cytokine secretion, and functioning as guardians of tissue homeostasis. Although ILCs have been extensively studied in model organisms, little is known about these "first responders" in humans, especially their lineage and functional kinships to cytokine-secreting T helper (Th) cell counterparts. Here, we report gene regulatory circuitries for four human ILC-Th counterparts derived from mucosal environments, revealing that each ILC subset diverges as a distinct lineage from Th and circulating natural killer cells but shares circuitry devoted to functional polarization with their Th counterparts. Super-enhancers demarcate cohorts of cell-identity genes in each lineage, uncovering new modes of regulation for signature cytokines, new molecules that likely impart important functions to ILCs, and potential mechanisms for autoimmune disease SNP associations within ILC-Th subsets. PMID:27156452

  9. Ozone-Induced Type 2 Immunity in Nasal Airways. Development and Lymphoid Cell Dependence in Mice.

    PubMed

    Ong, Chee Bing; Kumagai, Kazuyoshi; Brooks, Phillip T; Brandenberger, Christina; Lewandowski, Ryan P; Jackson-Humbles, Daven N; Nault, Rance; Zacharewski, Timothy R; Wagner, James G; Harkema, Jack R

    2016-03-01

    Inhalation exposures to ozone commonly encountered in photochemical smog cause airway injury and inflammation. Elevated ambient ozone concentrations have been epidemiologically associated with nasal airway activation of neutrophils and eosinophils. In the present study, we elucidated the temporal onset and lymphoid cell dependency of eosinophilic rhinitis and associated epithelial changes in mice repeatedly exposed to ozone. Lymphoid cell-sufficient C57BL/6 mice were exposed to 0 or 0.5 parts per million (ppm) ozone for 1, 2, 4, or 9 consecutive weekdays (4 h/d). Lymphoid cell-deficient, Rag2(-/-)Il2rg(-/-) mice were similarly exposed for 9 weekdays. Nasal tissues were taken at 2 or 24 hours after exposure for morphometric and gene expression analyses. C57BL/6 mice exposed to ozone for 1 day had acute neutrophilic rhinitis, with airway epithelial necrosis and overexpression of mucosal Ccl2 (MCP-1), Ccl11 (eotaxin), Cxcl1 (KC), Cxcl2 (MIP-2), Hmox1, Il1b, Il5, Il6, Il13, and Tnf mRNA. In contrast, 9-day ozone exposure elicited type 2 immune responses in C57BL/6 mice, with mucosal mRNA overexpression of Arg1, Ccl8 (MCP-2), Ccl11, Chil4 (Ym2), Clca1 (Gob5), Il5, Il10, and Il13; increased density of mucosal eosinophils; and nasal epithelial remodeling (e.g., hyperplasia/hypertrophy, mucous cell metaplasia, hyalinosis, and increased YM1/YM2 proteins). Rag2(-/-)Il2rg(-/-) mice exposed to ozone for 9 days, however, had no nasal pathology or overexpression of transcripts related to type 2 immunity. These results provide a plausible paradigm for the activation of eosinophilic inflammation and type 2 immunity found in the nasal airways of nonatopic individuals subjected to episodic exposures to high ambient ozone. PMID:26203683

  10. Ozone-Induced Nasal Type 2 Immunity in Mice Is Dependent on Innate Lymphoid Cells.

    PubMed

    Kumagai, Kazuyoshi; Lewandowski, Ryan; Jackson-Humbles, Daven N; Li, Ning; Van Dyken, Steven J; Wagner, James G; Harkema, Jack R

    2016-06-01

    Epidemiological studies suggest that elevated ambient concentrations of ozone are associated with activation of eosinophils in the nasal airways of atopic and nonatopic children. Mice repeatedly exposed to ozone develop eosinophilic rhinitis and type 2 immune responses. In this study, we determined the role of innate lymphoid cells (ILCs) in the pathogenesis of ozone-induced eosinophilic rhinitis by using lymphoid-sufficient C57BL/6 mice, Rag2(-/-) mice that are devoid of T cells and B cells, and Rag2(-/-)Il2rg(-/-) mice that are depleted of all lymphoid cells including ILCs. The animals were exposed to 0 or 0.8 ppm ozone for 9 consecutive weekdays (4 h/d). Mice were killed 24 hours after exposure, and nasal tissues were selected for histopathology and gene expression analysis. ILC-sufficient C57BL/6 and Rag2(-/-) mice exposed to ozone developed marked eosinophilic rhinitis and epithelial remodeling (e.g., epithelial hyperplasia and mucous cell metaplasia). Chitinase-like proteins and alarmins (IL-33, IL-25, and thymic stromal lymphopoietin) were also increased morphometrically in the nasal epithelium of ozone-exposed C57BL/6 and Rag2(-/-) mice. Ozone exposure elicited increased expression of Il4, Il5, Il13, St2, eotaxin, MCP-2, Gob5, Arg1, Fizz1, and Ym2 mRNA in C57BL/6 and Rag2(-/-) mice. In contrast, ozone-exposed ILC-deficient Rag2(-/-)Il2rg(-/-) mice had no nasal lesions or overexpression of Th2- or ILC2-related transcripts. These results indicate that ozone-induced eosinophilic rhinitis, nasal epithelial remodeling, and type 2 immune activation are dependent on ILCs. To the best of our knowledge, this is the first study to demonstrate that ILCs play an important role in the nasal pathology induced by repeated ozone exposure. PMID:26559808

  11. STAT5 regulation of BCL10 parallels constitutive NFκB activation in lymphoid tumor cells

    PubMed Central

    Nagy, Zsuzsanna S; LeBaron, Matthew J; Ross, Jeremy A; Mitra, Abhisek; Rui, Hallgeir; Kirken, Robert A

    2009-01-01

    Background Signal Transducer and Activator of Transcription 5 A and B (STAT5) are key survival factors in cells of the lymphoid lineage. Identification of novel, tissue-specific STAT5 regulated genes would advance the ability to combat diseases due to aberrant STAT5 signaling. In the present work a library of human STAT5 bound genomic elements was created and validated. Results Of several STAT5 responsive genomic regulatory elements identified, one was located within the first intron of the human BCL10 gene. Chromatin immuno-precipitation reactions confirmed constitutive in vivo STAT5 binding to this intronic fragment in various human lymphoid tumor cell lines. Interestingly, non-phosphorylated STAT5 was found in the nuclei of Kit225 and YT cells in the absence of cytokine stimulation that paralleled constitutive NFκB activation. Inhibition of the hyperactive JAK3/STAT5 pathway in MT-2 cells via the Mannich-base, NC1153, diminished the constitutive in vivo occupancy of BCL10-SBR by STAT5, reduced NFκB activity and BCL10 protein expression in a dose dependent manner. Moreover, depletion of STAT5 via selective antisense oligonucleotide treatment similarly resulted in decreased BCL10 mRNA and protein expression, cellular viability and impaired NFκB activity independent of IL-2. Conclusion These results suggest that the NFκB regulator BCL10 is an IL-2-independent STAT5 target gene. These findings proffer a model in which un-activated STAT5 can regulate pathways critical for lymphoid cell survival and inhibitors that disrupt STAT5 function independent of tyrosine phosphorylation may be therapeutically effective in treating certain leukemias/lymphomas. PMID:19709433

  12. Granuloma annulare with prominent lymphoid infiltrates ("pseudolymphomatous" granuloma annulare).

    PubMed

    Cota, Carlo; Ferrara, Gerardo; Cerroni, Lorenzo

    2012-05-01

    Granuloma annulare (GA) is characterized histopathologically by 3 patterns: necrobiotic granuloma, interstitial incomplete form and, rarely, sarcoidal or tuberculoid granuloma. The amount of lymphoid infiltrate in GA is usually limited. We describe 10 cases of GA with prominent "pseudolymphomatous" lymphoid infiltrates mimicking cutaneous lymphoid hyperplasia. Patients were 6 males and 4 females (mean age 49.9 years, median age 47 years, age range 25-70). Lesions were localized to a limited area of the body (n = 6), or involved the entire trunk (n = 3), or were generalized (n = 1). The correct clinical diagnosis of GA was provided only in 30% of the cases. In all cases, histopathologic features were characterized by dense, nodular, superficial, and deep infiltrates of lymphocytes. Immunohistology revealed predominance of T lymphocytes in 7 of 7 tested cases. This "pseudolymphomatous" variant of GA represents a pitfall in the histopathologic diagnosis of the disease and may be misinterpreted as other types of cutaneous lymphoproliferative disorders. PMID:22207445

  13. Age-Related Changes in Population of Stromal Precursor Cells in Hematopoietic and Lymphoid Organs.

    PubMed

    Gorskaya, Yulia F.; Latzinik, Natalia V.; Shuklina, Ekaterina U.; Nesterenko, Vladimir G.

    2000-07-01

    It is shown that the content of precursor cells of stromal tissue (CFC-F) in the hemopoietic and lymphoid organs of SAMP (rapidly-ageing mice) and SAMR mice (mice with a normal ageing rate) decreases as the animals grow older. However the decrease in the content of CFC-F in SAMP mice begins substantially earlier - in the age group of 9-11 months, while in the SAMR mice - only in the age group of 16-19 months. It was found that the age reduction of the number to an equal degree relates to the whole population of CFC-F, in particular both the fraction of weakly-linked CFC-F, which is isolated by means of mechanical disaggregation of the tissue, and the fraction which may only be isolated using trypsin. It is shown that the concentration of inducible osteogenic precursor cells (IOPC) in the spleen of guinea pigs does not change with age, but their content in that organ in old animals (2-3 years old) drops by two times. It was found that in elderly animals the mass of the ectopic osseous tissue, formed by the implantation of an osteoinductor (autologous epithelium of the urinary bladder) in a system open for entrance of cells, decreases by two times. After curettage of the medullary cavity of guinea pig tibia (i.e. under conditions of an increased demand for osteogenic cells) the mass of induced ectopic osseous tissue decreases by 4 times, which indicates to the possible functional relationship between the pool of determined and inducible osteogenic precursor cells. On the whole, the obtained data show that during ageing there is a reduction in the number of stromal precursor cells (CFC-F and IOPC), which form a specific microenvironment for hemopoietic and lymphoid organs, which is important to understand the role of these cells in the development of age pathologies, in particular senile osteoporosis. PMID:12687170

  14. [Meningeal tertiary lymphoid organs: Major actors in intrathecal autoimmunity].

    PubMed

    Bonnan, M

    2015-01-01

    Multiple sclerosis (MS) is characterized by an intrathecal synthesis of immunoglobulins synthesized by B-cell clones and by a brain infiltrate of clonal T-cells. The clonal maturation of these lymphocytes takes place in tertiary lymphoid organs (TLO) developed in the intrathecal compartment. TLO are acquired lymphoid organs able to develop in the vicinity of the inflammatory sites, where they mount a complete antigen-driven immune response. We here review TLO pathophysiology in animal models of MS and human MS. Several pieces of evidence suggest that intrathecal TLO may play a major role in the clinical impairment. Potential therapeutic applications are examined. PMID:25555848

  15. Molecular Pathology: Predictive, Prognostic, and Diagnostic Markers in Lymphoid Neoplasms.

    PubMed

    Ho, Caleb; Kluk, Michael J

    2016-09-01

    Lymphoid neoplasms show great diversity in morphology, immunophenotypic profile, and postulated cells of origin, which also reflects the variety of genetic alterations within this group of tumors. This review discusses many of the currently known genetic alterations in selected mature B-cell and T-cell lymphoid neoplasms, and their significance as diagnostic, prognostic, and therapeutic markers. Given the rapidly increasing number of genetic alterations that have been described in this group of tumors, and that the clinical significance of many is still being studied, this is not an entirely exhaustive review of all of the genetic alterations that have been reported. PMID:27523974

  16. Calpain expression in lymphoid cells. Increased mRNA and protein levels after cell activation.

    PubMed

    Deshpande, R V; Goust, J M; Chakrabarti, A K; Barbosa, E; Hogan, E L; Banik, N L

    1995-02-10

    Although calpain is ubiquitously present in human tissues and is thought to play a role in demyelination, its activity is very low in resting normal lymphocytes. To determine the nature of calpain expression at the mRNA and protein levels in human lymphoid cells, we studied human T lymphocytic, B lymphocytic, and monocytic lines as well as peripheral blood mononuclear cells. Stimulation of cells with the phorbol ester phorbol myristate acetate and the calcium ionophore A23187 resulted in increased calpain mRNA and protein expression. Calpain mRNA expression is also increased in human T cells stimulated with anti-CD3. A dissociation between the increases of RNA and protein suggested that calpain could be released from the cells; the subsequent experiments showed its presence in the extracellular environment. 5,6-Dichloro-1b-D-ribofuranosylbenzimidazole, a reversible inhibitor of mRNA synthesis, reduced calpain mRNA levels by 50-67% and protein levels by 72-91%. Its removal resulted in resumption of both calpain mRNA and protein synthesis. Cycloheximide, a translational inhibitor, reduced calpain protein levels by 77-81% and calpain mRNA levels by 96% in activated THP-1 cells. Interferon-gamma induced calpain mRNA and protein in U-937 and THP-1 cells. Dexamethasone increased mRNA expression in THP-1 cells. Our results indicate that activation of lymphoid cells results in de novo synthesis and secretion of calpain. PMID:7852311

  17. Group 3 innate lymphoid cells continuously require the transcription factor GATA3 after commitment

    PubMed Central

    Zhong, Chao; Cui, Kairong; Wilhelm, Christoph; Hu, Gangqing; Mao, Kairui; Belkaid, Yasmine; Zhao, Keji; Zhu, Jinfang

    2015-01-01

    The transcription factor GATA3 is indispensable for the development of all interleukin-7 receptor α (IL-7Rα)-expressing innate lymphoid cells (ILCs). However, the functional role of low GATA3 expression in committed ILC3s has not been identified. We report that GATA3 regulates homeostasis of ILC3s by controlling IL-7Rα expression. In addition, GATA3 is critical for the development of the NKp46+ ILC3 subset by regulating the balance between the transcription factors T-bet and RORγt. Alhough GATA3 positively regulates NKp46+ ILC3 subset-specific genes, it negatively regulates CCR6+ ILC3 subset lymphoid tissue inducer (LTi)-specific genes in NKp46+ ILC3s. Furthermore, GATA3 is required for IL-22 production in both LTi and NKp46+ ILC3s. Thus, despite its low expression, GATA3 is critical for the homeostasis, development and function of ILC3 subsets. PMID:26595886

  18. Group 3 innate lymphoid cells continuously require the transcription factor GATA-3 after commitment.

    PubMed

    Zhong, Chao; Cui, Kairong; Wilhelm, Christoph; Hu, Gangqing; Mao, Kairui; Belkaid, Yasmine; Zhao, Keji; Zhu, Jinfang

    2016-02-01

    The transcription factor GATA-3 is indispensable for the development of all innate lymphoid cells (ILCs) that express the interleukin 7 receptor α-chain (IL-7Rα). However, the function of low GATA-3 expression in committed group 3 ILCs (ILC3 cells) has not been identified. We found that GATA-3 regulated the homeostasis of ILC3 cells by controlling IL-7Rα expression. In addition, GATA-3 served a critical function in the development of the NKp46(+) ILC3 subset by regulating the balance between the transcription factors T-bet and RORγt. Among NKp46(+) ILC3 cells, although GATA-3 positively regulated genes specific to the NKp46(+) ILC3 subset, it negatively regulated genes specific to lymphoid tissue-inducer (LTi) or LTi-like ILC3 cells. Furthermore, GATA-3 was required for IL-22 production in both ILC3 subsets. Thus, despite its low expression, GATA-3 was critical for the homeostasis, development and function of ILC3 subsets. PMID:26595886

  19. Notch signaling in group 3 innate lymphoid cells modulates their plasticity.

    PubMed

    Chea, Sylvestre; Perchet, Thibaut; Petit, Maxime; Verrier, Thomas; Guy-Grand, Delphine; Banchi, Elena-Gaia; Vosshenrich, Christian A J; Di Santo, James P; Cumano, Ana; Golub, Rachel

    2016-01-01

    The Notch signaling pathway is conserved throughout evolution, and it controls various processes, including cell fate determination, differentiation, and proliferation. Innate lymphoid cells (ILCs) are lymphoid cells lacking antigen receptors that fulfill effector and regulatory functions in innate immunity and tissue remodeling. Type 3 ILCs (ILC3s) reinforce the epithelial barrier and maintain homeostasis with intestinal microbiota. We demonstrated that the population of natural cytotoxicity receptor-positive (NCR(+)) ILC3s in mice is composed of two subsets that have distinct developmental requirements. A major subset depended on the activation of Notch2 in NCR(-) ILC3 precursors in the lamina propria of the small intestine to stimulate expression of the genes encoding the transcription factors T-bet, RORγt, and aryl hydrocarbon receptor (AhR). Notch signaling contributed to the transition of NCR(-) cells into NCR(+) cells, the more proinflammatory subset, in a cell-autonomous manner. In the absence of Notch signaling, this subset of NCR(-) ILC3s did not acquire the gene expression profile of NCR(+) ILC3s. A second subset of NCR(+) ILC3s did not depend on Notch for their development or for increased transcription factor abundance; however, their production of cytokines and cell surface abundance of NCRs were decreased in the absence of Notch signaling. Together, our data suggest that Notch is a regulator of the plasticity of ILC3s by controlling NCR(+) cell fate. PMID:27141929

  20. Pip, a novel IRF family member, is a lymphoid-specific, PU.1-dependent transcriptional activator.

    PubMed

    Eisenbeis, C F; Singh, H; Storb, U

    1995-06-01

    The immunoglobulin light-chain gene enhancers E kappa 3', E lambda 2-4, and E lambda 3-1 contain a conserved cell type-specific composite element essential for their activities. This element binds a B cell-specific heterodimeric protein complex that consists of the Ets family member PU.1 and a second factor (NF-EM5), whose participation in the formation of the complex is dependent on the presence of DNA-bound PU.1. In this report we describe the cloning and characterization of Pip (PU.1 interaction partner), a lymphoid-specific protein that is most likely NF-EM5. As expected, the Pip protein binds the composite element only in the presence of PU.1; furthermore, the formation of this ternary complex is critically dependent on phosphorylation of PU.1 at serine-148. The Pip gene is expressed specifically in lymphoid tissues in both B- and T-cell lines. When coexpressed in NIH-3T3 cells, Pip and PU.1 function as mutually dependent transcription activators of the composite element. The amino-terminal DNA-binding domain of Pip exhibits a high degree of homology to the DNA-binding domains of members of the interferon regulatory factor (IRF) family, which includes IRF-1, IRF-2, ICSBP, and ISGF3 gamma. PMID:7797077

  1. Bcl11b is essential for group 2 innate lymphoid cell development

    PubMed Central

    Oliphant, Christopher J.; Englezakis, Alexandros; Yu, Yong; Clare, Simon; Rodewald, Hans-Reimer; Belz, Gabrielle; Liu, Pentao; Fallon, Padraic G.

    2015-01-01

    Group 2 innate lymphoid cells (ILC2s) are often found associated with mucosal surfaces where they contribute to protective immunity, inappropriate allergic responses, and tissue repair. Although we know they develop from a common lymphoid progenitor in the bone marrow (BM), the specific lineage path and transcriptional regulators that are involved are only starting to emerge. After ILC2 gene expression analysis we investigated the role of Bcl11b, a factor previously linked to T cell commitment, in ILC2 development. Using combined Bcl11b-tom and Id2-gfp reporter mice, we show that Bcl11b is expressed in ILC2 precursors in the BM and maintained in mature ILC2s. In vivo deletion of Bcl11b, by conditional tamoxifen-induced depletion or by Bcl11b−/− fetal liver chimera reconstitution, demonstrates that ILC2s are wholly dependent on Bcl11b for their development. Notably, in the absence of Bcl11b there is a concomitant expansion of the RORγt+ ILC3 population, suggesting that Bcl11b may negatively regulate this lineage. Using Nippostrongylus brasiliensis infection, we reveal that the absence of Bcl11b leads to impaired worm expulsion, caused by a deficit in ILC2s, whereas Citrobacter rodentium infection is cleared efficiently. These data clearly establish Bcl11b as a new factor in the differentiation of ILC2s. PMID:25964370

  2. Nonselective inhibition of the epigenetic transcriptional regulator BET induces marked lymphoid and hematopoietic toxicity in mice.

    PubMed

    Lee, Dong U; Katavolos, Paula; Palanisamy, Gopinath; Katewa, Arna; Sioson, Charly; Corpuz, Janice; Pang, Jodie; DeMent, Kevin; Choo, Edna; Ghilardi, Nico; Diaz, Dolores; Danilenko, Dimitry M

    2016-06-01

    Bromo and extra terminal (BET) proteins (BRD2, BRD3, BRD4 and BRDT) are epigenetic transcriptional regulators required for efficient expression of growth promoting, cell cycle progression and antiapoptotic genes. Through their bromodomain, these proteins bind to acetylated lysine residues of histones and are recruited to transcriptionally active chromatin. Inhibition of the BET-histone interaction provides a tractable therapeutic strategy to treat diseases that may have epigenetic dysregulation. JQ1 is a small molecule that blocks BET interaction with histones. It has been shown to decrease proliferation of patient-derived multiple myeloma in vitro and to decrease tumor burden in vivo in xenograft mouse models. While targeting BET appears to be a viable and efficacious approach, the nonclinical safety profile of BET inhibition remains to be well-defined. We report that mice dosed with JQ1 at efficacious exposures demonstrate dose-dependent decreases in their lymphoid and immune cell compartments. At higher doses, JQ1 was not tolerated and due to induction of significant body weight loss led to early euthanasia. Flow cytometry analysis of lymphoid tissues showed a decrease in both B- and T-lymphocytes with a concomitant decrease in peripheral white blood cells that was confirmed by hematology. Further investigation with the inactive enantiomer of JQ1 showed that these in vivo effects were on-target mediated and not elicited through secondary pharmacology due to chemical structure. PMID:27078884

  3. Ectopic expression of B-lymphoid kinase in cutaneous T-cell lymphoma

    PubMed Central

    Krejsgaard, Thorbjørn; Vetter-Kauczok, Claudia S.; Woetmann, Anders; Kneitz, Hermann; Eriksen, Karsten W.; Lovato, Paola; Zhang, Qian; Wasik, Mariusz A.; Geisler, Carsten; Ralfkiaer, Elisabeth; Becker, Juergen C.

    2009-01-01

    B-lymphoid kinase (Blk) is exclusively expressed in B cells and thymocytes. Interestingly, transgenic expression of a constitutively active form of Blk in the T-cell lineage of mice results in the development of T-lymphoid lymphomas. Here, we demonstrate nuclear factor–kappa B (NF-κB)–mediated ectopic expression of Blk in malignant T-cell lines established from patients with cutaneous T-cell lymphoma (CTCL). Importantly, Blk is also expressed in situ in lesional tissue specimens from 26 of 31 patients with CTCL. Already in early disease the majority of epidermotropic T cells express Blk, whereas Blk expression is not observed in patients with benign inflammatory skin disorders. In a longitudinal study of an additional 24 patients biopsied for suspected CTCL, Blk expression significantly correlated with a subsequently confirmed diagnosis of CTCL. Blk is constitutively tyrosine phosphorylated in malignant CTCL cell lines and spontaneously active in kinase assays. Furthermore, targeting Blk activity and expression by Src kinase inhibitors and small interfering RNA (siRNA) inhibit the proliferation of the malignant T cells. In conclusion, this is the first report of Blk expression in CTCL, thereby providing new clues to the pathogenesis of the disease. PMID:19351960

  4. PrP(CWD) lymphoid cell targets in early and advanced chronic wasting disease of mule deer.

    PubMed

    Sigurdson, Christina J; Barillas-Mury, Carolina; Miller, Michael W; Oesch, Bruno; van Keulen, Lucien J M; Langeveld, Jan P M; Hoover, Edward A

    2002-10-01

    Up to 15% of free-ranging mule deer in northeastern Colorado and southeastern Wyoming, USA, are afflicted with a prion disease, or transmissible spongiform encephalopathy (TSE), known as chronic wasting disease (CWD). CWD is similar to a subset of TSEs including scrapie and variant Creutzfeldt-Jakob disease in which the abnormal prion protein isoform, PrP(CWD), accumulates in lymphoid tissue. Experimental scrapie studies have indicated that this early lymphoid phase is an important constituent of prion replication interposed between mucosal entry and central nervous system accumulation. To identify the lymphoid target cells associated with PrP(CWD), we used triple-label immunofluorescence and high-resolution confocal microscopy on tonsils from naturally infected deer in advanced disease. We detected PrP(CWD) primarily extracellularly in association with follicular dendritic and B cell membranes as determined by frequent co-localization with antibodies against membrane bound immunoglobulin and CD21. There was minimal co-localization with cytoplasmic labels for follicular dendritic cells (FDC). This finding could indicate FDC capture of PrP(CWD), potentially in association with immunoglobulin or complement, or PrP(C) conversion on FDC. In addition, scattered tingible body macrophages in the germinal centre contained coarse intracytoplasmic aggregates of PrP(CWD), reflecting either phagocytosis of PrP(CWD) on FDC processes, apoptotic FDC or B cells, or actual PrP(CWD) replication within tingible body macrophages. To compare lymphoid cell targets in early and advanced disease, we also examined: (i) PrP(CWD) distribution in lymphoid cells of fawns within 3 months of oral CWD exposure and (ii) tonsil biopsies from preclinical deer with naturally acquired CWD. These studies revealed that the early lymphoid cellular distribution of PrP(CWD) was similar to that in advanced disease, i.e. in a pattern suggesting FDC association. We conclude that in deer, PrP(CWD) accumulates

  5. The human thymus. A chimeric organ comprised of central and peripheral lymphoid components.

    PubMed

    Haynes, B F; Hale, L P

    1998-01-01

    The human thymus is a lymphoepithelial organ in which T cells develop during fetal life. After maturation and selection in the fetal thymic microenvironment, T cells emigrate to peripheral lymphoid tissues such as the spleen, gut, and lymph nodes, and establish the peripheral T cell repertoire. Although the thymus has enormous regenerative capacity during fetal development, the regenerative capacity of the human postnatal thymus decreases over time. With the advent of intensive chemotherapy regimens for a variety of cancer syndromes, and the discovery that infection with the Human Immunodeficiency Virus (HIV) leads to severe loss of CD4+ T cells, has come the need to understand the role of the human thymus in reconstitution of the immune system in adults. During a recent study of the thymus in HIV infection, we observed many CD8+ T cells in AIDS thymuses that had markers consistent with those of mature effector cytotoxic T cells usually found in peripheral immune tissues, and noted these CD8+ effector T cells were predominantly located in a thymic zone termed the thymic perivascular space. This article reviews our own work on the thymus in HIV-1 infection, and discusses the work of others that, taken together, suggest that the thymus contains peripheral immune cell components not only in the setting of HIV infection, but also in myasthenia gravis, as well as throughout normal life during the process of thymus involution. Thus, the human thymus can be thought of as a chimeric organ comprised of both central and peripheral lymphoid tissues. These observations have led us to postulate that the thymic epithelial atrophy and decrease in thymopoiesis that occurs in myasthenia gravis, HIV-1 infection, and thymic involution may in part derive from cytokines or other factors produced by peripheral immune cells within the thymic perivascular space. PMID:9951649

  6. Developmental acquisition of regulomes underlies innate lymphoid cell functionality

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Innate lymphoid cells (ILCs) play key roles in host defense, barrier integrity, and homeostasis, and they mirror adaptive CD4+ T helper (Th) cell subtypes in both usages of effector molecules and ·transcription factors. To better understand ILC subsets and their relationship with Th cells, we measur...

  7. 'Managing' the immune system with total lymphoid irradiation

    SciTech Connect

    Strober, S.

    1981-06-01

    Total lymphoid irradiation (TLI), which in the past was limited to the treatment of malignant disease, is now emerging as a practical technique in the management of unwanted immune reactions in the areas of transplant tolerance and various autoimmune diseases. Current studies are particularly promising for application of TLI in rheumatoid arthritis and lupus nephritis.

  8. Targeting bone marrow lymphoid niches in acute lymphoblastic leukemia.

    PubMed

    Uy, Geoffrey L; Hsu, Yen-Michael S; Schmidt, Amy P; Stock, Wendy; Fletcher, Theresa R; Trinkaus, Kathryn M; Westervelt, Peter; DiPersio, John F; Link, Daniel C

    2015-12-01

    In acute lymphoblastic leukemia (ALL) the bone marrow microenvironment provides growth and survival signals that may confer resistance to chemotherapy. Granulocyte colony-stimulating factor (G-CSF) potently inhibits lymphopoiesis by targeting stromal cells that comprise the lymphoid niche in the bone marrow. To determine whether lymphoid niche disruption by G-CSF sensitizes ALL cells to chemotherapy, we conducted a pilot study of G-CSF in combination with chemotherapy in patients with relapsed or refractory ALL. Thirteen patients were treated on study; three patients achieved a complete remission (CR/CRi) for an overall response rate of 23%. In the healthy volunteers, G-CSF treatment disrupted the lymphoid niche, as evidenced by reduced expression of CXCL12, interleukin-7, and osteocalcin. However, in most patients with relapsed/refractory ALL expression of these genes was markedly suppressed at baseline. Thus, although G-CSF treatment was associated with ALL cell mobilization into the blood, and increased apoptosis of bone marrow resident ALL cells, alterations in the bone marrow microenvironment were modest and highly variable. These data suggest that disruption of lymphoid niches by G-CSF to sensitize ALL cells to chemotherapy may be best accomplished in the consolidation where the bone marrow microenvironment is more likely to be normal. PMID:26467815

  9. 9 CFR 113.31 - Detection of avian lymphoid leukosis.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 9 Animals and Animal Products 1 2011-01-01 2011-01-01 false Detection of avian lymphoid leukosis. 113.31 Section 113.31 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE VIRUSES, SERUMS, TOXINS, AND ANALOGOUS PRODUCTS; ORGANISMS AND VECTORS STANDARD REQUIREMENTS Standard Procedures §...

  10. 9 CFR 113.31 - Detection of avian lymphoid leukosis.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    .... 113.31 Section 113.31 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE... Plant Health Inspection Service that the agent used to inactivate the vaccine virus would also... lymphoid leukosis virus can be propagated on cell culture during the 21-day growth period. If a...

  11. 9 CFR 113.31 - Detection of avian lymphoid leukosis.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 9 Animals and Animal Products 1 2012-01-01 2012-01-01 false Detection of avian lymphoid leukosis. 113.31 Section 113.31 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE VIRUSES, SERUMS, TOXINS, AND ANALOGOUS PRODUCTS; ORGANISMS AND VECTORS STANDARD REQUIREMENTS Standard Procedures §...

  12. 9 CFR 113.31 - Detection of avian lymphoid leukosis.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    .... 113.31 Section 113.31 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE... Plant Health Inspection Service that the agent used to inactivate the vaccine virus would also... lymphoid leukosis virus can be propagated on cell culture during the 21-day growth period. If a...

  13. 9 CFR 113.31 - Detection of avian lymphoid leukosis.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 9 Animals and Animal Products 1 2010-01-01 2010-01-01 false Detection of avian lymphoid leukosis. 113.31 Section 113.31 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE VIRUSES, SERUMS, TOXINS, AND ANALOGOUS PRODUCTS; ORGANISMS AND VECTORS STANDARD REQUIREMENTS Standard Procedures §...

  14. Avian dendritic cells: Phenotype and ontogeny in lymphoid organs.

    PubMed

    Nagy, Nándor; Bódi, Ildikó; Oláh, Imre

    2016-05-01

    Dendritic cells (DC) are critically important accessory cells in the innate and adaptive immune systems. Avian DCs were originally identified in primary and secondary lymphoid organs by their typical morphology, displaying long cell processes with cytoplasmic granules. Several subtypes are known. Bursal secretory dendritic cells (BSDC) are elongated cells which express vimentin intermediate filaments, MHC II molecules, macrophage colony-stimulating factor 1 receptor (CSF1R), and produce 74.3+ secretory granules. Avian follicular dendritic cells (FDC) highly resemble BSDC, express the CD83, 74.3 and CSF1R molecules, and present antigen in germinal centers. Thymic dendritic cells (TDC), which express 74.3 and CD83, are concentrated in thymic medulla while interdigitating DC are found in T cell-rich areas of secondary lymphoid organs. Avian Langerhans cells are a specialized 74.3-/MHC II+ cell population found in stratified squamous epithelium and are capable of differentiating into 74.3+ migratory DCs. During organogenesis hematopoietic precursors of DC colonize the developing lymphoid organ primordia prior to immigration of lymphoid precursor cells. This review summarizes our current understanding of the ontogeny, cytoarchitecture, and immunophenotype of avian DC, and offers an antibody panel for the in vitro and in vivo identification of these heterogeneous cell types. PMID:26751596

  15. Class-switched anti-insulin antibodies originate from unconventional antigen presentation in multiple lymphoid sites.

    PubMed

    Wan, Xiaoxiao; Thomas, James W; Unanue, Emil R

    2016-05-30

    Autoantibodies to insulin are a harbinger of autoimmunity in type 1 diabetes in humans and in non-obese diabetic mice. To understand the genesis of these autoantibodies, we investigated the interactions of insulin-specific T and B lymphocytes using T cell and B cell receptor transgenic mice. We found spontaneous anti-insulin germinal center (GC) formation throughout lymphoid tissues with GC B cells binding insulin. Moreover, because of the nature of the insulin epitope recognized by the T cells, it was evident that GC B cells presented a broader repertoire of insulin epitopes. Such broader recognition was reproduced by activating naive B cells ex vivo with a combination of CD40 ligand and interleukin 4. Thus, insulin immunoreactivity extends beyond the pancreatic lymph node-islets of Langerhans axis and indicates that circulating insulin, despite its very low levels, can have an influence on diabetogenesis. PMID:27139492

  16. Group 2 innate lymphoid cells license dendritic cells to potentiate memory T helper 2 cell responses

    PubMed Central

    Halim, Timotheus YF; Hwang, You Yi; Scanlon, Seth T; Zaghouani, Habib; Garbi, Natalio; Fallon, Padraic G; McKenzie, Andrew NJ

    2015-01-01

    Rapid memory CD4+ T helper 2 (TH2) cell activation during allergic inflammation requires their recruitment into the affected tissue. Here we demonstrate that group 2 innate lymphoid cells (ILC2) play a critical role in memory TH2 cell responses, with targeted ILC2 depletion profoundly impairing TH2 cell localization to the lungs and skin of sensitized mice after allergen re-challenge. ILC2-derived interleukin-13 (IL-13) is critical for eliciting IRF4+CD11b+CD103− dendritic cells (DCs) to produce the TH2 cell-attracting chemokine CCL17. Consequently, the sentinel function of DCs is contingent on ILC2s for the generation of an efficient memory TH2 cell response. These results elucidate a key new innate mechanism in the regulation of the immune memory response to allergens. PMID:26523868

  17. Choreography of Cell Motility and Interaction Dynamics Imaged by Two-Photon Microscopy in Lymphoid Organs

    PubMed Central

    Cahalan, Michael D.; Parker, Ian

    2009-01-01

    The immune system is the most diffuse cellular system in the body. Accordingly, long-range migration of cells and short-range communication by local chemical signaling and by cell-cell contacts are vital to the control of an immune response. Cellular homing and migration within lymphoid organs, antigen recognition, and cell signaling and activation are clearly vital during an immune response, but these events had not been directly observed in vivo until recently. Introduced to the field of immunology in 2002, two-photon microscopy is the method of choice for visualizing living cells deep within native tissue environments, and it is now revealing an elegant cellular choreography that underlies the adaptive immune response to antigen challenge. We review cellular dynamics and molecular factors that contribute to basal motility of lymphocytes in the lymph node and cellular interactions leading to antigen capture and recognition, T cell activation, B cell activation, cytolytic effector function, and antibody production. PMID:18173372

  18. Lymphoid cell kinetics under continuous low dose-rate gamma irradiation: A comparison study

    NASA Technical Reports Server (NTRS)

    Foster, B. R.

    1975-01-01

    The mechanism of cell proliferation is studied in the lymphoid tissue of the mouse spleen under the stress of continuous irradiation at a dose-rate of 10 roentgens per day for 105 days. Autoradiography and specific labeling with tritiated thymidine were utilized. It was found that at least four compensatory mechanisms maintained a near-steady state of cellular growth: (1) an increase in the proportion of PAS-positive cells which stimulate mitotic activity, (2) maturation arrest of proliferating and differentiating cells which tend to replenish the cells damaged or destroyed by irradiation, (3) an increase in the proportion of cells proliferating, and (4) an increase in the proportion of precursor cells. The results are compared to previous findings observed in the thymus.

  19. Innate lymphoid cells in the initiation, regulation and resolution of inflammation

    PubMed Central

    Sonnenberg, Gregory F.; Artis, David

    2016-01-01

    A previously unappreciated cell type of the innate immune system, termed innate lymphoid cells (ILCs), has been characterized in mice and humans, and found to profoundly influence the induction, regulation and resolution of inflammation. ILCs play an important role in these processes in murine models of infection, inflammatory disease and tissue repair. Further, disease association studies in defined patient populations have identified significant alterations in ILC responses, suggesting a potential role for these cell populations in human health and disease. In this review, we discuss the emerging family of ILCs, the role of ILCs in inflammation, and how current or novel therapeutic strategies could be employed to selectively modulate ILC responses and limit chronic inflammatory diseases in patients. PMID:26121198

  20. NK cells and type 1 innate lymphoid cells: partners in host defense.

    PubMed

    Spits, Hergen; Bernink, Jochem H; Lanier, Lewis

    2016-06-21

    Innate lymphoid cells (ILCs) are effectors and regulators of innate immunity and tissue modeling and repair. Researchers have identified subsets of ILCs with differing functional activities, capacities to produce cytokines and transcription factors required for development and function. Natural killer (NK) cells represent the prototypical member of the ILC family. Together with ILC1s, NK cells constitute group 1 ILCs, which are characterized by their capacity to produce interferon-γ and their functional dependence on the transcription factor T-bet. NK cells and ILC1s are developmentally distinct but share so many features that they are difficult to distinguish, particularly under conditions of infection and inflammation. Here we review current knowledge of NK cells and the various ILC1 subsets. PMID:27328005

  1. Arginase 1 is an innate lymphoid-cell-intrinsic metabolic checkpoint controlling type 2 inflammation.

    PubMed

    Monticelli, Laurel A; Buck, Michael D; Flamar, Anne-Laure; Saenz, Steven A; Tait Wojno, Elia D; Yudanin, Naomi A; Osborne, Lisa C; Hepworth, Matthew R; Tran, Sara V; Rodewald, Hans-Reimer; Shah, Hardik; Cross, Justin R; Diamond, Joshua M; Cantu, Edward; Christie, Jason D; Pearce, Erika L; Artis, David

    2016-06-01

    Group 2 innate lymphoid cells (ILC2s) regulate tissue inflammation and repair after activation by cell-extrinsic factors such as host-derived cytokines. However, the cell-intrinsic metabolic pathways that control ILC2 function are undefined. Here we demonstrate that expression of the enzyme arginase-1 (Arg1) during acute or chronic lung inflammation is a conserved trait of mouse and human ILC2s. Deletion of mouse ILC-intrinsic Arg1 abrogated type 2 lung inflammation by restraining ILC2 proliferation and dampening cytokine production. Mechanistically, inhibition of Arg1 enzymatic activity disrupted multiple components of ILC2 metabolic programming by altering arginine catabolism, impairing polyamine biosynthesis and reducing aerobic glycolysis. These data identify Arg1 as a key regulator of ILC2 bioenergetics that controls proliferative capacity and proinflammatory functions promoting type 2 inflammation. PMID:27043409

  2. An in vitro model of innate lymphoid cell function and differentiation.

    PubMed

    Allan, D S J; Kirkham, C L; Aguilar, O A; Qu, L C; Chen, P; Fine, J H; Serra, P; Awong, G; Gommerman, J L; Zúñiga-Pflücker, J C; Carlyle, J R

    2015-03-01

    Innate lymphoid cells (ILC) are RAG-independent lymphocytes with important roles in innate immunity, and include group-1 (natural killer (NK) cell, ILC1), group-2 (ILC2), and group-3 (lymphoid tissue inducer (LTi), NCR(+) ILC3) subsets. Group-3 ILC express Rorγt, produce interleukin (IL)-22, and are critically important in the normal function of mucosal tissues. Here, we describe a novel model cell line for the study of ILC function and differentiation. The parental MNK cell line, derived from NKR-P1B(+) fetal thymocytes, shows a capacity to differentiate in γc cytokines. One IL-7-responsive subline, designated MNK-3, expresses Rorγt and produces high levels of IL-22 in response to IL-23 and IL-1β stimulation. MNK-3 cells display surface markers and transcript expression characteristic of group-3 ILC, including IL-7Rα (CD127), c-kit (CD117), CCR6, Thy1 (CD90), RANK, RANKL, and lymphotoxin (LTα1β2). Using an in vitro assay of LTi cell activity, MNK-3 cells induce ICAM-1 and VCAM-1 expression on stromal cells in a manner dependent upon LTα1β2 expression. A second IL-2-responsive subline, MNK-1, expresses several NK cell receptors, perforin and granzymes, and shows some cytotoxic activity. Thus, MNK-1 cells serve as a model of ILC1/NK development and differentiation, whereas MNK-3 cells provide an attractive in vitro system to study the function of ILC3/LTi cells. PMID:25138665

  3. Interferon-γ constrains cytokine production of group 2 innate lymphoid cells.

    PubMed

    Kudo, Fujimi; Ikutani, Masashi; Seki, Yoichi; Otsubo, Takeshi; Kawamura, Yuki I; Dohi, Taeko; Oshima, Kenshiro; Hattori, Masahira; Nakae, Susumu; Takatsu, Kiyoshi; Takaki, Satoshi

    2016-01-01

    Group 2 innate lymphoid cells (ILC2s) produce a significant amount of interleukin-5 (IL-5), which supports eosinophil responses in various tissues; they also produce IL-13, which induces mucus production and contributes to tissue repair or fibrosis. The ILC2s are activated by alarmins, such as IL-33 released from epithelia, macrophages and natural killer T (NKT) cells in response to infection and allergen exposure, leading to epithelial injury. We examined gene expression in lung ILC2s and found that ILC2s expressed Ifngr1, the receptor for interferon-γ (IFN-γ). Interferon-γ severely inhibited IL-5 and IL-13 production by lung and kidney ILC2s. To evaluate the effects in vivo, we used α-galactosylceramide (α-GalCer) to induce NKT cells to produce IL-33 and IFN-γ. Intraperitoneal injection of α-GalCer in mice induced NKT cell activation resulting in IL-5 and IL-13 production by ILC2s. Administration of anti-IFN-γ together with α-GalCer significantly enhanced the production of IL-5 and IL-13 by ILC2s in lung and kidney. Conversely, cytokine production from ILC2s was markedly suppressed after injection of exogenous IL-33 in Il33(-/-) mice pre-treated with α-GalCer. Hence, IFN-γ induced or already present in tissues can impact downstream pleiotropic functions mediated by ILC2s, such as inflammation and tissue repair. PMID:26425820

  4. Transforming Growth Factor-β Signaling Guides the Differentiation of Innate Lymphoid Cells in Salivary Glands.

    PubMed

    Cortez, Victor S; Cervantes-Barragan, Luisa; Robinette, Michelle L; Bando, Jennifer K; Wang, Yaming; Geiger, Theresa L; Gilfillan, Susan; Fuchs, Anja; Vivier, Eric; Sun, Joe C; Cella, Marina; Colonna, Marco

    2016-05-17

    The signals guiding differentiation of innate lymphoid cells (ILCs) within tissues are not well understood. Salivary gland (SG) ILCs as well as liver and intestinal intraepithelial ILC1 have markers that denote tissue residency and transforming growth factor-β (TGF-β) imprinting. We deleted Tgfbr2 in cells expressing the ILC and NK marker NKp46 and found that SG ILCs were reduced in number. They lost distinct tissue markers, such as CD49a, and the effector molecules TRAIL and CD73. Expression of the transcription factor Eomes, which promotes NK cell differentiation, was elevated. Conversely, Eomes deletion in NKp46(+) cells enhanced TGF-β-imprinting of SG ILCs. Thus, TGF-β induces SG ILC differentiation by suppressing Eomes. TGF-β acted through a JNK-dependent, Smad4-independent pathway. Transcriptome analysis demonstrated that SG ILCs had characteristic of both NK cells and ILC1. Finally, TGF-β imprinting of SG ILCs was synchronized with SG development, highlighting the impact of tissue microenvironment on ILC development. PMID:27156386

  5. Adipose-Resident Group 1 Innate Lymphoid Cells Promote Obesity-Associated Insulin Resistance.

    PubMed

    O'Sullivan, Timothy E; Rapp, Moritz; Fan, Xiying; Weizman, Orr-El; Bhardwaj, Priya; Adams, Nicholas M; Walzer, Thierry; Dannenberg, Andrew J; Sun, Joseph C

    2016-08-16

    Innate lymphoid cells (ILCs) function to protect epithelial barriers against pathogens and maintain tissue homeostasis in both barrier and non-barrier tissues. Here, utilizing Eomes reporter mice, we identify a subset of adipose group 1 ILC (ILC1) and demonstrate a role for these cells in metabolic disease. Adipose ILC1s were dependent on the transcription factors Nfil3 and T-bet but phenotypically and functionally distinct from adipose mature natural killer (NK) and immature NK cells. Analysis of parabiotic mice revealed that adipose ILC1s maintained long-term tissue residency. Diet-induced obesity drove early production of interleukin (IL)-12 in adipose tissue depots and led to the selective proliferation and accumulation of adipose-resident ILC1s in a manner dependent on the IL-12 receptor and STAT4. ILC1-derived interferon-γ was necessary and sufficient to drive proinflammatory macrophage polarization to promote obesity-associated insulin resistance. Thus, adipose-resident ILC1s contribute to obesity-related pathology in response to dysregulated local proinflammatory cytokine production. PMID:27496734

  6. Clinical outcomes of childhood x-irradiation for lymphoid hyperplasia

    SciTech Connect

    Pottern, L.M.

    1987-01-01

    A prospective study was conducted to explore the relationship between childhood x-irradiation for lymphoid hyperplasia and the subsequent development of thyroid gland and other head and neck disorders. All individuals under 18 years of age who were x-irradiated for lymphoid hyperplasia during the years 1938-69 at Children's Hospital Medical Center, Boston comprised the exposed population. The comparison group consisted of non-exposed, surgically treated individuals. The study included a health questionnaire and a clinical examination component. A history of thyroid cancer was reported by 11 exposed subjects and no non-exposed subjects. Significantly elevated standardized incidence ratios of thyroid cancer were seen for both exposed males and females, 19.9 and 12.1, respectively. The average thyroid radiation dose was 25.8 rads and the mean latency period was 17.3 years.

  7. Total lymphoid irradiation in refractory systemic lupus erythematosus

    SciTech Connect

    Ben-Chetrit, E.; Gross, D.J.; Braverman, A.; Weshler, Z.; Fuks, Z.; Slavin, S.; Eliakim, M.

    1986-07-01

    In two patients with systemic lupus erythematosus, conventional therapy was considered to have failed because of persistent disease activity and unacceptable side effects. Both were treated with total lymphoid irradiation without clinical benefit, despite adequate immunosuppression as documented by markedly reduced numbers of circulating T lymphocytes and T-lymphocyte-dependent proliferative responses in vitro. The first patient developed herpes zoster, gram-negative septicemia, neurologic symptoms, and deterioration of lupus nephritis. The second patient developed massive bronchopneumonia, necrotic cutaneous lesions, and progressive nephritis and died 2 weeks after completion of radiotherapy. These observations, although limited to two patients, indicate that total lymphoid irradiation in patients with severe systemic lupus erythematosus should be regarded as strictly experimental.

  8. Lymphoid proliferations in the orbit: malignant or benign?

    PubMed Central

    van der Gaag, R; Koornneef, L; van Heerde, P; Vroom, T M; Pegels, J H; Feltkamp, C A; Peeters, H J; Gillissen, J P; Bleeker, G M; Feltkamp, T E

    1984-01-01

    Clinical, pathological, and immunological analysis of 20 patients with ocular adnexal lymphoid disease has demonstrated several parameters which are useful for distinguishing malignant from benign lesions. Patients in the fourth or fifth decade of life presenting with an acute history of pain, oedema, epiphora, double vision, and ptosis, with a mass localised in the lacrimal gland area, are more likely to have a pseudolymphoma or a chronic inflammatory lesion than a true non-Hodgkin lymphoma (NHL). It is not possible to obtain a definite diagnosis without surgical intervention, because only three out of nine patients with orbital NHL had evidence of a monoclonal B cell population in peripheral blood on admission to the Orbital Centre. Furthermore it was confirmed that the identification of the various orbital lymphoid infiltrates becomes more distinct when immunological techniques are added to the clinical and histopathological methods of investigation. Multidisciplinary cooperation leads to further improvement of diagnosis and treatment of ocular adnexal lymphoproliferative disease. Images PMID:6391535

  9. Natural cytotoxicity of haemopoietic cell populations against murine lymphoid tumours.

    PubMed Central

    Burton, R. C.; Grail, D.; Warner, N. L.

    1978-01-01

    Homozygous nude and normal mice of 3 strains, BALB/c, CBA and C57BL, were used as sources of nucleated haemopoietic "natural killer" (NK) cells. These killer cells could lyse a wide range of syngeneic and allogeneic lymphoid tumour cell lines in vitro, and it was found that cell suspensions from nude mice were always significantly more active than those from normal mice, and that the most active effector population was a polymorph-enriched peritoneal-exudate cell suspension. Eosinophils did not appear to be involved in the phenomenon, and mononuclear peritoneal-exudate cell suspensions were actually highly inhibitory. Three non-lymphoid tumours, a carcinoma, a fibrosarcoma and a mastocytoma, were totally resistant to in vitro lysis. Although all susceptible tumour cell lines were C-type virus-associated, not all of these tumours were killed by all strain sources of spleen cells, indicating a specificity of killing. PMID:656308

  10. Type-2 Innate Lymphoid Cells in Asthma and Allergy

    PubMed Central

    2014-01-01

    Type-2 innate lymphoid cells (ILC2) belong to an expanding family of innate lymphocytes that provide a potent source of immune effector cytokines at the initiation of immune responses. ILC2 arise, under the control of the transcription factors RORα and GATA3, from lymphoid progenitors in the bone marrow, to secrete type-2 cytokines including IL-5 and IL-13. Using experimental models, ILC2 have been implicated in allergic diseases, such as asthma and atopic dermatitis, but also in metabolic homeostasis. Furthermore, recent reports have indicated that ILC2 not only play roles at the initiation of type-2 immunity but can also contribute to chronic pathology, such as fibrosis, and can impact on the priming of the adaptive T-cell response. The identification of ILC2 in patients with allergic dermatitis and allergic rhinitis indicates that these cells may represent new therapeutic targets. PMID:25525730

  11. Immunosuppression and organ transplantation tolerance using total lymphoid irradiation

    SciTech Connect

    Slavin, S.; Strober, S.; Fuks, Z.; Kaplan, H.S.

    1980-01-01

    Total lymphoid irradiation (TLI) is a method which delivers irradiation daily in fractionated doses (200 rads) to lymphoid organs while shielding bones, lungs, and the majority of the gastrointestinal tract. TLI is lymphocytopenic in mice, rats, dogs, and humans, and both T cells and B cells are eliminated from the circulation. TLI permits establishment of specific and long-lasting tolerance to alloantigens. Permanent acceptance of allogeneic bone marrow cells without graft-versus-host disease was achieved in rats and dogs across major histocompatibility barriers. Recipients were tolerant to allografts of skin, hearts, and kidney from animals syngeneic to marrow donors or to organs from the marrow donor. This approach may be suitable for pancreas transplantation in diabetes.

  12. Immunosuppression by fractionated total lymphoid irradiation in collagen arthritis

    SciTech Connect

    McCune, W.J.; Buckley, J.A.; Belli, J.A.; Trentham, D.E.

    1982-05-01

    Treatments with fractionated total lymphoid irradiation (TLI) and cyclophosphamide were evaluated for rats injected with type II collagen. Preadministration of TLI and repeated injections of cyclophosphamide suppressed the severity of arthritis and lowered antibody titers to collagen significantly. TLI initiated at the onset of collagen arthritis decreased humoral and cellular responses to collagen but did not affect the severity of arthritis. These data demonstrate that both TLi and cyclophosphamide are immunosuppressive in an experimentally inducible autoimmune disease.

  13. Cellular mechanisms of tolerance after total lymphoid irradiation (TLI)

    SciTech Connect

    Strober, S.; King, D.P.; Gottlieb, M.S.; Hoppe, R.T.; Kaplan, H.S.

    1981-03-01

    In this review article on the cellular mechanisms of tolerance after total lymphoid irradiation (TLI), the effect of radiation dose and time of bone marrow infusion in mice are studied. TLI is compared to whole body irradiation with respect to the development of graft-host reaction and the number of stable chimeras obtained. The relationship between nonspecific suppressor cells and the development of tolerance after TLI is discussed. (KRM)

  14. Treatment of intractable lupus nephritis with total lymphoid irradiation

    SciTech Connect

    Strober, S.; Field, E.; Hoppe, R.T.; Kotzin, B.L.; Shemesh, O.; Engleman, E.; Ross, J.C.; Myers, B.D.

    1985-04-01

    Ten patients with lupus nephritis and marked proteinuria (3.9 g or more/d) that did not respond adequately to treatment with prednisone alone or prednisone in combination with azathioprine were treated with total lymphoid irradiation in an uncontrolled feasibility study. Within 6 weeks after the start of total lymphoid irradiation, the serum albumin level rose in all patients in association with a reduction in the serum level of anti-DNA antibodies, an increase in the serum complement level, or both. Improvement in these variables persisted in eight patients followed for more than 1 year, with the stabilization or reduction of the serum creatinine level. Urinary leakage of albumin was substantially reduced in all patients. Side effects associated with radiotherapy included transient constitutional complaints in ten patients, transient blood element depressions in three, localized viral and bacterial infections in four, and ovarian failure in one. The results suggest that total lymphoid irradiation may provide an alternative to cytotoxic drugs in the treatment of lupus nephritis.

  15. Identification of a novel lymphoid population in the murine epidermis

    PubMed Central

    Almeida, Francisca F.; Tenno, Mari; Brzostek, Joanna; Li, Jackson LiangYao; Allies, Gabriele; Hoeffel, Guillaume; See, Peter; Ng, Lai Guan; Fehling, Hans Jörg; Gascoigne, Nicholas R. J.; Taniuchi, Ichiro; Ginhoux, Florent

    2015-01-01

    T cell progenitors are known to arise from the foetal liver in embryos and the bone marrow in adults; however different studies have shown that a pool of T cell progenitors may also exist in the periphery. Here, we identified a lymphoid population resembling peripheral T cell progenitors which transiently seed the epidermis during late embryogenesis in both wild-type and T cell-deficient mice. We named these cells ELCs (Epidermal Lymphoid Cells). ELCs expressed Thy1 and CD2, but lacked CD3 and TCRαβ/γδ at their surface, reminiscent of the phenotype of extra- or intra- thymic T cell progenitors. Similarly to Dendritic Epidermal T Cells (DETCs), ELCs were radioresistant and capable of self-renewal. However, despite their progenitor-like phenotype and expression of T cell lineage markers within the population, ELCs did not differentiate into conventional T cells or DETCs in in vitro, ex vivo or in vivo differentiation assays. Finally, we show that ELC expressed NK markers and secreted IFN-γ upon stimulation. Therefore we report the discovery of a unique population of lymphoid cells within the murine epidermis that appears related to NK cells with as-yet-unidentified functions. PMID:26223192

  16. Approach to Cutaneous Lymphoid Infiltrates: When to Consider Lymphoma?

    PubMed Central

    Charli-Joseph, Yann Vincent; Gatica-Torres, Michelle; Pincus, Laura Beth

    2016-01-01

    Cutaneous lymphoid infiltrates (CLIs) are common in routine dermatopathology. However, differentiating a reactive CLI from a malignant lymphocytic infiltrate is often a significant challenge since many inflammatory dermatoses can clinically and/or histopathologically mimic cutaneous lymphomas, coined pseudolymphomas. We conducted a literature review from 1966 to July 1, 2015, at PubMed.gov using the search terms: Cutaneous lymphoma, cutaneous pseudolymphoma, cutaneous lymphoid hyperplasia, simulants/mimics/imitators of cutaneous lymphomas, and cutaneous lymphoid infiltrates. The diagnostic approach to CLIs and the most common differential imitators of lymphoma is discussed herein based on six predominant morphologic and immunophenotypic, histopathologic patterns: (1) Superficial dermal T-cell infiltrates (2) superficial and deep dermal perivascular and/or nodular natural killer/T-cell infiltrates (3) pan-dermal diffuse T-cell infiltrates (4) panniculitic T-cell infiltrates (5) small cell predominant B-cell infiltrates, and (6) large-cell predominant B-cell infiltrates. Since no single histopathological feature is sufficient to discern between a benign and a malignant CLI, the overall balance of clinical, histopathological, immunophenotypic, and molecular features should be considered carefully to establish a diagnosis. Despite advances in ancillary studies such as immunohistochemistry and molecular clonality, these studies often display specificity and sensitivity limitations. Therefore, proper clinicopathological correlation still remains the gold standard for the precise diagnosis of CLIs. PMID:27512181

  17. Group 2 Innate Lymphoid Cells: New Players in Human Allergic Diseases

    PubMed Central

    Doherty, TA; Broide, DH

    2015-01-01

    Allergic diseases are characterized by tissue eosinophilia, mucus secretion, IgE production, and activation of mast cells and TH2 cells. Production of TH2 cytokines including IL-4, IL-5, IL-9, and IL-13 has mainly been attributed to CD4+ TH2 cells. However, the recent discovery of group 2 innate lymphoid cells (ILC2s) in humans and findings from experimental disease models have challenged conventional concepts associated with the contribution of specific cells to type 2 inflammation in allergic diseases. ILC2s produce high levels of TH2 cytokines and have been detected in human lung tissue, peripheral blood, the gastrointestinal tract, skin, and sinonasal tissue, suggesting that ILC2s could contribute to chronic rhinosinusitis, asthma, atopic dermatitis, and gastrointestinal allergic disease. Moreover, depletion of ILC2s in animal models suggests a role for these cells in atopic dermatitis and asthma. This review will focus on the role of ILC2s in human allergy and asthma and provide a mechanistic insight from animal models. PMID:25898689

  18. The development of the immune tissues in marsupial pouch young.

    PubMed

    Borthwick, Casey R; Young, Lauren J; Old, Julie M

    2014-07-01

    Current knowledge of the development of the marsupial immune system, particularly in the context of lymphoid tissue development and the appearance of lymphocytes, has been examined and limitations identified. While primary lymphoid tissues like the thymus have been extensively studied, secondary lymphoid tissues such as the spleen and lymph nodes have been examined to a lesser extent, partly due to the difficulty of macroscopically identifying these structures, particularly in very small neonates. In addition, little research has been conducted on the mucosal-associated lymphoid tissues; tissues that directly trap antigens and play an important role in the maturity of adaptive immune responses. Research on the development of the marsupial immune tissues to date serves as a solid foundation for further research, particularly on the mechanisms behind the development of the immune system of marsupials. With the recent sequencing and annotation of whole marsupial genomes, the current wealth of sequence data will be essential in the development of marsupial specific reagents, including antibodies, that are required to widen our specific knowledge of the complex marsupial immune system and its development. PMID:24469962

  19. Ionizing radiation and autoimmunity: Induction of autoimmune disease in mice by high dose fractionated total lymphoid irradiation and its prevention by inoculating normal T cells

    SciTech Connect

    Sakaguchi, N.; Sakaguchi, S. Scripps Research Institute, La Jolla, CA PRESTO, JRDC, Institute of Phical and Chemical Research, Tsukuba, Ibaraki ); Miyai, K. )

    1992-11-01

    Ionizing radiation can functionally alter the immune system and break self-tolerance. High dose (42.5 Gy), fractionated (2.5 Gy 17 times) total lymphoid irradiation (TLI) on mice caused various organ-specific autoimmune diseases, such as gastritis, thyroiditis, and orchitis, depending on the radiation dosages, the extent of lymphoid irradiation, and the genetic background of the mouse strains. Radiation-induced tissue damage is not the primary cause of the autoimmune disease because irradiation of the target organs alone failed to elicit the autoimmunity and shielding of the organs from irradiation was unable to prevent it. In contrast, irradiation of both the thymus and the peripheral lymphoid organs/tissues was required for efficient induction of autoimmune disease by TLI. TLI eliminated the majority of mature thymocytes and the peripheral T cells for 1 mo, and inoculation of spleen cell, thymocyte, or bone marrow cell suspensions (prepared from syngeneic nonirradiated mice) within 2 wk after TLI effectively prevented the autoimmune development. Depletion of T cells from the inocula abrogated the preventive activity. CD4[sup +] T cells mediated the autoimmune prevention but CD8[sup +] T cells did not. CD4[sup +] T cells also appeared to mediate the TLI-induced autoimmune disease because CD4[sup +] T cells from disease-bearing TLI mice adoptively transferred the autoimmune disease to syngeneic naive mice. Taken together, these results indicate that high dose, fractionated ionizing radiation on the lymphoid organs/tissues can cause autoimmune disease by affecting the T cell immune system, rather than the target self-Ags, presumably by altering T cell-dependent control of self-reactive T cells. 62 refs., 9 figs., 2 tabs.

  20. Deciphering the transcriptional switches of innate lymphoid cell programming: the right factors at the right time.

    PubMed

    Lim, A W Y; McKenzie, A N J

    2015-01-01

    Innate lymphoid cells (ILCs) are increasingly recognised as an innate immune counterpart of adaptive T-helper (TH) cells. In addition to their similar effector cytokine production, there is a strong parallel between the transcription factors that control the differentiation of T(H)1, T(H)2 and T(H)17 cells and ILC groups 1, 2 and 3, respectively. Here, we review the transcriptional circuit that specifies the development of a common ILC progenitor and its subsequent programming into distinct ILC groups. Notch, GATA-3 (GATA-binding protein 3), Nfil3 (nuclear factor interleukin-3) and Id2 (inhibitor of DNA-binding 2) are identified as early factors that suppress B- and T-cell potentials and are turned on in favour of ILC commitment. Natural killer cells, which are the cytotoxic ILCs, develop along a pathway distinct from the rest of the helper-like ILCs that are derived from a common progenitor to all helper-like ILCs (CHILPs). PLZF(-) (promyelocytic leukaemia zinc-finger) CHILPs give rise to lymphoid tissue inducer cells, while PLZF(+) CHILPs have multilineage potential and could give rise to ILCs 1, 2 and 3. Such lineage specificity is dictated by the controlled expression of T-bet (T-box expressed in T cells), RORα (retinoic acid receptor-related orphan nuclear receptor-α), RORγt (retinoic acid receptor-related orphan nuclear receptor-γt) and AHR (aryl hydrocarbon receptor). In addition to the type of transcription factors, the developmental stages at which these factors are expressed are crucial in specifying the fate of the ILCs. PMID:25611557

  1. Lymphoid Gene Upregulation on Circulating Progenitors Participates in Their T-Lineage Commitment.

    PubMed

    Zepponi, Vanessa; Michaels Lopez, Victoria; Martinez-Cingolani, Carolina; Boudil, Amine; Pasqualetto, Valérie; Skhiri, Lamia; Gautreau, Laetitia; Legrand, Agnès; Megret, Jerome; Zavala, Flora; Ezine, Sophie

    2015-07-01

    Extrathymic T cell precursors can be detected in many tissues and represent an immediately competent population for rapid T cell reconstitution in the event of immunodeficiencies. Blood T cell progenitors have been detected, but their source in the bone marrow (BM) remains unclear. Prospective purification of BM-resident and circulating progenitors, together with RT-PCR single-cell analysis, was used to evaluate and compare multipotent progenitors (MPPs) and common lymphoid progenitors (CLPs). Molecular analysis of circulating progenitors in comparison with BM-resident progenitors revealed that CCR9(+) progenitors are more abundant in the blood than CCR7(+) progenitors. Second, although Flt3(-) CLPs are less common in the BM, they are abundant in the blood and have reduced Cd25(+)-expressing cells and downregulated c-Kit and IL-7Rα intensities. Third, in contrast, stage 3 MPP (MPP3) cells, the unique circulating MPP subset, have upregulated Il7r, Gata3, and Notch1 in comparison with BM-resident counterparts. Evaluation of the populations' respective abilities to generate splenic T cell precursors (Lin(-)Thy1.2(+)CD25(+)IL7Rα(+)) after grafting recipient nude mice revealed that MPP3 cells were the most effective subset (relative to CLPs). Although several lymphoid genes are expressed by MPP3 cells and Flt3(-) CLPs, the latter only give rise to B cells in the spleen, and Notch1 expression level is not modulated in the blood, as for MPP3 cells. We conclude that CLPs have reached the point where they cannot be a Notch1 target, a limiting condition on the path to T cell engagement. PMID:26026063

  2. Gel-Trapped Lymphorganogenic Chemokines Trigger Artificial Tertiary Lymphoid Organs and Mount Adaptive Immune Responses In Vivo.

    PubMed

    Kobayashi, Yuka; Watanabe, Takeshi

    2016-01-01

    We previously generated artificial lymph node-like tertiary lymphoid organs (artTLOs) in mice using lymphotoxin α-expressing stromal cells. Here, we show the construction of transplantable and functional artTLOs by applying soluble factors trapped in slow-releasing gels in the absence of lymphoid tissue organizer stromal cells. The resultant artTLOs were easily removable, transplantable, and were capable of attracting memory B and T cells. Importantly, artTLOs induced a powerful antigen-specific secondary immune response, which was particularly pronounced in immune-compromised hosts. Synthesis of functionally stable immune tissues/organs like those described here may be a first step to eventually develop immune system-based therapeutics. Although much needs to be learned from the precise mechanisms of action, they may offer ways in the future to reestablish immune functions to overcome hitherto untreatable diseases, including severe infection, cancer, autoimmune diseases, and various forms of immune deficiencies, including immune-senescence during aging. PMID:27597851

  3. IL-25 simultaneously elicits distinct populations of innate lymphoid cells and multipotent progenitor type 2 (MPPtype2) cells.

    PubMed

    Saenz, Steven A; Siracusa, Mark C; Monticelli, Laurel A; Ziegler, Carly G K; Kim, Brian S; Brestoff, Jonathan R; Peterson, Lance W; Wherry, E John; Goldrath, Ananda W; Bhandoola, Avinash; Artis, David

    2013-08-26

    The predominantly epithelial cell-derived cytokines IL-25, IL-33, and thymic stromal lymphopoietin (TSLP) can promote CD4(+) Th2 cell-dependent immunity, inflammation, and tissue repair at barrier surfaces through the induction of multiple innate immune cell populations. IL-25 and IL-33 were previously shown to elicit four innate cell populations, named natural helper cells, nuocytes, innate type 2 helper cells, and multipotent progenitor type 2 (MPP(type2)) cells, now collectively termed group 2 innate lymphoid cells (ILC2). In contrast to other types of ILC2, MPP(type2) cells exhibit multipotent potential and do not express T1/ST2 or IL-7Rα, suggesting that MPP(type2) cells may be a distinct population. Here, we show that IL-33 elicits robust ILC2 responses, whereas IL-25 predominantly promotes MPP(type2) cell responses at multiple tissue sites with limited effects on ILC2 responses. MPP(type2) cells were distinguished from ILC2 by their differential developmental requirements for specific transcription factors, distinct genome-wide transcriptional profile, and functional potential. Furthermore, IL-25-induced MPP(type2) cells promoted Th2 cytokine-associated inflammation after depletion of ILC2. These findings indicate that IL-25 simultaneously elicits phenotypically and functionally distinct innate lymphoid- and nonlymphoid-associated cell populations and implicate IL-25-elicited MPP(type2) cells and extramedullary hematopoiesis in the promotion of Th2 cytokine responses at mucosal surfaces. PMID:23960191

  4. Gel-Trapped Lymphorganogenic Chemokines Trigger Artificial Tertiary Lymphoid Organs and Mount Adaptive Immune Responses In Vivo

    PubMed Central

    Kobayashi, Yuka; Watanabe, Takeshi

    2016-01-01

    We previously generated artificial lymph node-like tertiary lymphoid organs (artTLOs) in mice using lymphotoxin α-expressing stromal cells. Here, we show the construction of transplantable and functional artTLOs by applying soluble factors trapped in slow-releasing gels in the absence of lymphoid tissue organizer stromal cells. The resultant artTLOs were easily removable, transplantable, and were capable of attracting memory B and T cells. Importantly, artTLOs induced a powerful antigen-specific secondary immune response, which was particularly pronounced in immune-compromised hosts. Synthesis of functionally stable immune tissues/organs like those described here may be a first step to eventually develop immune system-based therapeutics. Although much needs to be learned from the precise mechanisms of action, they may offer ways in the future to reestablish immune functions to overcome hitherto untreatable diseases, including severe infection, cancer, autoimmune diseases, and various forms of immune deficiencies, including immune-senescence during aging. PMID:27597851

  5. Regulation of B versus T lymphoid lineage fate decision by the proto-oncogene LRF

    PubMed Central

    Maeda, Takahiro; Merghoub, Taha; Hobbs, Robin M.; Dong, Lin; Maeda, Manami; Zakrzewski, Johannes; van den Brink, Marcel R. M.; Zelent, Arthur; Shigematsu, Hirokazu; Akashi, Koichi; Teruya-Feldstein, Julie; Cattoretti, Giorgio; Pandolfi, Pier Paolo

    2010-01-01

    Hematopoietic stem cells in the bone marrow give rise to lymphoid progenitors, which subsequently differentiate into B and T lymphocytes. Here we show that the proto-oncogene LRF plays an essential role in the B versus T lymphoid cell fate decision. We demonstrate that LRF is key for instructing early lymphoid progenitors to develop into B lineage cells by repressing T cell-instructive signals produced by the cell fate signal protein, Notch. We propose a new model for lymphoid lineage commitment, in which LRF acts as a master regulator of B versus T lineage fate decision. PMID:17495164

  6. Cystic lymphoid hyperplasia of the parotid gland as the initial manifestation of HIV infection

    PubMed Central

    Wu, Bingcheng; Ngo, Raymond; Petersson, Fredrik

    2014-01-01

    We report the case of a patient who presented with cystic lymphoid hyperplasia of the right parotid gland as the index diagnosis of HIV infection. Histological examination of the excised parotid gland revealed a solid-cystic lymphoepithelial lesion with a non-keratinous squamous epithelium, which grew into the lymphoid component via anastomosing cords and islands. These anastomosing cords and islands contained variably abundant B cells, several subepithelial multinucleated histiocytes, salivary ducts infiltrated by small lymphocytes, and a dense lymphoid infiltrate containing lymphoid follicles with enlarged, irregular germinal centres. PMID:24452982

  7. Soft tissue malignant lymphoma at sites of previous surgery.

    PubMed Central

    Radhi, J M; Ibrahiem, K; al-Tweigeri, T

    1998-01-01

    Three diffuse centroblastic lymphomas developed at the site of previous surgery. Two were preceded by atypical lymphoid infiltrates. Clinical data, microscopic features, and immunophenotypic studies were reviewed. All three patients presented with soft tissue masses at the site of previous surgery and metallic implants, with no evidence of lymphadenopathy, hepatosplenomegaly, or bone marrow involvement. There was no history of immunosuppression or risk factors. In two cases the initial diagnosis was of atypical lymphoid infiltrate progressing to lymphoma. Pathological examination showed a diffuse centroblastic lymphoma with an angiocentric pattern in one case. Phenotypic studies confirmed B cell origin. Soft tissue malignant lymphoma, though uncommon, can occur at the site of previous orthopaedic surgery, in particular joint replacement. Atypical lymphoid infiltrate may signal such an event. Images PMID:9828826

  8. Role of group 3 innate lymphoid cells during experimental otitis media in a rat model.

    PubMed

    Cho, Chang Gun; Gong, Sung Ho; Kim, Hee-Bok; Song, Jae-Jun; Park, Joo Hyun; Lim, Yun-Sung; Park, Seok-Won

    2016-09-01

    The objective of this study was to evaluate the role of group 3 innate lymphoid cells (ILC3) in the middle ear (ME) mucosal response to bacterial infection in a rat model. To confirm the role of ILC3 in bacterially induced otitis media (OM), the serum concentrations of IL-17 and IL-22 were determined by ELISA, and the tissue expression of IL-17 and IL-22 in infected ME mucosa was assessed by immunohistochemical staining. Immunohistochemical staining of specific cell surface markers was also assessed to confirm the origin of the cells expressing IL-17 and IL-22. Twenty Sprague-Dawley rats were used in the surgically-induced animal model of OM. OM was induced by inoculation of non-typeable Haemophilus influenzae into the ME cavity of the rats. The rats were divided into four experimental groups: three infected groups and one control group. Infected groups were subdivided into sets of 5 rats, one for each of the three time points (1, 4 and 7 days post-inoculation). For determination of rat IL-17 and IL-22 levels in infected rats and control rats, infected or control ME mucosa sections were analyzed by immunohistochemistry with specific antibodies directed against IL-17 and IL-22. Immunohistochemical staining for CD3, RORγt, and NKp46 were also conducted on the samples to confirm the origin of cells expressing IL-17 and IL-22. IL-17 and IL-22 serum concentrations were significantly increased in the infected rats compared to control rats. Immunohistochemical staining revealed increased IL-17 and IL-22 expressions in all infected ME mucosae from the first day after inoculation. In addition, the results of tissue staining for the specific surface markers were negative for CD3 and NKp46, but were highly positive for RORγt. IL-17 and IL-22 revealed their association with the bacterially induced proliferative and hyperplastic responses of ME mucosa, which are characteristic features in pathogenesis of OM. Surface marker examination showed that the source cells for IL-17

  9. Early lymphoid lesions: conceptual, diagnostic and clinical challenges

    PubMed Central

    Ganapathi, Karthik A.; Pittaluga, Stefania; Odejide, Oreofe O.; Freedman, Arnold S.; Jaffe, Elaine S.

    2014-01-01

    There are no “benign lymphomas”, a fact due to the nature of lymphoid cells to circulate and home as part of their normal function. Thus, benign clonal expansions of lymphocytes are only rarely recognized when localized. Recent studies have identified a number of lymphoid proliferations that lie at the interface between benign and malignant. Some of these are clonal proliferations that carry many of the molecular hallmarks of their malignant counterparts, such as BCL2/IGH and CCND1/IGH translocations associated with the in situ forms of follicular lymphoma and mantle cell lymphoma, respectively. There are other clonal B-cell proliferations with low risk of progression; these include the pediatric variants of follicular lymphoma and marginal zone lymphoma. Historically, early or incipient forms of T/NK-cell neoplasia also have been identified, such as lymphomatoid papulosis and refractory celiac disease. More recently an indolent form of T-cell lymphoproliferative disease affecting the gastrointestinal tract has been described. Usually, CD8+, the clonal cells are confined to the mucosa. The clinical course is chronic, but non-progressive. NK-cell enteropathy is a clinically similar condition, composed of cytologically atypical NK-cells that may involve the stomach, small bowel or colon. Breast implant-associated anaplastic large cell lymphoma is a cytologically alarming lesion that is self-limited if confined to the seroma cavity. Atypical lymphoid proliferations that lie at the border of benign and malignant can serve as instructive models of lymphomagenesis. It is also critical that they be correctly diagnosed to avoid unnecessary and potentially harmful therapy. PMID:25176983

  10. Gallium scanning in lymphoid interstitial pneumonitis of children with AIDS

    SciTech Connect

    Schiff, R.G.; Kabat, L.; Kamani, N.

    1987-12-01

    Lymphoid interstitial pneumonitis (LIP) is a frequent pulmonary complication in the child with the acquired immune deficiency syndrome (AIDS) and human immunodeficiency virus (HIV) infection. We report the gallium scan findings in two children with AIDS and LIP. Gallium scintigraphy in both children demonstrated increased radionuclide concentration throughout the lungs, a pattern indistinguishable scintigraphically from that of Pneumocystis carinii pneumonia (PCP). This should alert nuclear medicine practitioners and referring physicians to another cause of diffusely increased gallium uptake in the lungs of patients with AIDS.

  11. Innate lymphoid cell function in the context of adaptive immunity.

    PubMed

    Bando, Jennifer K; Colonna, Marco

    2016-06-21

    Innate lymphoid cells (ILCs) are a family of innate immune cells that have diverse functions during homeostasis and disease. Subsets of ILCs have phenotypes that mirror those of polarized helper T cell subsets in their expression of core transcription factors and effector cytokines. Given the similarities between these two classes of lymphocytes, it is important to understand which functions of ILCs are specialized and which are redundant with those of T cells. Here we discuss genetic mouse models that have been used to delineate the contributions of ILCs versus those of T cells and review the current understanding of the specialized in vivo functions of ILCs. PMID:27328008

  12. Identification of stable reference genes for quantitative PCR in cells derived from chicken lymphoid organs.

    PubMed

    Borowska, D; Rothwell, L; Bailey, R A; Watson, K; Kaiser, P

    2016-02-01

    Quantitative polymerase chain reaction (qPCR) is a powerful technique for quantification of gene expression, especially genes involved in immune responses. Although qPCR is a very efficient and sensitive tool, variations in the enzymatic efficiency, quality of RNA and the presence of inhibitors can lead to errors. Therefore, qPCR needs to be normalised to obtain reliable results and allow comparison. The most common approach is to use reference genes as internal controls in qPCR analyses. In this study, expression of seven genes, including β-actin (ACTB), β-2-microglobulin (B2M), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), β-glucuronidase (GUSB), TATA box binding protein (TBP), α-tubulin (TUBAT) and 28S ribosomal RNA (r28S), was determined in cells isolated from chicken lymphoid tissues and stimulated with three different mitogens. The stability of the genes was measured using geNorm, NormFinder and BestKeeper software. The results from both geNorm and NormFinder were that the three most stably expressed genes in this panel were TBP, GAPDH and r28S. BestKeeper did not generate clear answers because of the highly heterogeneous sample set. Based on these data we will include TBP in future qPCR normalisation. The study shows the importance of appropriate reference gene normalisation in other tissues before qPCR analysis. PMID:26872627

  13. Group 3 innate lymphoid cells: regulating host-commensal bacteria interactions in inflammation and cancer.

    PubMed

    Goc, Jeremy; Hepworth, Matthew R; Sonnenberg, Gregory F

    2016-01-01

    A delicate balance exists between the mammalian immune system and normally beneficial commensal bacteria that colonize the gastrointestinal tract, which is necessary to maintain tissue homeostasis. Dysregulation of these interactions between the host and commensal bacteria is causally associated with chronic inflammation and the development of cancer. In contrast, recent reports have highlighted that commensal bacteria also play an essential role in promoting anti-tumor immune responses in several contexts, highlighting a paradox whereby interactions between the host and commensal bacteria can influence both pro- and anti-tumor immunity. Given the critical roles for group 3 innate lymphoid cells (ILC3s) in regulating inflammation, tissue repair and host-microbe interactions in the intestine, here we discuss new evidence that ILC3s may profoundly influence the development, progression and control of tumors. In this review, we provide an overview of recent advances in understanding the impact of commensal bacteria on tumorigenesis, discuss recent findings identifying ILC3s as critical regulators of host-microbe interactions and highlight the emerging role of this immune cell population in cancer and their potential implication as a therapeutic target. PMID:26451009

  14. Innate lymphoid cells: models of plasticity for immune homeostasis and rapid responsiveness in protection.

    PubMed

    Almeida, F F; Belz, G T

    2016-09-01

    Innate lymphoid cells (ILCs) have stormed onto the immune landscape as "newly discovered" cell types. These tissue-resident sentinels are enriched at mucosal surfaces and engage in complex cross talk with elements of the adaptive immune system and microenvironment to orchestrate immune homeostasis. Many parallels exist between innate cells and T cells leading to the initial partitioning of ILCs into rather rigid subsets that reflect their "adaptive-like" effector cytokines profiles. ILCs themselves, however, have unique attributes that are only just beginning to be elucidated. These features result in complementarity with, rather than complete duplication of, functions of the adaptive immune system. Key transcription factors determine the pathway of differentiation of progenitors towards an ILC1, ILC2, or ILC3 subset. Once formed, flexibility in the responses of these subsets to stimuli unexpectedly allows transdifferentation between the different subsets and the acquisition of altered phenotypes and function. This provides a mechanism for rapid innate immune responsiveness. Here, we discuss the models of differentiation for maintenance and activation of tissue-resident ILCs in maintaining immune homeostasis and protection. PMID:27484190

  15. Epigenetic alteration by DNA-demethylating treatment restores apoptotic response to glucocorticoids in dexamethasone-resistant human malignant lymphoid cells

    PubMed Central

    2014-01-01

    Background Glucocorticoids (GCs) are often included in the therapy of lymphoid malignancies because they kill several types of malignant lymphoid cells. GCs activate the glucocorticoid receptor (GR), to regulate a complex genetic network, culminating in apoptosis. Normal lymphoblasts and many lymphoid malignancies are sensitive to GC-driven apoptosis. Resistance to GCs can be a significant clinical problem, however, and correlates with resistance to several other major chemotherapeutic agents. Methods We analyzed the effect of treatment with the cytosine analogue 5 aza-2’ deoxycytidine (AZA) on GC resistance in two acute lymphoblastic leukemia (T or pre-T ALL) cell lines- CEM and Molt-4- and a (B-cell) myeloma cell line, RPMI 8226. Methods employed included tissue culture, flow cytometry, and assays for clonogenicity, cytosine extension, immunochemical identification of proteins, and gene transactivation. High throughput DNA sequencing was used to confirm DNA methylation status. Conclusions Treatment of these cells with AZA resulted in altered DNA methylation and restored GC-evoked apoptosis in all 3 cell lines. In CEM cells the altered epigenetic state resulted in site-specific phosphorylation of the GR, increased GR potency, and GC-driven induction of the GR from promoters that lie in CpG islands. In RPMI 8226 cells, expression of relevant coregulators of GR function was altered. Activation of p38 mitogen-activated protein kinase (MAPK), which is central to a feed-forward mechanism of site-specific GR phosphorylation and ultimately, apoptosis, occurred in all 3 cell lines. These data show that in certain malignant hematologic B- and T-cell types, epigenetically controlled GC resistance can be reversed by cell exposure to a compound that causes DNA demethylation. The results encourage studies of application to in vivo systems, looking towards eventual clinical applications. PMID:24795534

  16. Evaluation of CD25-positive cells in relation to the subtypes and prognoses in various lymphoid tumours in dogs.

    PubMed

    Mizutani, Noriyuki; Goto-Koshino, Yuko; Tsuboi, Masaya; Kagawa, Yumiko; Ohno, Koichi; Uchida, Kazuyuki; Tsujimoto, Hajime

    2016-05-01

    Interleukin-2 receptor alpha chain (CD25) expression has been reported in human lymphoid tumours and suggested to correlate with the prognosis. In this study, we detected CD25-positive cells in various types of lymphoid tumours in dogs. Immunohistochemical analyses of the tissues from diffuse large B-cell lymphoma (DLBCL) (n=6), T-zone lymphoma (TZL) (n=5), and follicular lymphoma (FL) (n=2) revealed that cells strongly positive for CD25 were observed generally in accordance with lymphoma cell localization. CD25-positive cells were consistently detected in TZL and FL cases; however, the number of CD25-positive cells was variable among DLBCL cases. Furthermore, we evaluated the rate of CD25-positive cells by flow cytometric analysis in 29 dogs with lymphoid malignancies, including high-grade B-cell lymphoma (n=17), TZL (n=5), FL (n=2), cutaneous lymphoma (n=2), and acute lymphoblastic leukaemia (ALL) (n=3). CD25-positivity in the lymph node cells was significantly higher in dogs with high-grade B-cell lymphoma (mean±SD, 49.6±31.3%) or TZL (mean±SD, 80.2±10.0%) than that in healthy dogs (mean±SD, 9.8±2.8%). In prognostic analysis of 15 cases with high-grade B-cell lymphoma, the progression-free survival was significantly shorter in CD25-high group than that in CD25-low group. The results obtained in this study are useful for subtype differentiation and prognostic analysis of canine lymphomas and future development of molecular-targeted therapy directed at CD25. PMID:27090625

  17. [Dynamic tissue organizational view of the formation of functional immune system and medical perspectives of its research].

    PubMed

    Balogh, Péter

    2007-02-25

    Advances in molecular biological procedures, bioinformatics and transgenic technology and their rapidly broadening use have led to an immense increase of data concerning the cells comprising the immune system at molecular level. This new knowledge is mostly relevant to the hemopoietic components of structured lymphoid tissues, while similar research efforts aimed at investigating the non-hemopoietic stromal parts have until recently been rather neglected. However, the results of recent investigations have established the importance of tissue differentiation and functional maturation of these latter components within the lymphoid organs during the embryonic development for achieving the individual's immunological competence, as manifested in various forms of immune responses. Research performed on murine embryos have revealed the origin and developmental pathways of these less investigated stromal components, identified the molecular participants involved in their interactions with lymphoid cells, and determined the anatomic location of lymphoid-stromal domains and the sequence of interactions between the two tissue partners. In addition to the obvious theoretical importance of the above events, their resemblance to the occurrence of certain pathological conditions with inflammatory origin has also become apparent, where the course of the disease is characterized by the formation of "tertiary lymphoid tissue" in the affected organ. A more detailed understanding of the dependence of hemopoietic cells on their stromal environment in the lymphoid tissues may offer support for establishing a more efficient causal therapy for chronic inflammations. The purpose of the present account is to report these developmental events, and to emphasize the importance of the stromal development and functional dynamics during the interpretation of immune functions and place them at least as important a diagnostic and therapeutic target as the current clinical evaluation hitherto mainly

  18. Ectopic Lymphoid Structures Support Ongoing Production of Class-Switched Autoantibodies in Rheumatoid Synovium

    PubMed Central

    Manzo, Antonio; Kelly, Stephen; Blades, Mark C; Kirkham, Bruce; Spencer, Jo; Pitzalis, Costantino

    2009-01-01

    Background Follicular structures resembling germinal centres (GCs) that are characterized by follicular dendritic cell (FDC) networks have long been recognized in chronically inflamed tissues in autoimmune diseases, including the synovium of rheumatoid arthritis (RA). However, it is debated whether these ectopic structures promote autoimmunity and chronic inflammation driving the production of pathogenic autoantibodies. Anti-citrullinated protein/peptide antibodies (ACPA) are highly specific markers of RA, predict a poor prognosis, and have been suggested to be pathogenic. Therefore, the main study objectives were to determine whether ectopic lymphoid structures in RA synovium: (i) express activation-induced cytidine deaminase (AID), the enzyme required for somatic hypermutation and class-switch recombination (CSR) of Ig genes; (ii) support ongoing CSR and ACPA production; and (iii) remain functional in a RA/severe combined immunodeficiency (SCID) chimera model devoid of new immune cell influx into the synovium. Methods and Findings Using immunohistochemistry (IHC) and quantitative Taqman real-time PCR (QT-PCR) in synovial tissue from 55 patients with RA, we demonstrated that FDC+ structures invariably expressed AID with a distribution resembling secondary lymphoid organs. Further, AID+/CD21+ follicular structures were surrounded by ACPA+/CD138+ plasma cells, as demonstrated by immune reactivity to citrullinated fibrinogen. Moreover, we identified a novel subset of synovial AID+/CD20+ B cells outside GCs resembling interfollicular large B cells. In order to gain direct functional evidence that AID+ structures support CSR and in situ manufacturing of class-switched ACPA, 34 SCID mice were transplanted with RA synovium and humanely killed at 4 wk for harvesting of transplants and sera. Persistent expression of AID and Iγ-Cμ circular transcripts (identifying ongoing IgM-IgG class-switching) was observed in synovial grafts expressing FDCs/CD21L. Furthermore, synovial

  19. [Mathematical simulation of the regulation of the size of the lymphoid population in relation to chronic lymphoid leukemia].

    PubMed

    Stepanova, N V; Feofanova, T V; Itkin, B Z

    1988-01-01

    A model was constructed of accumulation kinetics of labeled lymphocytes based on the experiments of long-term injection of 3H-thymidine label in vivo into the blood of healthy and suffering from chronic lympholeucosis animals. There was found an essential difference between the coefficients of reproduction and death of cells of the proliferating pool for the normal, initial and advanced stages of the disease. This served as a basis for the creation of the closed non-linear model of autoregulation of lymphoid population size describing different stages of leucosis development. PMID:3390484

  20. Treatment of intractable rheumatoid arthritis with total lymphoid irradiation

    SciTech Connect

    Kotzin, B.L.; Strober, S.; Engleman, E.G.; Calin, A.; Hoppe, R.T.; Kansas, G.S.; Terrell, C.P.; Kaplan, H.S.

    1981-10-22

    Eleven patients with intractable rheumatoid arthritis were treated with total lymphoid irradiation (total dose, 2000 rad) in an uncontrolled feasibility study, as an alternative to long-term therapy with cytotoxic drugs such as cyclophosphamide and azathioprine. During a follow-up period of five to 18 months after total lymphoid irradiation, there was a profound and sustained suppression of the absolute lymphocyte count and in vitro lymphocyte function, as well as an increase in the ratio of Leu-2 (suppressor/cytotoxic) to Leu-3 (helper) T cells in the blood. Persistent circulating suppressor cells of the mixed leukocyte response and of pokeweek mitogen-induced immunoglobulin secretion developed in most patients. In nine of the 11 patients, these changes in immune status were associated with relief of joint tenderness and swelling and with improvement in function scores. Maximum improvement occurred approximately six months after irradiation and continued for the remainder of the observation period. Few severe or chronic side effects were associated with the radiotherapy.

  1. Treatment of intractable rheumatoid arthritis with total lymphoid irradiation

    SciTech Connect

    Kotzin, B.L.; Strober, S.; Engleman, E.G.; Calin, A.; Hoppe, R.T.; Kansas, G.S.; Terrell, C.P.; Kaplan, H.S.

    1981-10-01

    Eleven patients with intractable rheumatoid arthritis were treated with total lymphoid irradiation (total dose, 2000 rad) in an uncontrolled feasibility study, as an alternative to long-term therapy with cytotoxic drugs such as cyclophosphamide and azathioprine. During a follow-up period of five to 18 months after total lymphoid irradiation, there was a profound and sustained suppression of the absolute lymphocyte count and in vitro lymphocyte function, as well as an increase in the ratio of Leu-2 (suppressor/cytotoxic) to Leu-3 (helper) T cells in the blood. Persistent circulating suppressor cells of the mixed leukocyte response and of pokeweed mitogen-induced immunoglobulin secretion developed in most patients. In nine of the 11 patients, these changes in immune status were associated with relief of joint tenderness and swelling and with improvement in function scores. Maximum improvement occurred approximately six months after irradiation and continued for the remainder of the observation period. Few severe or chronic side effects were associated with the radiotherapy.

  2. Sustained improvement of intractable rheumatoid arthritis after total lymphoid irradiation

    SciTech Connect

    Field, E.H.; Strober, S.; Hoppe, R.T.; Calin, A.; Engleman, E.G.; Kotzin, B.L.; Tanay, A.S.; Calin, H.J.; Terrell, C.P.; Kaplan, H.S.

    1983-08-01

    Total lymphoid irradiation (TLI) was administered to 11 patients who had intractable rheumatoid arthritis that was unresponsive to conventional medical therapy, including aspirin, multiple nonsteroidal antiinflammatory drugs, gold salts, and D-penicillamine. Total lymphoid irradiation was given as an alternative to cytotoxic drugs such as azathioprine and cyclophosphamide. After radiotherapy, 9 of the 11 patients showed a marked improvement in clinical disease activity as measured by morning stiffness, joint tenderness, joint swelling, and overall functional abilities. The mean improvement of disease activity in all patients ranged from 40-70 percent and has persisted throughout a 13-28 month followup period. This improvement permitted the mean daily steroid dose to be reduced by 54%. Complications included severe fatigue and other constitutional symptoms during radiotherapy, development of Felty's syndrome in 1 patient, and an exacerbation of rheumatoid lung disease in another. After therapy, all patients exhibited a profound T lymphocytopenia, and a reversal in their T suppressor/cytotoxic cell to helper cell ratio. The proliferative responses of peripheral blood mononuclear cells to phytohemagglutinin, concanavalin A, and allogeneic leukocytes (mixed leukocyte reaction) were markedly reduced, as was in vitro immunoglobulin synthesis after stimulation with pokeweed mitogen. Alterations in T cell numbers and function persisted during the entire followup period, except that the mixed leukocyte reaction showed a tendency to return to normal values.

  3. Immunoglobulin Expression in Non-Lymphoid Lineage and Neoplastic Cells

    PubMed Central

    Chen, Zhengshan; Qiu, Xiaoyan; Gu, Jiang

    2009-01-01

    It has traditionally been believed that the production of immunoglobulin (Ig) molecules is restricted to B lineage cells. However, immunoglobulin genes and proteins have been recently found in a variety of types of cancer cells, as well as some proliferating epithelial cells and neurons. The immunoglobulin molecules expressed by these cells consist predominantly of IgG, IgM, and IgA, and the light chains expressed are mainly kappa chains. Recombination activating genes 1 and 2, which are required for V(D)J recombination, are also expressed in these cells. Knowledge about the function of these non-lymphoid cell-derived immunoglobulins is limited. Preliminary data suggests that Ig secreted by epithelial cancer cells has some unidentified capacity to promote the growth and survival of tumor cells. As immunoglobulins are known to have a wide spectrum of important functions, the discovery of non-lymphoid cells and cancers that produce immunoglobulin calls for in-depth investigation of the functional and pathological significance of this previously unrecognized phenomenon. PMID:19246641

  4. Radiation therapy of conjunctival and orbital lymphoid tumors

    SciTech Connect

    Jereb, B.; Lee, H.; Jakobiec, F.A.; Kutcher, J.

    1984-07-01

    Lymphoid tumors of the conjuctiva and orbit are rare and remain localized in the majority of cases. Sometimes it is not possible either clinically or histologically to differentiate between a non-Hodgkin's lymphoma (NHL) and benign lymphoid hyperplasia. A series of 24 patients is reported. Nineteen were classified as having malignant NHL and 5 benign hyperplasia; 1 of these 5 later developed metastases, however. All patients had systemic work-up: 18 had Stage I, 1 had Stage II, and 5 had Stage IV disease. All patients received local radiation therapy with doses of 2400 to 2750 rad in 2-3 weeks for lesions of the eyelid and conjunctiva, and between 3000 and 3750 rad in 3-4 weeks for retrobulbar lesions. A method of shielding the lens with a lead block mounted on a low vac lens is described, and the dose distribution within the eye and orbit is presented. Patients who were treated with doses higher than 3000 rad experienced conjunctivitis and skin erythema that resolved completely. No other effects of radiation on normal structures of the ocular adnexa were observed in the 20 patients who are alive and without signs of tumor 10-46 months with a median follow-up time of 22 months.

  5. Trafficking of. cap alpha. -L-fucosidase in lymphoid cells

    SciTech Connect

    DiCioccio, R.A.; Brown, K.S.

    1987-05-01

    The quantity of ..cap alpha..-L-fucosidase in human serum is determined by heredity. The mechanism controlling levels of the enzyme in serum is unknown. To investigate this, lymphoid cell lines derived from individuals with either low, intermediate or high ..cap alpha..-L-fucosidase in serum were established. Steady state levels of extracellular ..cap alpha..-L-fucosidase protein and activity overlapped among the cell lines. Thus, in vivo serum phenotypes of ..cap alpha..-L-fucosidase are not adequately expressed in this system. ..cap alpha..-L-Fucosidase was also metabolically labelled with /sup 35/S-methionine, immunoprecipitated, and examined by SDS-PAGE. Cells pulse-labelled from 0.25-2 h had a major intracellular form of enzyme (Mr = 58,000). Cells pulsed for 1.5 h and chased for 21 h with unlabeled methionine had an intracellular form of Mr = 60,000 and an extracellular form of Mr = 62,000. Cells treated with chloroquine had only the 58,000-form both intra- and extra-cellularly. Moreover, chloroquine did not effect the quantitative distribution of ..cap alpha..-L-fucosidase between cells and medium. In fibroblasts, chloroquine enhanced the secretion of newly made lysosomal enzymes and blocked the processing of intercellular enzyme forms from a higher to a lower molecular mass. Thus, there are trafficking differences between ..cap alpha..-L-fucosidase in lymphoid cells and lysosomal enzymes in fibroblasts. This suggests that alternative targeting mechanisms for lysosomal enzymes exist in these cells.

  6. Lymphoid hyperplasia and lymphoma in KSHV K1 transgenic mice.

    PubMed

    Berkova, Zuzana; Wang, Shu; Sehgal, Lalit; Patel, Keyur Pravinchandra; Prakash, Om; Samaniego, Felipe

    2015-05-01

    Growing evidence supports the involvement of human herpervirus 8, Kaposi's sarcoma associated herpesvirus (KSHV), in the pathology of primary effusion lymphoma, multicentric Castleman's disease, and Kaposi's sarcoma, but the exact mechanism of KSHV contribution to the oncogenic process remains elusive. We studied transgenic mice expressing the ORF K1 of KSHV, whose position in the KSHV genome corresponds to known lymphoproliferative genes of other herpesviruses. K1 protein was previously shown to contain a constitutively active ITAM domain, involved in activation of Akt and pro-survival signaling, and to inhibit Fas-mediated apoptosis by interfering with binding of FasL. All this pointed to a possible role of K1 in the pathogenesis of KSHV-associated cancers. K1 transgenic mice (80-90%) developed lymphoid hyperplasia and splenomegaly at 8 and 10 months of age, 25% had confirmed diagnosis of lymphoma, and 50% developed abdominal and/or hepatic tumors by 18 months of age. Histological examination showed loss of splenic architecture and increased cellularity. Lymph nodes showed disrupted architecture with effaced follicles and other pathological changes, including signs of angiofollicular lymphoid hyperplasia. One of the livers showed signs of angiosarcoma. In summary, our histology results revealed pathological changes in K1 transgenic mice similar to lymphoma, Castleman's disease, and angiosarcoma, suggesting that K1 may contribute to the development of KSHV-associated cancers. PMID:25301266

  7. HMGB1: The Central Cytokine for All Lymphoid Cells

    PubMed Central

    Li, Guanqiao; Liang, Xiaoyan; Lotze, Michael T.

    2013-01-01

    High-mobility group box 1 (HMGB1) is a leaderless cytokine, like the IL-1 and FGF family members, that has primary roles within the nucleus and the cytosol. Within the nucleus, it serves as another guardian of the genome, protecting it from oxidant injury and promoting access to transcriptional complexes such as nuclear hormone/nuclear hormone receptors and p53/p73 complexes. Within the cytosol it promotes autophagy and recruitment of the myddosome to Toll-like receptor (TLR) 9 vesicular compartments. Outside of the cell, it can either bind to specific receptors itself, or with high affinity to DNA, nucleosomes, IL-1β, lipopolysaccharide, and lipoteichoic acid to mediate responses in specific physiological or pathological conditions. Currently identified receptors include TLR2, TLR4, the receptor for advanced glycation end products, CD24-Siglec G/10, chemokine CXC receptor 4, and TIM-3. In terms of its effects or functions within lymphoid cells, HMGB1 is principally secreted from mature dendritic cells (DCs) to promote T-cell and B-cell reactivity and expansion and from activated natural killer cells to promote DC maturation during the afferent immune response. Some studies suggest that its primary role in the setting of chronic inflammation is to promote immunosuppression. As such, HMGB1 is a central cytokine for all lymphoid cells playing a role complementary to its better studied role in myeloid cells. PMID:23519706

  8. Disease-specific mutations in mature lymphoid neoplasms: Recent advances

    PubMed Central

    Sakata-Yanagimoto, Mamiko; Enami, Terukazu; Yokoyama, Yasuhisa; Chiba, Shigeru

    2014-01-01

    Mature lymphoid neoplasms (MLN) are clinically and pathologically more complex than precursor lymphoid neoplasms. Until recently, molecular characterization of MLN was mainly based on cytogenetics/fluorescence in situ hybridization, allele copy number, and mRNA expression, approaches that yielded scanty gene mutation information. Use of massive parallel sequencing technologies has changed this outcome, and now many gene mutations have been discovered. Some of these are considerably frequent in, and substantially specific to, distinct MLN subtypes, and occur at single or several hotspots. They include the V600E BRAF mutation in hairy cell leukemia, the L265P MYD88 mutation in Waldenström macroglobulinemia, the G17V RHOA mutation in angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma, not otherwise specified, and the Y640F//D661Y/V/H/I//N647I STAT3 mutations in T-cell large granular lymphocytic leukemia. Detecting these mutations is highly valuable in diagnosing MLN subtypes. Defining these mutations also sheds light on the molecular pathogenesis of MLN, furthering development of molecular targeting therapies. In this review, we focus on the disease-specific gene mutations in MLN discovered by recent massive sequencing technologies. PMID:24689848

  9. JAK2 in the Diagnosis and Treatment of Lymphoid Malignancies: A Review of the Literature.

    PubMed

    Fonseka, Lakshan N; Germán, Beatriz; Expósito, Francisco; Conde, Enrique; Bárcena, Sergio; Tirado, Carlos A

    2016-01-01

    In 2016, there will be an estimated 6,590 new cases of acute lymphocytic leukemia and 18,960 new cases of chronic lymphocytic leukemia in the United States. These and other lymphoid malignancies have a key player in common, JAK2, an enzyme from the Janus kinase (JAK) family. Deviations from the normal functioning of JAK2, particularly in the JAK-signal transducer and activator of transcription (STAT) pathway, can disrupt homeostasis and drive the accumulation of intermediate progenitors, contributing to the development of myeloid and lymphoid malignancies. In this review, the recent literature on JAK2 mutations in lymphoid malignancies is summarized, concluding with a discussion of the treatment of lymphoid malignancies. New directions for future research have been underlined to advance the clinical management of lymphoid malignancies. PMID:27606950

  10. Dermatan Sulfate-Free Mice Display Embryological Defects and Are Neonatal Lethal Despite Normal Lymphoid and Non-Lymphoid Organogenesis

    PubMed Central

    Stachtea, Xanthi N.; Tykesson, Emil; van Kuppevelt, Toin H.; Feinstein, Ricardo; Malmström, Anders; Reijmers, Rogier M.; Maccarana, Marco

    2015-01-01

    The epimerization of glucuronic acid into iduronic acid adds structural variability to chondroitin/dermatan sulfate polysaccharides. Iduronic acid-containing domains play essential roles in processes such as coagulation, chemokine and morphogen modulation, collagen maturation, and neurite sprouting. Therefore, we generated and characterized, for the first time, mice deficient in dermatan sulfate epimerase 1 and 2, two enzymes uniquely involved in dermatan sulfate biosynthesis. The resulting mice, termed DKO mice, were completely devoid of iduronic acid, and the resulting chondroitin sulfate chains were structurally different from the wild type chains, from which a different protein binding specificity can be expected. As a consequence, a vast majority of the DKO mice died perinatally, with greatly variable phenotypes at birth or late embryological stages such as umbilical hernia, exencephaly and a kinked tail. However, a minority of embryos were histologically unaffected, with apparently normal lung and bone/cartilage features. Interestingly, the binding of the chemokine CXCL13, an important modulator of lymphoid organogenesis, to mouse DKO embryonic fibroblasts was impaired. Nevertheless, the development of the secondary lymphoid organs, including the lymph nodes and spleen, was normal. Altogether, our results indicate an important role of dermatan sulfate in embryological development and perinatal survival. PMID:26488883

  11. Total lymphoid irradiation leads to transient depletion of the mouse thymic medulla and persistent abnormalities among medullary stromal cells

    SciTech Connect

    Adkins, B.; Gandour, D.; Strober, S.; Weissman, I.

    1988-05-15

    Mice given multiple doses of sublethal irradiation to both the thymus and the peripheral lymphoid tissues showed major transient, and some persistent disruptions in general thymic architecture and in thymic stromal components. At 2 wk after total lymphoid irradiation (TLI), the thymus lacked identifiable medullary regions by immunohistochemical analyses. Medullary stromal cells expression MHC Ag or a medullary epithelial cell Ag, as well as medullary macrophages, were undetectable. Instead, the processes of cortical epithelial cells were observed throughout the entire thymus. Strikingly, thymocyte subsets with mature phenotypes (CD4+CD8- and CD4-CD8+) were present in the apparent absence of a medulla. This early, gross effect was rapidly reversed such that by 1 to 2 mo after TLI, medullary areas with MHC Ag-positive cells were evident. However, abnormalities in a subset of medullary stromal cells appeared to be more persistent. Medullary epithelial cells, identified by the MD1 mAb, were greatly reduced in number and abnormally organized for at least 4 mo after TLI. In addition, macrophages containing endogenous peroxidase activity, normally abundant in medullary regions, were undetectable at all times examined after TLI. Therefore, this irradiation regimen induced both transient and long term effects in the thymus, primarily in medullary regions. These results suggest that TLI may be used as an experimental tool for studying the impact of selective depletion of medullary stromal cells on the development of specific T cell functions.

  12. Multiple Hemopoietic Defects and Lymphoid Hyperplasia in Mice Lacking the Transcriptional Activation Domain of the c-Rel Protein

    PubMed Central

    Carrasco, Daniel; Cheng, Janet; Lewin, Anne; Warr, Glenn; Yang, Hyekyung; Rizzo, Cheryl; Rosas, Fabio; Snapper, Clifford; Bravo, Rodrigo

    1998-01-01

    The c-rel protooncogene encodes a member of the Rel/nuclear factor (NF)-κB family of transcriptional factors. To assess the role of the transcriptional activation domain of c-Rel in vivo, we generated mice expressing a truncated c-Rel (Δc-Rel) that lacks the COOH-terminal region, but retains a functional Rel homology domain. Mice with an homozygous mutation in the c-rel region encoding the COOH terminus of c-Rel (c-relΔCT/ΔCT) display marked defects in proliferative and immune functions. c-relΔCT/ΔCT animals present histopathological alterations of hemopoietic tissues, such as an enlarged spleen due to lymphoid hyperplasia, extramedullary hematopoiesis, and bone marrow hypoplasia. In older c-relΔCT/ΔCT mice, lymphoid hyperplasia was also detected in lymph nodes, liver, lung, and stomach. These animals present a more severe phenotype than mice lacking the entire c-Rel protein. Thus, in c-relΔCT/ΔCT mice, the lack of c-Rel activity is less efficiently compensated by other NF-κB proteins. PMID:9529314

  13. Characterizing natural hydrogel for reconstruction of three-dimensional lymphoid stromal network to model T-cell interactions.

    PubMed

    Kim, Jiwon; Wu, Biming; Niedzielski, Steven M; Hill, Matthew T; Coleman, Rhima M; Ono, Akira; Shikanov, Ariella

    2015-08-01

    Hydrogels have been used in regenerative medicine because they provide a three-dimensional environment similar to soft tissues, allow diffusion of nutrients, present critical biological signals, and degrade via endogenous enzymatic mechanisms. Herein, we developed in vitro system mimicking cell-cell and cell-matrix interactions in secondary lymphoid organs (SLOs). Existing in vitro culture systems cannot accurately represent the complex interactions happening between T-cells and stromal cells in immune response. To model T-cell interaction in SLOs in vitro, we encapsulated stromal cells in fibrin, collagen, or fibrin-collagen hydrogels and studied how different mechanical and biological properties affect stromal network formation. Overall, fibrin supplemented with aprotinin was superior to collagen and fibrin-collagen in terms of network formation and promotion of T-cell penetration. After 8 days of culture, stromal networks formed through branching and joining with other adjacent cell populations. T-cells added to the newly formed stromal networks migrated and attached to stromal cells, similar to the T-cell zones of the lymph nodes in vivo. Our results suggest that the constructed three-dimensional lymphoid stromal network can mimic the in vivo environment and allow the modeling of T-cell interaction in SLOs. PMID:25649205

  14. Group 2 innate lymphoid cells promote beiging of adipose and limit obesity

    PubMed Central

    Brestoff, Jonathan R.; Kim, Brian S.; Saenz, Steven A.; Stine, Rachel R.; Monticelli, Laurel A.; Sonnenberg, Gregory F.; Thome, Joseph J.; Farber, Donna L.; Lutfy, Kabirullah; Seale, Patrick; Artis, David

    2015-01-01

    Obesity is an increasingly prevalent disease regulated by genetic and environmental factors. Emerging studies indicate that immune cells, including monocytes, granulocytes and lymphocytes, regulate metabolic homeostasis and are dysregulated in obesity1,2. Group 2 innate lymphoid cells (ILC2s) can regulate adaptive immunity3,4 and eosinophil and alternatively-activated macrophage responses5, and were recently identified in murine white adipose tissue (WAT)5 where they may act to limit the development of obesity6. However, ILC2s have not been identified in human adipose tissue, and the mechanisms by which ILC2s regulate metabolic homeostasis remain unknown. Here, we identify ILC2s in human WAT and demonstrate that decreased ILC2 responses in WAT are a conserved characteristic of obesity in humans and mice. Interleukin (IL)-33 was found to be critical for the maintenance of ILC2s in WAT and in limiting adiposity in mice by increasing caloric expenditure. This was associated with recruitment of uncoupling protein 1 (UCP1)+ beige adipocytes in WAT, a process known as beiging or browning that regulates caloric expenditure7–9. IL-33-induced beiging was dependent on ILC2s, and IL-33 treatment or transfer of IL-33-elicited ILC2s was sufficient to drive beiging independently of the adaptive immune system, eosinophils or IL-4 receptor signaling. We found that ILC2s produce methionine-enkephalin peptides that can act directly on adipocytes to upregulate Ucp1 expression in vitro and that promote beiging in vivo. Collectively, these studies indicate that in addition to responding to infection or tissue damage, ILC2s can regulate adipose function and metabolic homeostasis in part via production of enkephalin peptides that elicit beiging. PMID:25533952

  15. Complementarity and redundancy of IL-22-producing innate lymphoid cells

    PubMed Central

    Rankin, Lucille C.; Girard-Madoux, Mathilde J. H.; Seillet, Cyril; Mielke, Lisa A.; Kerdiles, Yann; Fenis, Aurore; Wieduwild, Elisabeth; Putoczki, Tracy; Mondot, Stanislas; Lantz, Olivier; Demon, Dieter; Papenfuss, Anthony T.; Smyth, Gordon K.; Lamkanfi, Mohamed; Carotta, Sebastian; Renauld, Jean-Christophe; Shi, Wei; Carpentier, Sabrina; Soos, Tim; Arendt, Christopher; Ugolini, Sophie; Huntington, Nicholas D.; Belz, Gabrielle T.; Vivier, Eric

    2015-01-01

    Intestinal T cells and group 3 innate lymphoid cells (ILC3) control the composition of the microbiota and gut immune responses. Within the gut there coexists ILC3 subsets which either express or lack the Natural cytoxicity receptor (NCR) NKp46. We identify here the transcriptional signature associated with the T-bet-dependent differentiation of NCR− ILC3 into NCR+ ILC3. Contrary to the prevailing view, we show by conditional deletion of the key ILC3 genes Stat3, Il22, Tbx21 and Mcl1 that NCR+ ILC3 were redundant for the control of mouse colonic infections with Citrobacter rodentium in the presence of T cells. However, NCR+ ILC3 were essential for cecum homeostasis. Our data show that interplay between intestinal ILC3 and adaptive lymphocytes results in robust complementary fail-safe mechanisms ensuring gut homeostasis. PMID:26595889

  16. Enhanced isolation of lymphoid cells from human skin.

    PubMed

    Salimi, M; Subramaniam, S; Selvakumar, T; Wang, X; Zemenides, S; Johnson, D; Ogg, G

    2016-07-01

    Studying skin immune cells under various pathophysiological conditions is vital for understanding the nature of cutaneous inflammatory responses. Available methods of isolating cells from the skin have relatively low yield or require in vitro culture. To increase the effective isolation of skin immune cells, we used collagenase P treatment. The number of T cells obtained ex vivo using this technique was dramatically greater than that obtained with conventional methods, without the need for long-term culture. The phenotype and function of isolated cells were comparable with those of cells isolated by EDTA treatment. Collagenase P-based methods will enhance the ability to investigate lymphoid cell function in both healthy and diseased skin. PMID:26805629

  17. Complementarity and redundancy of IL-22-producing innate lymphoid cells.

    PubMed

    Rankin, Lucille C; Girard-Madoux, Mathilde J H; Seillet, Cyril; Mielke, Lisa A; Kerdiles, Yann; Fenis, Aurore; Wieduwild, Elisabeth; Putoczki, Tracy; Mondot, Stanislas; Lantz, Olivier; Demon, Dieter; Papenfuss, Anthony T; Smyth, Gordon K; Lamkanfi, Mohamed; Carotta, Sebastian; Renauld, Jean-Christophe; Shi, Wei; Carpentier, Sabrina; Soos, Tim; Arendt, Christopher; Ugolini, Sophie; Huntington, Nicholas D; Belz, Gabrielle T; Vivier, Eric

    2016-02-01

    Intestinal T cells and group 3 innate lymphoid cells (ILC3 cells) control the composition of the microbiota and gut immune responses. Within the gut, ILC3 subsets coexist that either express or lack the natural cytoxicity receptor (NCR) NKp46. We identified here the transcriptional signature associated with the transcription factor T-bet-dependent differentiation of NCR(-) ILC3 cells into NCR(+) ILC3 cells. Contrary to the prevailing view, we found by conditional deletion of the key ILC3 genes Stat3, Il22, Tbx21 and Mcl1 that NCR(+) ILC3 cells were redundant for the control of mouse colonic infection with Citrobacter rodentium in the presence of T cells. However, NCR(+) ILC3 cells were essential for cecal homeostasis. Our data show that interplay between intestinal ILC3 cells and adaptive lymphocytes results in robust complementary failsafe mechanisms that ensure gut homeostasis. PMID:26595889

  18. Immunophenotypic characterization of lymphoid cell infiltrates in vitiligo

    PubMed Central

    Sanchez-Sosa, S; Aguirre-Lombardo, M; Jimenez-Brito, G; Ruiz-Argüelles, A

    2013-01-01

    The pathogenesis of vitiligo is still controversial. The purpose of this study was to gain insight into the nature of lymphoid cells infiltrating depigmented areas of skin in vitiligo. Immunochemical procedures were carried out in biopsies from 20 patients with active lesions to search for cells expressing CD1a, CD2, CD3, CD4, CD5, CD8, CD20, CD25, CD30, CD56, CD68 and CD79a. Results indicate that early lesions are infiltrated mainly by dendritic cells, whereas older lesions display significantly lower proportions of these cells and increased percentages of mature T cells. This finding might suggest that the autoimmune reactivity towards melanocyte antigens might be T cell-dependent and antigen-driven. It is possible that a non-immune offence of melanocytes is responsible for the exposure of intracellular antigens, while autoreactivity might be a secondary, self-perpetuating mechanism. PMID:23607858

  19. Invasive fungal diseases in patients with acute lymphoid leukemia.

    PubMed

    Nicolato, Andrea; Nouér, Simone A; Garnica, Marcia; Portugal, Rodrigo; Maiolino, Angelo; Nucci, Marcio

    2016-09-01

    Invasive fungal disease (IFD) represents an important complication in patients with acute lymphoid leukemia (ALL). The objectives of this study were to determine the prevalence of IFD in ALL patients with neutropenia, identify factors associated with IFD, and estimate the impact of IFD on the outcome. All patients with ALL who developed febrile neutropenia from 1987 to 2013 were evaluated. Cases of IFD were classified as proven or probable. Factors associated with IFD were evaluated by comparing episodes with and without a diagnosis of IFD. Among 350 episodes of febrile neutropenia, 31 IFDs were diagnosed (8.8%). Prolonged neutropenia was the only factor associated with IFD caused by yeasts. Factors associated with IFD caused by molds by multivariate analysis were the period after 2008, receipt of allogeneic transplant, relapsed ALL and prolonged neutropenia. Patients in relapse should receive induction chemotherapy in rooms with HEPA filter and receive antifungal prophylaxis. PMID:26949001

  20. Runx3 specifies lineage commitment of innate lymphoid cells

    PubMed Central

    Ebihara, Takashi; Song, Christina; Ryu, Stacy H.; Plougastel-Douglas, Beatrice; Yang, Liping; Levanon, Ditsa; Groner, Yoram; Bern, Michael D.; Stappenbeck, Thaddeus S.; Colonna, Marco; Egawa, Takeshi; Yokoyama, Wayne M.

    2015-01-01

    Subsets of innate lymphoid cells (ILCs) reside in the mucosa and regulate immune responses against external pathogens. While ILCs can be phenotypically classified into ILC1, ILC2 and ILC3 cells, the transcriptional control of lineage commitment for each ILC subset is incompletely understood. Here we report that the transcription factor Runx3 was essential for normal development of ILC1 and ILC3, but not ILC2 cells. Runx3 controlled the survival of ILC1, but not ILC3 cells. Runx3 was required for the expression of RORγt and its downstream target, aryl hydrocarbon receptor, in ILC3 cells. The absence of Runx3 in ILCs exacerbated C. rodentium infections. Therefore, our data establish Runx3 as a key transcription factor for lineage-specific differentiation of ILC1 and ILC3 cells. PMID:26414766

  1. Innate lymphoid cells regulate intestinal epithelial cell glycosylation.

    PubMed

    Goto, Yoshiyuki; Obata, Takashi; Kunisawa, Jun; Sato, Shintaro; Ivanov, Ivaylo I; Lamichhane, Aayam; Takeyama, Natsumi; Kamioka, Mariko; Sakamoto, Mitsuo; Matsuki, Takahiro; Setoyama, Hiromi; Imaoka, Akemi; Uematsu, Satoshi; Akira, Shizuo; Domino, Steven E; Kulig, Paulina; Becher, Burkhard; Renauld, Jean-Christophe; Sasakawa, Chihiro; Umesaki, Yoshinori; Benno, Yoshimi; Kiyono, Hiroshi

    2014-09-12

    Fucosylation of intestinal epithelial cells, catalyzed by fucosyltransferase 2 (Fut2), is a major glycosylation mechanism of host-microbiota symbiosis. Commensal bacteria induce epithelial fucosylation, and epithelial fucose is used as a dietary carbohydrate by many of these bacteria. However, the molecular and cellular mechanisms that regulate the induction of epithelial fucosylation are unknown. Here, we show that type 3 innate lymphoid cells (ILC3) induced intestinal epithelial Fut2 expression and fucosylation in mice. This induction required the cytokines interleukin-22 and lymphotoxin in a commensal bacteria-dependent and -independent manner, respectively. Disruption of intestinal fucosylation led to increased susceptibility to infection by Salmonella typhimurium. Our data reveal a role for ILC3 in shaping the gut microenvironment through the regulation of epithelial glycosylation. PMID:25214634

  2. Prolonged heart xenograft survival using combined total lymphoid irradiation and cyclosporine

    SciTech Connect

    Knechtle, S.J.; Halperin, E.C.; Saad, T.; Bollinger, R.R.

    1986-05-01

    Total lymphoid irradiation and cyclosporine have profound immunosuppressive properties and permit successful heart allotransplantation. Cyclosporine used alone has not permitted consistently successful transplantation between species in all cases. Total lymphoid irradiation has not been applied to xenotransplantation. The efficacy of total lymphoid irradiation alone and in combination with cyclosporine was examined using an animal model of heart xenotransplantation. Heterotopic heart transplants were performed using inbred Syrian hamsters as donors and Lewis rats as recipients. Total lymphoid irradiation was administered preoperatively over 3 weeks for a total dose of 15 gray. Cyclosporine was started on the day of surgery and was given as a daily intramuscular injection of 2.5, 5, or 10 mg/kg/day until rejection was complete. Neither total lymphoid irradiation nor cyclosporine alone markedly prolonged graft survival. However, combined total lymphoid irradiation and cyclosporine, 5 or 10 mg/kg/day, dramatically prolonged graft survival to greater than 100 days in most recipients. There were no treatment-related deaths. In conclusion, combined total lymphoid irradiation and cyclosporine permit successful long-term survival of heart xenotransplants in this hamster-to-rat model.

  3. Dietary repletion can replenish reduced T cell subset numbers and lymphoid organ weight in zinc-deficient and energy-restricted rats.

    PubMed

    Hosea, Heather J; Rector, Edward S; Taylor, Carla G

    2004-05-01

    The objective of the present study was to investigate the time course for recovery of lymphoid tissue and T cell subset numbers when Zn-deficient (ZD) or energy-restricted (ER) rats were repleted with control diet; in a second experiment, the link between the stress axis and lymphoid organs was explored. During the deficiency phase, rats were fed a ZD (<1 mg Zn/kg) or control diet (30 mg Zn/kg, nutritionally complete) either as pair-fed controls (ER) or ad libitum-fed controls (CTL) for 3 weeks. During the repletion phase, all rats were fed control diet ad libitum for 3, 7 or 23 d. After the deficiency phase, ZD and ER had lower T cell subset numbers in the thymus compared with CTL, and ZD had reduced T cell subset numbers in the spleen compared with both ER and CTL. T cell subset numbers and lymphoid organ weights recovered from dietary Zn deficiency and energy restriction by 7 d of repletion (except 23 d for thymus weight in ZD), while body weight required more than 23 d for recovery. At the end of the deficiency phase, ZD and ER had higher circulating corticosterone concentrations compared with CTL; plasma TNFalpha was not detectable and there were no differences in plasma haptoglobin, an acute-phase protein. In conclusion, Zn deficiency and energy restriction elevated circulating corticosterone and reduced T cell subset numbers in the thymus and spleen of growing rats. Repletion with a nutritionally complete diet allowed recovery of T cell subset numbers and lymphoid organ weight. PMID:15137926

  4. Mechanisms of Innate Lymphoid Cell and Natural Killer T Cell Activation during Mucosal Inflammation

    PubMed Central

    Altmayer, Nora

    2014-01-01

    Mucosal surfaces in the airways and the gastrointestinal tract are critical for the interactions of the host with its environment. Due to their abundance at mucosal tissue sites and their powerful immunomodulatory capacities, the role of innate lymphoid cells (ILCs) and natural killer T (NKT) cells in the maintenance of mucosal tolerance has recently moved into the focus of attention. While NKT cells as well as ILCs utilize distinct transcription factors for their development and lineage diversification, both cell populations can be further divided into three polarized subpopulations reflecting the distinction into Th1, Th2, and Th17 cells in the adaptive immune system. While bystander activation through cytokines mediates the induction of ILC and NKT cell responses, NKT cells become activated also through the engagement of their canonical T cell receptors (TCRs) by (glyco)lipid antigens (cognate recognition) presented by the atypical MHC I like molecule CD1d on antigen presenting cells (APCs). As both innate lymphocyte populations influence inflammatory responses due to the explosive release of copious amounts of different cytokines, they might represent interesting targets for clinical intervention. Thus, we will provide an outlook on pathways that might be interesting to evaluate in this context. PMID:24987710

  5. Glial-cell-derived neuroregulators control type 3 innate lymphoid cells and gut defence.

    PubMed

    Ibiza, Sales; García-Cassani, Bethania; Ribeiro, Hélder; Carvalho, Tânia; Almeida, Luís; Marques, Rute; Misic, Ana M; Bartow-McKenney, Casey; Larson, Denise M; Pavan, William J; Eberl, Gérard; Grice, Elizabeth A; Veiga-Fernandes, Henrique

    2016-07-21

    Group 3 innate lymphoid cells (ILC3) are major regulators of inflammation and infection at mucosal barriers. ILC3 development is thought to be programmed, but how ILC3 perceive, integrate and respond to local environmental signals remains unclear. Here we show that ILC3 in mice sense their environment and control gut defence as part of a glial–ILC3–epithelial cell unit orchestrated by neurotrophic factors. We found that enteric ILC3 express the neuroregulatory receptor RET. ILC3-autonomous Ret ablation led to decreased innate interleukin-22 (IL-22), impaired epithelial reactivity, dysbiosis and increased susceptibility to bowel inflammation and infection. Neurotrophic factors directly controlled innate Il22 downstream of the p38 MAPK/ERK-AKT cascade and STAT3 activation. Notably, ILC3 were adjacent to neurotrophic-factor-expressing glial cells that exhibited stellate-shaped projections into ILC3 aggregates. Glial cells sensed microenvironmental cues in a MYD88-dependent manner to control neurotrophic factors and innate IL-22. Accordingly, glial-intrinsic Myd88 deletion led to impaired production of ILC3-derived IL-22 and a pronounced propensity towards gut inflammation and infection. Our work sheds light on a novel multi-tissue defence unit, revealing that glial cells are central hubs of neuron and innate immune regulation by neurotrophic factor signals. PMID:27409807

  6. Science Signaling Podcast for 3 May 2016: Innate lymphoid cell plasticity.

    PubMed

    Vivier, Eric; Golub, Rachel; VanHook, Annalisa M

    2016-01-01

    This Podcast features an interview with Rachel Golub and Eric Vivier, authors of two Research Articles that appear in the 3 May 2016 issue of Science Signaling, about plasticity of innate lymphoid cells (ILCs). ILCs are related to the T cells and B cells of the adaptive immune system, and they regulate immune responses by secreting cytokines. ILCs are a heterogeneous population of cells that can be classified into several subtypes. Type 3 ILCs (ILC3s) can be further subdivided into distinct subpopulations. Chea et al found that Notch signaling controlled the relative proportions of different ILC3 subtypes in the mouse intestine. A related study by Viant et al reports that the Notch and transforming growth factor-β (TGF-β) signaling pathways antagonize one another to control the balance between different subsets of ILC3s. Both studies demonstrate that ILC3 fate is plastic and can be influenced by signals present in the microenvironment of these tissue-resident cells.Listen to Podcast. PMID:27141927

  7. Pleural cavity type 2 innate lymphoid cells precede Th2 expansion in murine Litomosoides sigmodontis infection.

    PubMed

    Boyd, Alexis; Killoran, Kristin; Mitre, Edward; Nutman, Thomas B

    2015-12-01

    Recently, a family of innate cells has been identified that respond to IL-25 and IL-33 in murine intestinal helminths. Termed Type 2 innate lymphoid cells (ILC2s) they facilitate the development of Th2 responses responsible for helminth clearance. We evaluated these cells in a tissue-invasive helminth model. Using Litomosides sigmodontis (a strong Th2 polarizing filarial infection) we observed a robust Th2 response in the pleural cavity, where adult worms reside, marked by increased levels of IL-5 and IL-13 in infected mice. In parallel, ILC2s were expanded in the pleural cavity early in the infection, peaking during the pre-patent period. L. sigmodontis also elicits a strong systemic Th2 response, which includes significantly increased levels of IgG1, IgE and IL-5 in the plasma of infected mice. Although ILC2s were expanded locally, they were not expanded in the spleen, blood, or mediastinal lymph nodes in response to L. sigmodontis infection, suggesting that ILC2s function primarily at the site of infection. The increase in ILC2s in the pleural cavity and the expansion in Th2 responses indicates a probable role for these cells in initiating and maintaining the Th2 response and highlights the importance of these cells in helminth infections and their role in Th2 immunity. PMID:26394284

  8. Monoclonal Antibody Therapy Before Stem Cell Transplant in Treating Patients With Relapsed or Refractory Lymphoid Malignancies

    ClinicalTrials.gov

    2015-12-07

    Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Noncutaneous Extranodal Lymphoma; Peripheral T-cell Lymphoma; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Hairy Cell Leukemia; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; T-cell Large Granular Lymphocyte Leukemia; Testicular Lymphoma; Waldenström Macroglobulinemia

  9. The Residual Innate Lymphoid Cells in NFIL3-Deficient Mice Support Suboptimal Maternal Adaptations to Pregnancy

    PubMed Central

    Boulenouar, Selma; Doisne, Jean-Marc; Sferruzzi-Perri, Amanda; Gaynor, Louise M.; Kieckbusch, Jens; Balmas, Elisa; Yung, Hong Wa; Javadzadeh, Shagayegh; Volmer, Léa; Hawkes, Delia A.; Phillips, Keli; Brady, Hugh J.M.; Fowden, Abigail L.; Burton, Graham J.; Moffett, Ashley; Colucci, Francesco

    2016-01-01

    Uterine NK cells are innate lymphoid cells (ILC) that populate the uterus and expand during pregnancy, regulating placental development and fetal growth in humans and mice. We have recently characterized the composition of uterine ILCs (uILCs), some of which require the transcription factor NFIL3, but the extent to which NFIL3-dependent cells support successful reproduction in mice is unknown. By mating Nfil3−/− females with wild-type males, here we show the effects of NFIL3 deficiency in maternal cells on both the changes in uILCs during pregnancy and the downstream consequences on reproduction. Despite the presence of CD49a+Eomes− uILC1s and the considerable expansion of residual CD49a+Eomes+ tissue-resident NK cells and uILC3s in pregnant Nfil3−/− mice, we found incomplete remodeling of uterine arteries and decidua, placental defects, and fetal growth restriction in litters of normal size. These results show that maternal NFIL3 mediates non-redundant functions in mouse reproduction. PMID:26925058

  10. Gemcitabine Hydrochloride, Carboplatin, Dexamethasone, and Rituximab in Treating Patients With Previously Treated Lymphoid Malignancies

    ClinicalTrials.gov

    2013-11-25

    Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Noncutaneous Extranodal Lymphoma; Peripheral T-cell Lymphoma; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Testicular Lymphoma; Waldenstrom Macroglobulinemia

  11. Concurrent Gastric Adenocarcinoma of Fundic Gland Type and Carcinoma with Lymphoid Stroma: A Rare Case Report

    PubMed Central

    Cha, Hee Jeong; Kim, Kyungbin; Kim, Misung; Choi, Hyejeong; Kim, Young Min; Suh, Jae Hee

    2016-01-01

    Both gastric adenocarcinoma of fundic gland type (ADC-FG) and carcinoma with lymphoid stroma (lymphoepithelioma-like carcinoma, LELC) are relatively rare. Epstein-Barr virus (EBV) has been implicated in the pathogenesis of LELC. However, the pathogenesis of ADC-FG, as well as the role of EBV in the carcinogenesis of LELC, remain unclear and under debate. The current study presents a case of concurrent ADC-FG and LELC in the stomach in a 69-year-old man. Total gastrectomy was performed, and two separate masses were identified. Upon histological and immunohistochemical examination, the mass located in the lower body was determined to be LELC and the mass in the upper body was diagnosed as ADC-FG. The lesions were characterized by different mucin phenotypes and EBV in situ results. In the lower-body mass, EBV in situ hybridization expression was diffusely strongly positive, but MUC2, MUC5AC, MUC6, and CD10 were all negative. On the other hand, in the upper-body mass, the results were positive for MUC6 but negative for MUC2, MUC5AC, CD10, and EBV by in situ hybridization. The remaining gastric tissue was unremarkable, and perigastric lymph node metastases were absent. Seven months after the gastrectomy, a postoperative computed tomography scan revealed no recurrence or metastasis. PMID:27462199

  12. IL-12 drives functional plasticity of human group 2 innate lymphoid cells.

    PubMed

    Lim, Ai Ing; Menegatti, Silvia; Bustamante, Jacinta; Le Bourhis, Lionel; Allez, Matthieu; Rogge, Lars; Casanova, Jean-Laurent; Yssel, Hans; Di Santo, James P

    2016-04-01

    Group 2 innate lymphoid cells (ILC2) include IL-5- and IL-13-producing CRTh2(+)CD127(+)cells that are implicated in early protective immunity at mucosal surfaces. Whereas functional plasticity has been demonstrated for both human and mouse ILC3 subsets that can reversibly give rise to IFN-γ-producing ILC1, plasticity of human or mouse ILC2 has not been shown. Here, we analyze the phenotypic and functional heterogeneity of human peripheral blood ILC2. Although subsets of human CRTh2(+)ILC2 differentially express CD117 (c-kit receptor), some ILC2 surface phenotypes are unstable and can be modulated in vitro. Surprisingly, human IL-13(+)ILC2 can acquire the capacity to produce IFN-γ, thereby generating plastic ILC2. ILC2 cultures demonstrated that IFN-γ(+)ILC2 clones could be derived and were stably associated with increased T-BET expression. The inductive mechanism for ILC2 plasticity was mapped to the IL-12-IL-12R signaling pathway and was confirmed through analysis of patients with Mendelian susceptibility to mycobacterial disease due to IL-12Rβ1 deficiencies that failed to generate plastic ILC2. We also detected IL-13(+)IFN-γ(+)ILC2 ex vivo in intestinal samples from Crohn's disease patients. These results demonstrate cytokine production plasticity for human ILC2 and further suggest that environmental cues can dictate ILC phenotype and function for these tissue-resident innate effector cells. PMID:26976630

  13. Locally elevated cortisol in lymphoid organs of the developing zebra finch but not Japanese quail or chicken.

    PubMed

    Taves, Matthew D; Losie, Jennifer A; Rahim, Titissa; Schmidt, Kim L; Sandkam, Benjamin A; Ma, Chunqi; Silversides, Frederick G; Soma, Kiran K

    2016-01-01

    Glucocorticoids are important for production of functional lymphocytes and immunity. In altricial neonates, adrenal glands are unresponsive and local glucocorticoid synthesis in lymphoid organs may be necessary to support lymphocyte development. Precocial neonates, in contrast, have fully responsive adrenal glucocorticoid production, and lymphoid glucocorticoid synthesis may not be necessary. Here, we found that in altricial zebra finch hatchlings, lymphoid organs had dramatically elevated endogenous glucocorticoid (and precursor) levels compared to levels in circulating blood. Furthermore, while avian adrenals produce corticosterone, finch lymphoid organs had much higher levels of cortisol, an unexpected glucocorticoid in birds. In contrast, precocial Japanese quail and chicken offspring did not have locally elevated lymphoid glucocorticoid levels, nor did their lymphoid organs contain high proportions of cortisol. These results show that lymphoid glucocorticoids differ in identity, concentration, and possibly source, in hatchlings of three different bird species. Locally-regulated glucocorticoids might have species-specific roles in immune development. PMID:26366679

  14. Immune polarization by hookworms: taking cues from T helper type 2, type 2 innate lymphoid cells and alternatively activated macrophages.

    PubMed

    Nair, Meera G; Herbert, De'Broski R

    2016-06-01

    Cellular and molecular investigation of parasitic helminth infections has greatly accelerated the understanding of type 2 immune responses. However, there remains considerable debate regarding the specific leucocytes that kill parasites and whether these mechanisms are distinct from those responsible for tissue repair. Herein, we chronicle discoveries over the past decade highlighting current paradigms in type 2 immunity with a particular emphasis upon how CD4(+) T helper type 2 cells, type 2 innate lymphoid cells and alternatively activated macrophages coordinately control helminth-induced parasitism. Primarily, this review will draw from studies of the murine nematode parasite Nippostrongylus brasiliensis, which bears important similarities to the human hookworms Ancylostoma duodenale and Necator americanus. Given that one or more hookworm species currently infect millions of individuals across the globe, we propose that vaccine and/or pharmaceutical-based cure strategies targeting these affected human populations should incorporate the conceptual advances outlined herein. PMID:26928141

  15. Interferon and IL-27 antagonize the function of group 2 innate lymphoid cells and type 2 innate immune responses.

    PubMed

    Moro, Kazuyo; Kabata, Hiroki; Tanabe, Masanobu; Koga, Satoshi; Takeno, Natsuki; Mochizuki, Miho; Fukunaga, Koichi; Asano, Koichiro; Betsuyaku, Tomoko; Koyasu, Shigeo

    2016-01-01

    Group 2 innate lymphoid cells (ILC2 cells) are type 2 cytokine-producing cells of the innate immune system with important roles in helminth infection and allergic inflammation. Here we found that tissue-resident ILC2 cells proliferated in situ without migrating during inflammatory responses. Both type I and type II interferons and interleukin 27 (IL-27) suppressed ILC2 function in a manner dependent on the transcription factor STAT1. ILC2-mediated lung inflammation was enhanced in the absence of the interferon-γ (IFN-γ) receptor on ILC2 cells in vivo. IFN-γ effectively suppressed the function of tissue-resident ILC2 cells but not that of inflammatory ILC2 cells, and IL-27 suppressed tissue-resident ILC2 cells but not tissue-resident TH2 cells during lung inflammation induced by Alternaria alternata. Our results demonstrate that suppression mediated by interferon and IL-27 is a negative feedback mechanism for ILC2 function in vivo. PMID:26595888

  16. Curcumin improves regulatory T cells in gut-associated lymphoid tissue of colitis mice

    PubMed Central

    Zhao, Hai-Mei; Xu, Rong; Huang, Xiao-Ying; Cheng, Shao-Min; Huang, Min-Fang; Yue, Hai-Yang; Wang, Xin; Zou, Yong; Lu, Ai-Ping; Liu, Duan-Yong

    2016-01-01

    AIM: To explore the probable pathway by which curcumin (Cur) regulates the function of Treg cells by observing the expression of costimulatory molecules of dendritic cells (DCs). METHODS: Experimental colitis was induced by administering 2, 4, 6-trinitrobenzene sulfonic acid (TNBS)/ethanol solution. Forty male C57BL/6 mice were randomly divided into four groups: normal, TNBS + Cur, TNBS + mesalazine (Mes) and TNBS groups. The mice in the TNBS + Cur and TNBS +Mes groups were treated with Cur and Mes, respectively, while those in the TNBS group were treated with physiological saline for 7 d. After treatment, the curative effect of Cur was evaluated by colonic weight, colonic length, weight index of the colon, and histological observation and score. The levels of CD4+CD25+Foxp3+ T cells (Treg cells) and costimulatory molecules of DCs were measured by flow cytometry. Also, related cytokines were analyzed by enzyme-linked immunosorbent assay. RESULTS: Cur alleviated inflammatory injury of the colonic mucosa, decreased colonic weigh and histological score, and restored colonic length. The number of Treg cells was increased, while the secretion of TNF-α, IL-2, IL-6, IL-12 p40, IL-17 and IL-21 and the expression of costimulatory molecules (CD205, CD54 [ICAM-1], TLR4, CD252[OX40 L], CD256 [RANK] and CD254 [RANK L]) of DCs were notably inhibited in colitis mice treated with Cur. CONCLUSION: Cur potentially modulates activation of DCs to enhance the suppressive functions of Treg cells and promote the recovery of damaged colonic mucosa in inflammatory bowel disease. PMID:27340353

  17. Architecture of secondary lymphoid tissue in sheep experimentally challenged with scrapie.

    PubMed

    Davies, Marie L; Hopkins, Lee J; Halliday, Sue; Houston, Fiona; Hunter, Nora; McConnell, Ian

    2004-02-01

    Scrapie is a transmissible spongiform encephalopathy in which there is an accumulation of the abnormal form of the prion protein, PrPsc, in the lymphoreticular system and nervous system. There is a particular accumulation of PrPsc on follicular dendritic cells within the germinal centre of B-cell follicles. Because accumulation of PrPsc in the nervous system leads to neuronal cell loss we have examined PrPsc accumulation in the prescapular and mesenteric lymph nodes in relation to lymph node architecture of scrapie-challenged sheep. We demonstrate that an accumulation of PrPsc in the lymph node fails to result in gross defects in the microanatomy and phenotype of T- and B-cell areas in the lymph nodes. PMID:15027909

  18. Augmented transport and metabolism of sex steroids in lymphoid neoplasia in the rat

    SciTech Connect

    Cefalu, W.T.; Pardridge, W.M.

    1987-03-01

    Sex steroid hormones have been shown to influence a number of biological properties of lymphoid neoplastic tissue. Receptor occupancy is a function of the pool size of cellular exchangeable hormone therefore it is important to understand the mechanisms regulating hormone transport from the microcirculation and hormone metabolism. In this study, steroid hormone transport and metabolism were investigated in control and neoplastic lymph nodes after transplanting control rats with the WR-6 leukemic line. Steroid hormone transport and metabolism were studied after pulse labeling the nodal tissue in vivo with arterial bolus injections of (/sup 3/H)testosterone. Residual vascular radioactivity was monitored by simultaneously injecting 113m indium chelated to bovine transferrin. Both testosterone and estradiol were partially available for transport through the capillary barriers of control and neoplastic lymph nodes from the circulating albumin-bound pool. Estradiol was readily available for transport from the circulating sex hormone-binding globulin-bound pool in both control and neoplastic lymph nodes. Testosterone was not available for transport from the sex hormone-binding globulin-bound pool in control lymph nodes, but was readily available for transport in metastatic lymph nodes. Thaw-mount autoradiography and physiological measurements showed that plasma proteins such as albumin or transferrin were confined to the microcirculation compartment. The transport of protein-bound hormones into lymph node represents a mechanism of enhanced steroid hormone dissociation from the binding protein without the plasma protein per se significantly exiting the microcirculation compartment. Metabolic studies showed no measurable metabolism of (/sup 3/H)testosterone in the control lymph nodes by 60 sec after arterial injection.

  19. Group 2 Innate Lymphoid Cells Promote an Early Antibody Response to a Respiratory Antigen in Mice.

    PubMed

    Drake, Li Yin; Iijima, Koji; Bartemes, Kathleen; Kita, Hirohito

    2016-08-15

    Innate lymphoid cells (ILCs) are a new family of immune cells that play important roles in innate immunity in mucosal tissues, and in the maintenance of tissue and metabolic homeostasis. Recently, group 2 ILCs (ILC2s) were found to promote the development and effector functions of Th2-type CD4(+) T cells by interacting directly with T cells or by activating dendritic cells, suggesting a role for ILC2s in regulating adaptive immunity. However, our current knowledge on the role of ILCs in humoral immunity is limited. In this study, we found that ILC2s isolated from the lungs of naive BALB/c mice enhanced the proliferation of B1- as well as B2-type B cells and promoted the production of IgM, IgG1, IgA, and IgE by these cells in vitro. Soluble factors secreted by ILC2s were sufficient to enhance B cell Ig production. By using blocking Abs and ILC2s isolated from IL-5-deficient mice, we found that ILC2-derived IL-5 is critically involved in the enhanced production of IgM. Furthermore, when adoptively transferred to Il7r(-/-) mice, which lack ILC2s and mature T cells, lung ILC2s promoted the production of IgM Abs to a polysaccharide Ag, 4-hydroxy-3-nitrophenylacetyl Ficoll, within 7 d of airway exposure in vivo. These findings add to the growing body of literature regarding the regulatory functions of ILCs in adaptive immunity, and suggest that lung ILC2s promote B cell production of early Abs to a respiratory Ag even in the absence of T cells. PMID:27421480

  20. Heterogeneity and diversity of group 3 innate lymphoid cells: new cells on the block.

    PubMed

    Satoh-Takayama, Naoko

    2016-01-01

    Innate lymphoid cells (ILCs) are a newly identified subset of innate cells that play fundamentally crucial roles for early immune defense at mucosal and non-mucosal sites. ILCs consist of ILC1s, ILC2s and ILC3s, which each have distinct transcription factors controlling their development and function. Interestingly, each of the ILC subsets represents the innate counterparts of CD4(+) helper T-cell subsets T(h1), T(h2) and T(h17) on the basis of transcriptional regulation. ILC1s that produce IFN-γ or TNF-α, ILC2s that produce T(h2)-type cytokines mainly such as IL-5 or IL-13 and ILC3s have been recently reported and reviewed in terms of IL-22- or IL-17-producing function and cell development. However, in this relatively new field, it remains likely that additional functional and regulatory mechanisms remain to be explored. More recent findings show that ILC3s are regulated by RORγt, which plays an important role for the mucosal barrier and surface protection against pathogenic bacterial infection. ILC3s might cooperate with other cells (e.g. T cells or dendritic cells) directly or indirectly, and subsequently ILC3s have impact on tissues with prompt regulation. Especially, ILC3s in mucosal site are well known to protect the intestinal surface barrier through inducible anti-microbial peptides via IL-22. Here, I will summarize and discuss the roles, function and heterogeneity of ILC3s in mucosal tissues. PMID:26462712

  1. Characterization of lymphoid cells in the blood of healthy adults: sequential immunological, cytochemical and cytokinetic studies

    SciTech Connect

    Hirt, A.; Wagner, H.P.

    1980-01-01

    With a new method, sequential immunological, cytochemical and cytokinetic studies were done on lymphoid cells in the peripheral blood of 12 healthy adults. Every single lymphoid cell could therefore be characterized by the following markers: surface immunoglobulins (sIg); rosetting with sheep red blood cells (E); unspecific acid alpha-naphthyl acetate esterase (ANAE); and 3HdT incorporation. Significantly more E+sIg-ANAE-cells (51% and 22% of all lymphoid cells, respectively). Of all ANAE+ cells 90% were E+, but 64% of all ANAE- cells were also E+. In all individuals a subpopulation of E+sIg+ cells was found. The esterase pattern of these cells was similar to that of E-sIg+ cells. The overall labeling index of the lymphoid cells examined was less than or equal to 0.2%.

  2. LncRNA profiling of human lymphoid progenitors reveals transcriptional divergence of B and T lineages

    PubMed Central

    Casero, David; Sandoval, Salemiz; Seet, Christopher S.; Scholes, Jessica; Zhu, Yuhua; Ha, Vi Luan; Luong, Annie; Parekh, Chintan; Crooks, Gay M.

    2015-01-01

    To elucidate the transcriptional landscape that regulates human lymphoid commitment during postnatal life, we used RNA sequencing to assemble the long non-coding transcriptome across human bone marrow and thymic progenitors spanning the earliest stages of B and T lymphoid specification. Over 3000 novel long non-coding RNA genes (lncRNAs) were revealed through the analysis of these rare populations. Lymphoid commitment was characterized by lncRNA expression patterns that were highly stage-specific and more lineage-specific than protein coding patterns. Protein-coding genes co-expressed with neighboring lncRNA genes were enriched for ontologies related to lymphoid differentiation. The exquisite cell-type specificity of global lncRNA expression patterns independently revealed new developmental relationships between the earliest progenitors in the human bone marrow and thymus. PMID:26502406

  3. Lymphotoxin organizes contributions to host defense and metabolic illness from innate lymphoid cells

    PubMed Central

    Upadhyay, Vaibhav; Fu, Yang-Xin

    2014-01-01

    The lymphotoxin (LT)-pathway is a unique constituent branch of the Tumor Necrosis Superfamily (TNFSF). Use of LT is a critical mechanism by which fetal innate lymphoid cells regulate lymphoid organogenesis. Within recent years, adult innate lymphoid cells have been discovered to utilize this same pathway to regulate IL-22 and IL-23 production for host defense. Notably, genetic studies have linked polymorphisms in the genes encoding LTα to several phenotypes contributing to metabolic syndrome. The role of the LT-pathway may lay the foundation for a bridge between host immune response, microbiota, and metabolic syndrome. The contribution of the LT-pathway to innate lymphoid cell function and metabolic syndrome will be visited in this review. PMID:24411493

  4. The helminth T2 RNase ω1 promotes metabolic homeostasis in an IL-33– and group 2 innate lymphoid cell–dependent mechanism

    PubMed Central

    Hams, Emily; Bermingham, Rachel; Wurlod, Felicity A.; Hogan, Andrew E.; O’Shea, Donal; Preston, Roger J.; Rodewald, Hans-Reimer; McKenzie, Andrew N. J.; Fallon, Padraic G.

    2016-01-01

    Induction of a type 2 cellular response in the white adipose tissue leads to weight loss and improves glucose homeostasis in obese animals. Injection of obese mice with recombinant helminth-derived Schistosoma mansoni egg-derived ω1 (ω1), a potent inducer of type 2 activation, improves metabolic status involving a mechanism reliant upon release of the type 2 initiator cytokine IL-33. IL-33 initiates the accumulation of group 2 innate lymphoid cells (ILC2s), eosinophils, and alternatively activated macrophages in the adipose tissue. IL-33 release from cells in the adipose tissue is mediated by the RNase activity of ω1; however, the ability of ω1 to improve metabolic status is reliant upon effective binding of ω1 to CD206. We demonstrate a novel mechanism for RNase-mediated release of IL-33 inducing ILC2-dependent improvements in the metabolic status of obese animals.— Hams, E., Bermingham, R., Wurlod, F. A., Hogan, A. E., O’Shea, D., Preston, R. J., Rodewald, H.-R., McKenzie, A. N. J., Fallon, P. G. The helminth T2 RNase ω1 promotes metabolic homeostasis in an IL-33– and group 2 innate lymphoid cell–dependent mechanism. PMID:26490658

  5. Treatment of lupus nephritis with total lymphoid irradiation. Observations during a 12-79-month followup

    SciTech Connect

    Strober, S.; Farinas, M.C.; Field, E.H.; Solovera, J.J.; Kiberd, B.A.; Myers, B.D.; Hoppe, R.T.

    1988-07-01

    Seventeen patients with intractable lupus nephritis and nephrotic syndrome were treated with total lymphoid irradiation. Statistically significant improvement in mean renal disease and serologic activity parameters occurred within 3 months and persisted for at least 3 years. Although there was a marked reduction of T helper cell numbers and function after total lymphoid irradiation, recovery of these parameters was not associated with a return of disease activity. Risks of sterility, severe infections, and hematologic malignancy appeared to be lower than with alkylating agents.

  6. Pyrimidine starvation induced by adenosine in fibroblasts and lymphoid cells: role of adenosine deaminase.

    PubMed

    Green, H; Chan, T

    1973-11-23

    In the presence of 10(-4) to 10(-5) molar adenosine, established cell lines of fibroblastic or lymphoid origin die of pyrimidine starvation. Less than lethal concentrations inhibit cell growth. Over a broad concentration range, the effects of adenosine are prevented by providing a suitable pyrimidine source. We suggest that the recently described immune deficiency disease associated with absence of adenosine deaminase may be the result of pyrimidine starvation induced by adenosine nucleotides in cells of the lymphoid system. PMID:4795749

  7. The prevalence of lymphoid follicles in Helicobacter pylori associated gastritis in patients with ulcers and non-ulcer dyspepsia.

    PubMed Central

    Zaitoun, A M

    1995-01-01

    AIMS--To determine the prevalence of lymphoid follicles in Helicobacter pylori positive and negative gastritis in antral and body type gastric mucosa in patients with non-ulcer dyspepsia (NUD), duodenal ulcer, or gastric ulcer; to correlate follicle presence with patient age; to evaluate the correlation between the prevalence of lymphoid follicles and active and inactive gastritis and its severity; and to assess the positive predictive value of lymphoid follicle prevalence with respect to H pylori infection. METHODS--Gastric biopsy specimens, graded according to the Sydney system, from 337 patients were studied. RESULTS--Lymphoid follicles occurred more often in antral mucosa (78%) than in body type mucosa (41%) and were observed in 85% of patients with H pylori positive gastritis. There was no significant difference between NUD and gastric and duodenal ulcer disease with regard to the presence of lymphoid follicles. The positive predictive value of the presence of lymphoid follicles in H pylori infection was 96%. Lymphoid follicles were more commonly observed in patients aged between 10 and 29 years. Lymphoid follicles were more frequently found in pangastritis of all subtypes than in antral gastritis and also in active gastritis than in inactive gastritis. The presence of lymphoid follicles correlated strongly with the degree and severity of gastritis. CONCLUSION--Lymphoid follicles are a constant morphological feature of H pylori associated gastritis. Images PMID:7615851

  8. The helminth T2 RNase ω1 promotes metabolic homeostasis in an IL-33- and group 2 innate lymphoid cell-dependent mechanism.

    PubMed

    Hams, Emily; Bermingham, Rachel; Wurlod, Felicity A; Hogan, Andrew E; O'Shea, Donal; Preston, Roger J; Rodewald, Hans-Reimer; McKenzie, Andrew N J; Fallon, Padraic G

    2016-02-01

    Induction of a type 2 cellular response in the white adipose tissue leads to weight loss and improves glucose homeostasis in obese animals. Injection of obese mice with recombinant helminth-derived Schistosoma mansoni egg-derived ω1 (ω1), a potent inducer of type 2 activation, improves metabolic status involving a mechanism reliant upon release of the type 2 initiator cytokine IL-33. IL-33 initiates the accumulation of group 2 innate lymphoid cells (ILC2s), eosinophils, and alternatively activated macrophages in the adipose tissue. IL-33 release from cells in the adipose tissue is mediated by the RNase activity of ω1; however, the ability of ω1 to improve metabolic status is reliant upon effective binding of ω1 to CD206. We demonstrate a novel mechanism for RNase-mediated release of IL-33 inducing ILC2-dependent improvements in the metabolic status of obese animals. PMID:26490658

  9. Calpain secreted by activated human lymphoid cells degrades myelin.

    PubMed

    Deshpande, R V; Goust, J M; Hogan, E L; Banik, N L

    1995-10-01

    Calpain secreted by lymphoid (MOLT-3, M.R.) or monocytic (U-937, THP-1) cell lines activated with PMA and A23187 degraded myelin antigens. The degradative effect of enzymes released in the extracellular medium was tested on purified myelin basic protein and rat central nervous system myelin in vitro. The extent of protein degradation was determined by SDS-PAGE and densitometric analysis. Various proteinase inhibitors were used to determine to what extent protein degradation was mediated by calpain and/or other enzymes. Lysosomal and serine proteinase inhibitors inhibited 20-40% of the myelin-degradative activity found in the incubation media of cell lines, whereas the calcium chelator (EGTA), the calpain-specific inhibitor (calpastatin), and a monoclonal antibody to m calpain blocked myelin degradation by 60-80%. Since breakdown products of MBP generated by calpain may include fragments with antigenic epitopes, this enzyme may play an important role in the initiation of immune-mediated demyelination. PMID:8568927

  10. Clinical drawbacks of total lymphoid irradiation: the cons

    SciTech Connect

    Myers, L.W.; Ellison, G.W.; Fahey, J.L.; Tesler, A.; Gottlieb, M.S.

    1988-07-01

    Success has been reported with use of total lymphoid irradiation (TLI) in organ transplant recipients and in patients with rheumatoid arthritis and other autoimmune diseases. In a well-conducted randomized double blind clinical trial, Cook et al have found that TLI was superior to sham irradiation of patients with multiple sclerosis (MS). However, it is clear from looking at this data that not all patients responded to TLI and that with time disease activity returned. Our own experience with TLI in two MS patients was very disappointing. Despite its apparent benefit in some conditions, considerable drawbacks are associated with TLI. These include high financial cost, unpleasant treatment-related side effects, and the possibility that more serious morbidity as well as mortality may be treatment-related. Furthermore, the optimum therapeutic regimen for TLI has not yet been established. Issues related to cumulative dose, dose per fraction, frequency of fractions, field of irradiation, and interaction with other therapies still need clarification. For these reasons we do not recommend TLI as a treatment for MS.

  11. Innate Lymphoid Cells: The Innate Counterpart to T Helper Cells.

    PubMed

    Padro Dietz, Caroline; Luong, Amber

    2016-01-01

    Innate lymphoid cells (ILCs) are a recently discovered subset of innate immune cells that are capable of secreting great amounts of cytokines that have been found to influence effector cell activity. Chronic rhinosinusitis (CRS) in the absence (CRSsNP) or presence (CRSwNP) of nasal polyps has been characterized as type 1- and type 2-skewed, respectively, based on the presence of cytokines characteristic of type 1 and 2 immune responses. Based on the ability of type 1 ILCs to secrete interferon-x03B3;, a type 1 cytokine found elevated in CRSsNP and type 2 ILCs to secrete IL-5 and IL-13, type 2 cytokines found elevated in CRSwNP, it is essential to examine the role that ILCs may play in the pathogenesis of CRS. This chapter introduces each subset of ILC (type 1-3) and the non-CRS pathologies they have been associated with in both mouse and human models. It will discuss the current research into ILCs in CRS, particularly ILC2s and NK cells in CRSwNP. Finally, the chapter will consider the therapeutic implications of ILC involvement in CRS and highlight the needs for future research into the role that ILCs play in CRS. PMID:27466847

  12. Prions and lymphoid organs: solved and remaining mysteries.

    PubMed

    O'Connor, Tracy; Aguzzi, Adriano

    2013-01-01

    Prion colonization of secondary lymphoid organs (SLOs) is a critical step preceding neuroinvasion in prion pathogenesis. Follicular dendritic cells (FDCs), which depend on both tumor necrosis factor receptor 1 (TNFR1) and lymphotoxin β receptor (LTβR) signaling for maintenance, are thought to be the primary sites of prion accumulation in SLOs. However, prion titers in RML-infected TNFR1 (-/-) lymph nodes and rates of neuroinvasion in TNFR1 (-/-) mice remain high despite the absence of mature FDCs. Recently, we discovered that TNFR1-independent prion accumulation in lymph nodes relies on LTβR signaling. Loss of LTβR signaling in TNFR1 (-/-) lymph nodes coincided with the de-differentiation of high endothelial venules (HEVs)-the primary sites of lymphocyte entry into lymph nodes. These findings suggest that HEVs are the sites through which prions initially invade lymph nodes from the bloodstream. Identification of HEVs as entry portals for prions clarifies a number of previous observations concerning peripheral prion pathogenesis. However, a number of questions still remain: What is the mechanism by which prions are taken up by HEVs? Which cells are responsible for delivering prions to lymph nodes? Are HEVs the main entry site for prions into lymph nodes or do alternative routes also exist? These questions and others are considered in this article. PMID:23357827

  13. Transcriptional Regulatory Network for the Development of Innate Lymphoid Cells

    PubMed Central

    Zhong, Chao; Zhu, Jinfang

    2015-01-01

    Recent studies on innate lymphoid cells (ILCs) have expanded our knowledge about the innate arm of the immune system. Helper-like ILCs share both the “innate” feature of conventional natural killer (cNK) cells and the “helper” feature of CD4+ T helper (Th) cells. With this combination, helper-like ILCs are capable of initiating early immune responses similar to cNK cells, but via secretion of a set of effector cytokines similar to those produced by Th cells. Although many studies have revealed the functional similarity between helper-like ILCs and Th cells, some aspects of ILCs including the development of this lineage remain elusive. It is intriguing that the majority of transcription factors involved in multiple stages of T cell development, differentiation, and function also play critical roles during ILC development. Regulators such as Id2, GATA-3, Nfil3, TOX, and TCF-1 are expressed and function at various stages of ILC development. In this review, we will summarize the expression and functions of these transcription factors shared by ILCs and Th cells. We will also propose a complex transcriptional regulatory network for the lineage commitment of ILCs. PMID:26379372

  14. Type-2 innate lymphoid cells in human allergic disease

    PubMed Central

    Barlow, Jillian L.; McKenzie, Andrew N.J.

    2014-01-01

    Purpose of review Recent decades have seen allergic diseases become endemic in a number of developed countries. Understanding the inflammatory processes that dictate these allergic responses is therefore important. Recent findings Critical to many allergic responses is the inappropriate release of the type-2 immune-regulatory cytokines: interleukin-4, interleukin-5, interleukin-9, and interleukin-13. The study of these inflammatory mediators has led directly to the development of two new asthma treatments: anti-interleukin-5 and anti-interleukin-13. Until recently, T helper 2 cells were considered to be the major cellular source of type-2 cytokines; however, a paradigm shift occurred with the discovery of a novel population, type-2 innate lymphoid cells (ILC2s), that can produce huge levels of type-2 cytokines and are sufficient to induce allergy in mice. This discovery raises interesting questions about how innate and adaptive type-2 immunity might interact to induce relapsing and remitting episodes of allergy in patients. Summary It is essential that alongside the mechanistic investigation using model organisms, the roles of ILC2s in human disease be explored. Here, we discuss how ILC2 traits, discovered in mouse models, have informed research in humans and how newly identified human ILC2 pathways might provide potential therapeutic benefits in the future. PMID:25115682

  15. Developmental Acquisition of Regulomes Underlies Innate Lymphoid Cell Functionality.

    PubMed

    Shih, Han-Yu; Sciumè, Giuseppe; Mikami, Yohei; Guo, Liying; Sun, Hong-Wei; Brooks, Stephen R; Urban, Joseph F; Davis, Fred P; Kanno, Yuka; O'Shea, John J

    2016-05-19

    Innate lymphoid cells (ILCs) play key roles in host defense, barrier integrity, and homeostasis and mirror adaptive CD4(+) T helper (Th) cell subtypes in both usage of effector molecules and transcription factors. To better understand the relationship between ILC subsets and their Th cell counterparts, we measured genome-wide chromatin accessibility. We find that chromatin in proximity to effector genes is selectively accessible in ILCs prior to high-level transcription upon activation. Accessibility of these regions is acquired in a stepwise manner during development and changes little after in vitro or in vivo activation. Conversely, dramatic chromatin remodeling occurs in naive CD4(+) T cells during Th cell differentiation using a type-2-infection model. This alteration results in a substantial convergence of Th2 cells toward ILC2 regulomes. Our data indicate extensive sharing of regulatory circuitry across the innate and adaptive compartments of the immune system, in spite of their divergent developing pathways. PMID:27156451

  16. [Treatment Strategy for Gastric Carcinoma with Lymphoid Stroma].

    PubMed

    Kobayashi, Ryosuke; Takiguchi, Nobuhiro; Nabeya, Yoshihiro; Ikeda, Atsushi; Souda, Hiroaki; Kainuma, Osamu; Tonooka, Toru; Imanishi, Shunsuke; Arimitsu, Hidehito; Chibana, Tomofumi; Ishige, Fumitaka; Sasaki, Kosuke; Yamamoto, Hiroshi

    2015-11-01

    Gastric carcinoma with lymphoid stroma (GCLS) is a histological type with severe lymphocytic infiltration. GCLS is very rare and few cases have been reported. We examined the clinical features, problems of preoperative diagnosis, and treatment of 14 cases (1.8%) that were diagnosed as GCLS out of 790 gastric cancers surgically resected in our hospital. The mean age was 69 years. Six, 8, and 0 cases were located in the upper, middle, and lower fields of the stomach, respectively, and 8, 1, 4, and 1 cases were macroscopically 0-Ⅱc, 0-Ⅰ, type 2, and type 3, respectively. The depth of invasion was M, SM1, SM2, MP, and SS in 0, 0, 9, 3, and 2 cases, respectively. There were 12 cases(86%)with infection by Epstein-Barr virus, and just 1 case with lymph node metastasis. All cases have had no evidence of recurrence. There were no cases that were diagnosed as GCLS before surgery. GCLS is recognized as having a more favorable prognosis compared with other types of gastric carcinoma, so an aggressive surgery might achieve good outcomes. However, preoperative diagnosis is very difficult and there is a compelling need for new techniques or criteria for diagnosis of GCLS. PMID:26805251

  17. Kidney allograft survival in dogs treated with total lymphoid irradiation

    SciTech Connect

    Howard, R.J.; Sutherland, D.E.R.; Lum, C.T.; Lewis, W.I.; Kim, T.H.; Slavin, S.; Najarian, J.S.

    1981-02-01

    Total lymphoid irradiation (TLI) is immunosuppressive and, in rodents, can induce a state where transplantation of allogenic bone marrow results in chimerism and permanent acceptance of organ allografts from the donor strain. Twelve splenectomized dogs were treated with TLI (150 rads per fraction, total dose 1950 to 3000 rads) before bilateral nephrectomy and renal allotransplantation. Eight dogs received bone marrow from the kidney donor. In 13 untreated control dogs renal allografts functioned for a mean +- (SE) of 4.7 +- 0.3 days. In the four TLI treated dogs who did not receive bone marrow the renal allografts functioned for 15 to 76 days (two dogs died with functioning grafts). In the eight TLI treated dogs who received donor bone marrow, two died immediately after transplantation, two rejected at 3 and 13 days, one died at 13 days with a functioning graft, and two have had the grafts function for longer than 500 days. Chimerism was not detected in the one dog tested. The response of peripheral blood lymphocytes to stimulation with phytohemaglutinin and in mixed lymphocyte culture was suppressed for at least one month after TLI. The results confirm the immunosuppressive effect of TLI. The absence of kidney rejection in two recipients of donor bone marrow show the potential of this approach to induce long-term immunologic unresponsiveness as to an organ allograft, but the outcome is unpredictable and further experiments are needed to define the optimal conditions for administration of TLI and bone marrow to the recipients.

  18. Persistent HIV-1 replication maintains the tissue reservoir during therapy

    PubMed Central

    Bedford, Trevor; Kim, Eun-Young; Archer, John; Pond, Sergei L. Kosakovsky; Chung, Yoon-Seok; Penugonda, Sudhir; Chipman, Jeffrey; Fletcher, Courtney V.; Schacker, Timothy W.; Malim, Michael H.; Rambaut, Andrew; Haase, Ashley T.; McLean, Angela R.; Wolinsky, Steven M.

    2015-01-01

    Lymphoid tissue is a key reservoir established by HIV-1 during acute infection. It is a site of viral production, storage of viral particles in immune complexes, and viral persistence. Whilst combinations of antiretroviral drugs usually suppress viral replication and reduce viral RNA to undetectable levels in blood, it is unclear whether treatment fully suppresses viral replication in lymphoid tissue reservoirs. Here we show that virus evolution and trafficking between tissue compartments continues in patients with undetectable levels of virus in their bloodstream. A spatial dynamic model of persistent viral replication and spread explains why the development of drug resistance is not a foregone conclusion under conditions where drug concentrations are insufficient to completely block virus replication. These data provide fresh insights into the evolutionary and infection dynamics of the virus population within the host, revealing that HIV-1 can continue to replicate and refill the viral reservoir despite potent antiretroviral therapy. PMID:26814962

  19. Persistent HIV-1 replication maintains the tissue reservoir during therapy.

    PubMed

    Lorenzo-Redondo, Ramon; Fryer, Helen R; Bedford, Trevor; Kim, Eun-Young; Archer, John; Kosakovsky Pond, Sergei L; Chung, Yoon-Seok; Penugonda, Sudhir; Chipman, Jeffrey G; Fletcher, Courtney V; Schacker, Timothy W; Malim, Michael H; Rambaut, Andrew; Haase, Ashley T; McLean, Angela R; Wolinsky, Steven M

    2016-02-01

    Lymphoid tissue is a key reservoir established by HIV-1 during acute infection. It is a site associated with viral production, storage of viral particles in immune complexes, and viral persistence. Although combinations of antiretroviral drugs usually suppress viral replication and reduce viral RNA to undetectable levels in blood, it is unclear whether treatment fully suppresses viral replication in lymphoid tissue reservoirs. Here we show that virus evolution and trafficking between tissue compartments continues in patients with undetectable levels of virus in their bloodstream. We present a spatial and dynamic model of persistent viral replication and spread that indicates why the development of drug resistance is not a foregone conclusion under conditions in which drug concentrations are insufficient to completely block virus replication. These data provide new insights into the evolutionary and infection dynamics of the virus population within the host, revealing that HIV-1 can continue to replicate and replenish the viral reservoir despite potent antiretroviral therapy. PMID:26814962

  20. The prostaglandin D2 receptor CRTH2 regulates accumulation of group 2 innate lymphoid cells in the inflamed lung

    PubMed Central

    Tait Wojno, ED; Monticelli, LA; Tran, SV; Alenghat, T; Osborne, LC; Thome, JJ; Willis, C; Budelsky, A; Farber, DL; Artis, D

    2015-01-01

    Group 2 innate lymphoid cells (ILC2s) promote type 2 cytokine-dependent immunity, inflammation and tissue repair. While epithelial cell-derived cytokines regulate ILC2 effector functions, the pathways that control the in vivo migration of ILC2s into inflamed tissues remain poorly understood. Here, we provide the first demonstration that expression of the prostaglandin D2 (PGD2) receptor CRTH2 (chemoattractant receptor homologous molecule expressed on Th2 cells) regulates the in vivo accumulation of ILC2s in the lung. While a significant proportion of ILC2s isolated from healthy human peripheral blood expressed CRTH2, a smaller proportion of ILC2s isolated from non-diseased human lung expressed CRTH2, suggesting that dynamic regulation of CRTH2 expression might be associated with the migration of ILC2s into tissues. Consistent with this, murine ILC2s expressed CRTH2, migrated towards PGD2 in vitro and accumulated in the lung in response to PGD2 in vivo. Further, mice deficient in CRTH2 exhibited reduced ILC2 responses and inflammation in a murine model of helminth-induced pulmonary type 2 inflammation. Critically, adoptive transfer of CRTH2-sufficient ILC2s restored pulmonary inflammation in CRTH2-deficient mice. Together, these data identify a role for the PGD2-CRTH2 pathway in regulating the in vivo accumulation of ILC2s and the development of type 2 inflammation in the lung. PMID:25850654

  1. G9a regulates group 2 innate lymphoid cell development by repressing the group 3 innate lymphoid cell program.

    PubMed

    Antignano, Frann; Braam, Mitchell; Hughes, Michael R; Chenery, Alistair L; Burrows, Kyle; Gold, Matthew J; Oudhoff, Menno J; Rattray, David; Halim, Timotheus Y; Cait, Alissa; Takei, Fumio; Rossi, Fabio M; McNagny, Kelly M; Zaph, Colby

    2016-06-27

    Innate lymphoid cells (ILCs) are emerging as important regulators of homeostatic and disease-associated immune processes. Despite recent advances in defining the molecular pathways that control development and function of ILCs, the epigenetic mechanisms that regulate ILC biology are unknown. Here, we identify a role for the lysine methyltransferase G9a in regulating ILC2 development and function. Mice with a hematopoietic cell-specific deletion of G9a (Vav.G9a(-/-) mice) have a severe reduction in ILC2s in peripheral sites, associated with impaired development of immature ILC2s in the bone marrow. Accordingly, Vav.G9a(-/-) mice are resistant to the development of allergic lung inflammation. G9a-dependent dimethylation of histone 3 lysine 9 (H3K9me2) is a repressive histone mark that is associated with gene silencing. Genome-wide expression analysis demonstrated that the absence of G9a led to increased expression of ILC3-associated genes in developing ILC2 populations. Further, we found high levels of G9a-dependent H3K9me2 at ILC3-specific genetic loci, demonstrating that G9a-mediated repression of ILC3-associated genes is critical for the optimal development of ILC2s. Together, these results provide the first identification of an epigenetic regulatory mechanism in ILC development and function. PMID:27298444

  2. Cooperation between Monocyte-Derived Cells and Lymphoid Cells in the Acute Response to a Bacterial Lung Pathogen

    PubMed Central

    Brown, Andrew S.; Yang, Chao; Fung, Ka Yee; Bachem, Annabell; Bourges, Dorothée; Bedoui, Sammy; Hartland, Elizabeth L.; van Driel, Ian R.

    2016-01-01

    Legionella pneumophila is the causative agent of Legionnaires’ disease, a potentially fatal lung infection. Alveolar macrophages support intracellular replication of L. pneumophila, however the contributions of other immune cell types to bacterial killing during infection are unclear. Here, we used recently described methods to characterise the major inflammatory cells in lung after acute respiratory infection of mice with L. pneumophila. We observed that the numbers of alveolar macrophages rapidly decreased after infection coincident with a rapid infiltration of the lung by monocyte-derived cells (MC), which, together with neutrophils, became the dominant inflammatory cells associated with the bacteria. Using mice in which the ability of MC to infiltrate tissues is impaired it was found that MC were required for bacterial clearance and were the major source of IL12. IL12 was needed to induce IFNγ production by lymphoid cells including NK cells, memory T cells, NKT cells and γδ T cells. Memory T cells that produced IFNγ appeared to be circulating effector/memory T cells that infiltrated the lung after infection. IFNγ production by memory T cells was stimulated in an antigen-independent fashion and could effectively clear bacteria from the lung indicating that memory T cells are an important contributor to innate bacterial defence. We also determined that a major function of IFNγ was to stimulate bactericidal activity of MC. On the other hand, neutrophils did not require IFNγ to kill bacteria and alveolar macrophages remained poorly bactericidal even in the presence of IFNγ. This work has revealed a cooperative innate immune circuit between lymphoid cells and MC that combats acute L. pneumophila infection and defines a specific role for IFNγ in anti-bacterial immunity. PMID:27300652

  3. CXCL13 blockade disrupts B lymphocyte organization in tertiary lymphoid structures without altering B cell receptor bias or preventing diabetes in nonobese diabetic mice.

    PubMed

    Henry, Rachel A; Kendall, Peggy L

    2010-08-01

    Lymphocytes that invade nonlymphoid tissues often organize into follicle-like structures known as tertiary lymphoid organs (TLOs). These structures resemble those found in spleen or lymph nodes, but their function is unknown. TLOs are recognized in many autoimmune diseases, including the NOD mouse model of type 1 diabetes. In some cases, TLOs have been associated with the B lymphocyte chemoattractant, CXCL13. Studies presented in this article show that CXCL13 is present in inflamed islets of NOD mice. Ab blockade of this chemokine unraveled B lymphocyte organization in islet TLOs, without reducing their proportion in the islets. These chaotic milieus contained B lymphocytes with the same distinct repertoire of B cell receptors as those found in mice with well-organized structures. Somatic hypermutation, associated with T-B interactions, was not impaired in these disorganized insulitis lesions. Finally, loss of B lymphocyte organization in islets did not provide disease protection. Thus, B lymphocytes infiltrating islets in NOD mice do not require the morphology of secondary lymphoid tissues to support their role in disease. PMID:20574003

  4. p53 mutations in human lymphoid malignancies: Association with Burkitt lymphoma and chronic lymphocytic leukemia

    SciTech Connect

    Gaidano, G.; Ballerini, P.; Gong, J.Z.; Inghirami, G.; Knowles, D.M.; Dalla-Favera, R. ); Neri, A, Centro Malattie del Sangue G. Marcora, Milan ); Newcomb, E.W. ); Magrath, I.T. )

    1991-06-15

    The authors have investigated the frequency of p53 mutations in B- and T-cell human lymphoid malignancies, including acute lymphoblastic leukemia, the major subtypes of non-Hodgkin lymphoma, and chronic lymphocytic leukemia. p53 exons 5-9 were studied by using genomic DNA from 197 primary tumors and 27 cell lines by single-strand conformation polymorphism analysis and by direst sequencing of PCR-amplified fragments. Mutations were found associated with (i) Burkitt lymphoma (9/27 biopsoes; 17/27 cell lines) and its leukemic counterpart L{sub 3}-type B-cell acute lymphoblastic leukemia (5/9), both of which also carry activated c-myc oncogenes, and (ii) B-cell chronic lymphocytic leukemia (6/40) and, in particular, its stage of progression known as Richter's transformation (3/7). Mutations were not found at any significant frequency in other types of non-Hodgkin lymphoma or acute lymphoblastic leukemia. In many cases, only the mutated allele was detectable, implying loss of the normal allele. These results suggest that (1) significant differences in the frequency of p53 mutations are present among subtypes of neoplasms derived from the same tissue; (2) p53 may play a role in tumor progression in B-cell chronic lymphocytic leukemia; (3) the presence of both p53 loss/inactivation and c-myc oncogene activation may be important in the pathogenesis of Burkitt lymphoma and its leukemia form L{sub 3}-type B-cell acute lymphoblastic leukemia.

  5. Extramedullary Relapse Following Total Marrow and Lymphoid Irradiation in Patients Undergoing Allogeneic Hematopoietic Cell Transplantation

    SciTech Connect

    Kim, Ji Hyun; Stein, Anthony; Schultheiss, Timothy E.; Palmer, Joycelynne; Liu, An; Rosenthal, Joseph; Forman, Stephen J.

    2014-05-01

    Purpose: Approximately 5% to 20% of patients who undergo total body irradiation (TBI) in preparation for hematopoietic cell transplantation (HCT) can develop extramedullary (EM) relapse. Whereas total marrow and lymphoid irradiation (TMLI) provides a more conformally targeted radiation therapy for patients, organ sparing has the potential to place the patient at a higher risk for EM relapse than TBI. This study evaluated EM relapse in patients treated with TMLI at our institution. Methods and Materials: Patients eligible for analysis had been enrolled in 1 of 3 prospective TMLI trials between 2006 and 2012. The TMLI targeted bones, major lymph node chains, liver, spleen, testes, and brain, using image-guided tomotherapy with total dose ranging from 12 to 15 Gy. Results: A total of 101 patients with a median age of 47 years were studied. The median follow-up was 12.8 months. Incidence of EM relapse and bone marrow (BM) relapse were 12.9% and 25.7%, respectively. Of the 13 patients who had EM relapse, 4 also had BM relapse, and 7 had EM disease prior to HCT. There were a total of 19 EM relapse sites as the site of initial recurrence: 11 soft tissue, 6 lymph node, 2 skin. Nine of these sites were within the target region and received ≥12 Gy. Ten initial EM relapse sites were outside of the target region: 5 sites received 10.1 to 11.4 Gy while 5 sites received <10 Gy. Pretransplantation EM was the only significant predictor of subsequent EM relapse. The cumulative incidence of EM relapse was 4% at 1 year and 11.4% at 2 years. Conclusions: EM relapse incidence was as frequent in regions receiving ≥10 Gy as those receiving <10 Gy. EM relapse rates following TMLI that included HCT regimens were comparable to published results with regimens including TBI and suggest that TMLI is not associated with an increased EM relapse risk.

  6. Epithelial-intrinsic IKKα expression regulates group 3 innate lymphoid cell responses and antibacterial immunity

    PubMed Central

    Giacomin, Paul R.; Moy, Ryan H.; Noti, Mario; Osborne, Lisa C.; Siracusa, Mark C.; Alenghat, Theresa; Liu, Bigang; McCorkell, Kelly A.; Troy, Amy E.; Rak, Gregory D.; Hu, Yinling; May, Michael J.; Ma, Hak-Ling; Fouser, Lynette A.; Sonnenberg, Gregory F.

    2015-01-01

    Innate lymphoid cells (ILCs) are critical for maintaining epithelial barrier integrity at mucosal surfaces; however, the tissue-specific factors that regulate ILC responses remain poorly characterized. Using mice with intestinal epithelial cell (IEC)–specific deletions in either inhibitor of κB kinase (IKK)α or IKKβ, two critical regulators of NFκB activation, we demonstrate that IEC-intrinsic IKKα expression selectively regulates group 3 ILC (ILC3)–dependent antibacterial immunity in the intestine. Although IKKβΔIEC mice efficiently controlled Citrobacter rodentium infection, IKKαΔIEC mice exhibited severe intestinal inflammation, increased bacterial dissemination to peripheral organs, and increased host mortality. Consistent with weakened innate immunity to C. rodentium, IKKαΔIEC mice displayed impaired IL-22 production by RORγt+ ILC3s, and therapeutic delivery of rIL-22 or transfer of sort-purified IL-22–competent ILCs from control mice could protect IKKαΔIEC mice from C. rodentium–induced morbidity. Defective ILC3 responses in IKKαΔIEC mice were associated with overproduction of thymic stromal lymphopoietin (TSLP) by IECs, which negatively regulated IL-22 production by ILC3s and impaired innate immunity to C. rodentium. IEC-intrinsic IKKα expression was similarly critical for regulation of intestinal inflammation after chemically induced intestinal damage and colitis. Collectively, these data identify a previously unrecognized role for epithelial cell–intrinsic IKKα expression and TSLP in regulating ILC3 responses required to maintain intestinal barrier immunity. PMID:26371187

  7. Adventitial Tertiary Lymphoid Organs as Potential Source of MicroRNA Biomarkers for Abdominal Aortic Aneurysm.

    PubMed

    Spear, Rafaelle; Boytard, Ludovic; Blervaque, Renaud; Chwastyniak, Maggy; Hot, David; Vanhoutte, Jonathan; Staels, Bart; Lemoine, Yves; Lamblin, Nicolas; Pruvot, François-René; Haulon, Stephan; Amouyel, Philippe; Pinet, Florence

    2015-01-01

    Abdominal aortic aneurysm (AAA) is an inflammatory disease associated with marked changes in the cellular composition of the aortic wall. This study aims to identify microRNA (miRNA) expression in aneurysmal inflammatory cells isolated by laser microdissection from human tissue samples. The distribution of inflammatory cells (neutrophils, B and T lymphocytes, mast cells) was evaluated in human AAA biopsies. We observed in half of the samples that adventitial tertiary lymphoid organs (ATLOs) with a thickness from 0.5 to 2 mm were located exclusively in the adventitia. Out of the 850 miRNA that were screened by microarray in isolated ATLOs (n = 2), 164 miRNAs were detected in ATLOs. The three miRNAs (miR-15a-3p, miR-30a-5p and miR-489-3p) with the highest expression levels were chosen and their expression quantified by RT-PCR in isolated ATLOs (n = 4), M1 (n = 2) and M2 macrophages (n = 2) and entire aneurysmal biopsies (n = 3). Except for the miR-30a-5p, a similar modulation was found in ATLOs and the two subtypes of macrophages. The modulated miRNAs were then evaluated in the plasma of AAA patients for their potential as AAA biomarkers. Our data emphasize the potential of miR-15a-3p and miR-30a-5p as biomarkers of AAA but also as triggers of ATLO evolution. Further investigations will be required to evaluate their targets in order to better understand AAA pathophysiology. PMID:25993295

  8. Adventitial Tertiary Lymphoid Organs as Potential Source of MicroRNA Biomarkers for Abdominal Aortic Aneurysm

    PubMed Central

    Spear, Rafaelle; Boytard, Ludovic; Blervaque, Renaud; Chwastyniak, Maggy; Hot, David; Vanhoutte, Jonathan; Staels, Bart; Lemoine, Yves; Lamblin, Nicolas; Pruvot, François-René; Haulon, Stephan; Amouyel, Philippe; Pinet, Florence

    2015-01-01

    Abdominal aortic aneurysm (AAA) is an inflammatory disease associated with marked changes in the cellular composition of the aortic wall. This study aims to identify microRNA (miRNA) expression in aneurysmal inflammatory cells isolated by laser microdissection from human tissue samples. The distribution of inflammatory cells (neutrophils, B and T lymphocytes, mast cells) was evaluated in human AAA biopsies. We observed in half of the samples that adventitial tertiary lymphoid organs (ATLOs) with a thickness from 0.5 to 2 mm were located exclusively in the adventitia. Out of the 850 miRNA that were screened by microarray in isolated ATLOs (n = 2), 164 miRNAs were detected in ATLOs. The three miRNAs (miR-15a-3p, miR-30a-5p and miR-489-3p) with the highest expression levels were chosen and their expression quantified by RT-PCR in isolated ATLOs (n = 4), M1 (n = 2) and M2 macrophages (n = 2) and entire aneurysmal biopsies (n = 3). Except for the miR-30a-5p, a similar modulation was found in ATLOs and the two subtypes of macrophages. The modulated miRNAs were then evaluated in the plasma of AAA patients for their potential as AAA biomarkers. Our data emphasize the potential of miR-15a-3p and miR-30a-5p as biomarkers of AAA but also as triggers of ATLO evolution. Further investigations will be required to evaluate their targets in order to better understand AAA pathophysiology. PMID:25993295

  9. Lymphoid and Myeloid Recovery in Rhesus Macaques Following Total Body X-Irradiation.

    PubMed

    Farese, Ann M; Hankey, Kim G; Cohen, Melanie Veirs; MacVittie, Thomas J

    2015-11-01

    Recovery from severe immunosuppression requires hematopoietic stem cell reconstitution and effective thymopoiesis to restore a functional immune cell repertoire. Herein, a model of immune cell reconstitution consequent to potentially lethal doses of irradiation is described, which may be valuable in evaluating potential medical countermeasures. Male rhesus macaques were total body irradiated by exposure to 6.00 Gy 250 kVp x-radiation (midline tissue dose, 0.13 Gy min), resulting in an approximate LD10/60 (n = 5/59). Animals received medical management, and hematopoietic and immune cell recovery was assessed (n ≤ 14) through 370 d post exposure. A subset of animals (n ≤ 8) was examined through 700 d. Myeloid recovery was assessed by neutrophil and platelet-related parameters. Lymphoid recovery was assessed by the absolute lymphocyte count and FACS-based phenotyping of B- and T-cell subsets. Recent thymic emigrants were identified by T cell receptor excision circle quantification. Severe neutropenia, lymphopenia, and thrombocytopenia resolved within 30 d. Total CD3+ cells μL required 60 d to reach values 60% of normal, followed by subsequent slow recovery to approximately normal by 180 d post irradiation. Recovery of CD3+4+ and CD3+8+ cell memory and naïve subsets were markedly different. Memory populations were ≥ 100% of normal by day 60, whereas naïve populations were only 57% normal at 180 d and never fully recovered to baseline post irradiation. Total (CD20+) B cells μL were within normal levels by 77 d post exposure. This animal model elucidates the variable T- and B-cell subset recovery kinetics after a potentially lethal dose of total-body irradiation that are dependent on marrow-derived stem and progenitor cell recovery, peripheral homeostatic expansion, and thymopoiesis. PMID:26425902

  10. Reactive lymphoid hyperplasia of the liver mimicking hepatocellular carcinoma: incidental finding of two cases.

    PubMed

    Lv, Ang; Liu, Wendy; Qian, Hong-Gang; Leng, Jia-Hua; Hao, Chun-Yi

    2015-01-01

    Reactive lymphoid hyperplasia is a rare disease that forms a mass-like lesion and is characterized by the proliferation of non-neoplastic, polyclonal lymphocytes forming follicles. We recently encountered 2 cases of reactive lymphoid hyperplasia of liver, both of which were asymptomatic and mimicked hepatocellular carcinoma by various imaging modalities. Based on the clinical impression of hepatocellular carcinoma, surgical resections were performed. Microscopic findings revealed that both lesions consisted of an aggregation of lymphocytes consisting of predominantly B-cells, with multiple lymphoid follicles positive for CD10 and negative for bcl-2, consistent with the diagnosis of reactive lymphoid hyperplasia. Polyclonality of both lesions was further confirmed by B cell receptor gene rearrangement study. The incidence of reactive lymphoid hyperplasia in the liver is exceedingly rare, and it is difficult to differentiate such lesions from hepatic malignancies based upon clinical grounds. The clinicopathological findings and literature review of this report may be helpful to improve the clinical decision-making. PMID:26191310

  11. Computerized interactive morphometry and the diagnosis of lymphoid-rich effusions.

    PubMed

    Walts, A E; Morimoto, R; Marchevsky, A M

    1993-05-01

    An experimental computerized interactive morphometry system for the classification of lymphoid-rich effusions is presented. The relatively inexpensive microcomputer-based system was assembled in our laboratory with commercially available hardware and software. One hundred twenty-two effusions (86 benign lymphocytoses, 26 lymphomas, and 10 chronic lymphocytic leukemias) were studied. Lymphoid cells were selected randomly by the system from real-time images of Papanicolaou-fixed and stained cytospin smears of pleural, peritoneal, and pericardial effusions. Parameters of nuclear shape, area, and optical density were measured automatically. Multiparameter statistical procedures of discriminant classificatory analysis analyzed the distribution of lymphoid nuclear profile integrated optical density to yield three groups of effusions, each with a predictive value of diagnosis of 100%. Neither these statistical procedures nor a simple rule-based expert system accurately classified chronic lymphocytic leukemia effusions based on the distribution of lymphoid nuclear profile area. When chronic lymphocytic leukemia effusions were excluded, however, the predictive values of a diagnosis of lymphoma by statistical analysis and by rule-based expert system were 92.3% and 88.9%, respectively, whereas the predictive values of a diagnosis of benign lymphocytosis were 97.7% and 91.3%, respectively. Potential applications and limitations of this technology for the diagnosis of lymphoid-rich effusions are discussed. PMID:8493950

  12. Clinical and immunologic effects of fractionated total lymphoid irradiation in refractory rheumatoid arthritis

    SciTech Connect

    Trentham, D.E.; Belli, J.A.; Anderson, R.J.; Buckley, J.A.; Goetzl, E.J.; David, J.R.; Austen, K.F.

    1981-10-22

    Ten patients with refractory rheumatoid arthritis were given 3000 rad of fractionated total lymphoid irradiation in an uncontrolled therapeutic trial. Total lymphoid irradiation was associated with objective evidence of considerable clinical improvement in eight patients and with reduced blood lymphocyte counts in all 10. On completion of irradiation, there was an abrogation of lymphocyte reactivity in vitro in the patients with clinical responses, but abnormal antibody activities characteristic of rheumatoid arthritis and normal components of humoral immunity were not suppressed. Partial recrudescence of arthritis occurred shortly after a year after the completion of irradiation and was paralleled by a restitution of lymphocyte concentrations and responsiveness to mitogens to levels similar to those observed before irradiation. These data provide further evidence of T-cell involvement in the pathogenesis of rheumatoid arthritis and demonstrate that total lymphoid irradiation can induce temporary relief, but they do not ascertain whether the natural history of this disease was altered.

  13. Clinical and immunologic effects of fractionated total lymphoid irradiation in refractory rheumatoid arthritis

    SciTech Connect

    Trentham, D.E.; Belli, J.A.Anderson, R.J.; Buckley, J.A.; Goetzl, E.J.; David, J.R.; Austen, K.F.

    1981-10-01

    Ten patients with refractory rheumatoid arthritis were given 3000 rad of fractionated total lymphoid irradiation in an uncontrolled therapeutic trial. Total lymphoid irradiation was associated with objective evidence of considerable clinical improvement in eight patients and with reduced blood lymphocyte counts in all 10. On completion of irradiation, there was an abrogation of lymphocyte reactivity in vitro in the patients with clinical responses, but abnormal antibody activities characteristic of rheumatoid arthritis and normal components of humoral immunity were not suppressed. Partial recrudescence of arthritis occurred shortly before a year after the completion of irradiation and was paralleled by a restitution of lymphocyte concentrations and responsiveness to mitogens to levels similar to those observed before irradiation. These data provide further evidence of T-cell involvement in the pathogenesis of rheumatoid arthritis and demonstrate that total lymphoid irradiation can induce temporary relief, but they do not ascertain whether the natural history of this disease was altered.

  14. The 2016 revision of the World Health Organization classification of lymphoid neoplasms.

    PubMed

    Swerdlow, Steven H; Campo, Elias; Pileri, Stefano A; Harris, Nancy Lee; Stein, Harald; Siebert, Reiner; Advani, Ranjana; Ghielmini, Michele; Salles, Gilles A; Zelenetz, Andrew D; Jaffe, Elaine S

    2016-05-19

    A revision of the nearly 8-year-old World Health Organization classification of the lymphoid neoplasms and the accompanying monograph is being published. It reflects a consensus among hematopathologists, geneticists, and clinicians regarding both updates to current entities as well as the addition of a limited number of new provisional entities. The revision clarifies the diagnosis and management of lesions at the very early stages of lymphomagenesis, refines the diagnostic criteria for some entities, details the expanding genetic/molecular landscape of numerous lymphoid neoplasms and their clinical correlates, and refers to investigations leading to more targeted therapeutic strategies. The major changes are reviewed with an emphasis on the most important advances in our understanding that impact our diagnostic approach, clinical expectations, and therapeutic strategies for the lymphoid neoplasms. PMID:26980727

  15. The transcriptional architecture of early human hematopoiesis identifies multilevel control of lymphoid commitment

    PubMed Central

    Laurenti, Elisa; Doulatov, Sergei; Zandi, Sasan; Plumb, Ian; Chen, Jing; April, Craig; Fan, Jian-Bing; Dick, John E.

    2016-01-01

    Understanding how differentiation programs originate from within the gene expression landscape of hematopoietic stem cells (HSC) is crucial to develop new clinical therapies. We mapped the transcriptional dynamics underlying the first steps of commitment by tracking transcriptome changes in human HSC and eight early progenitor populations. Transcriptional programs are extensively shared, extend across lineage-potential boundaries, and are not strictly lineage-affiliated. Elements of stem, lymphoid and myeloid programs are retained in multi-lymphoid progenitors (MLP), reflecting a hybrid transcriptional state. Based on functional single cell analysis, BCL11A, SOX4 and TEAD1 governed transcriptional networks within MLPs, leading to B cell specification. Overall, we show that integrated transcriptome approaches can identify novel regulators of multipotency and uncover additional complexity in lymphoid commitment. PMID:23708252

  16. Innate lymphoid cell development requires TOX-dependent generation of a common ILC progenitor

    PubMed Central

    Seehus, Corey R.; Aliahmad, Parinaz; de la Torre, Brian; Iliev, Iliyan D.; Spurka, Lindsay; Funari, Vincent A.; Kaye, Jonathan

    2015-01-01

    Diverse innate lymphoid cell (ILC) subtypes have been defined, based on effector function and transcription factor expression. ILCs derive from common lymphoid progenitors, although the transcriptional pathways leading to ILC lineage specification remain poorly characterized. Here we demonstrate that transcriptional regulator TOX is required for the in vivo differentiation of common lymphoid progenitors to ILC lineage-restricted cells. In vitro modeling demonstrates that TOX deficiency results in early defects in progenitor cell survival or expansion as well as later stage ILC differentiation. In addition, comparative transcriptome analysis of bone marrow progenitors reveals that TOX-deficient cells fail to upregulate many aspects of the ILC gene program, including Notch gene targets, implicating TOX as a key determinant of early ILC lineage specification. PMID:25915732

  17. mTOR Regulation of Lymphoid Cells in Immunity to Pathogens

    PubMed Central

    Keating, Rachael; McGargill, Maureen Ann

    2016-01-01

    Immunity to pathogens exists as a fine balance between promoting activation and expansion of effector cells, while simultaneously limiting normal and aberrant responses. These seemingly opposing functions are kept in check by immune regulators. The mechanistic target of rapamycin (mTOR) is a serine/threonine kinase that senses nutrient availability and, in turn, regulates cell metabolism, growth, and survival accordingly. mTOR plays a pivotal role in facilitating immune defense against invading pathogens by regulating the differentiation, activation, and effector functions of lymphoid cells. Here, we focus on the emerging and sometimes contradictory roles of mTOR in orchestrating lymphoid cell-mediated host immune responses to pathogens. A thorough understanding of how mTOR impacts lymphoid cells in pathogen defense will provide the necessary base for developing therapeutic interventions for infectious diseases. PMID:27242787

  18. mTOR Regulation of Lymphoid Cells in Immunity to Pathogens.

    PubMed

    Keating, Rachael; McGargill, Maureen Ann

    2016-01-01

    Immunity to pathogens exists as a fine balance between promoting activation and expansion of effector cells, while simultaneously limiting normal and aberrant responses. These seemingly opposing functions are kept in check by immune regulators. The mechanistic target of rapamycin (mTOR) is a serine/threonine kinase that senses nutrient availability and, in turn, regulates cell metabolism, growth, and survival accordingly. mTOR plays a pivotal role in facilitating immune defense against invading pathogens by regulating the differentiation, activation, and effector functions of lymphoid cells. Here, we focus on the emerging and sometimes contradictory roles of mTOR in orchestrating lymphoid cell-mediated host immune responses to pathogens. A thorough understanding of how mTOR impacts lymphoid cells in pathogen defense will provide the necessary base for developing therapeutic interventions for infectious diseases. PMID:27242787

  19. Ibrutinib versus Ofatumumab in Previously Treated Chronic Lymphoid Leukemia

    PubMed Central

    Byrd, J.C.; Brown, J.R.; O’Brien, S.; Barrientos, J.C.; Kay, N.E.; Reddy, N.M.; Coutre, S.; Tam, C.S.; Mulligan, S.P.; Jaeger, U.; Devereux, S.; Barr, P.M.; Furman, R.R.; Kipps, T.J.; Cymbalista, F.; Pocock, C.; Thornton, P.; Caligaris-Cappio, F.; Robak, T.; Delgado, J.; Schuster, S.J.; Montillo, M.; Schuh, A.; de Vos, S.; Gill, D.; Bloor, A.; Dearden, C.; Moreno, C.; Jones, J.J.; Chu, A.D.; Fardis, M.; McGreivy, J.; Clow, F.; James, D.F.; Hillmen, P.

    2014-01-01

    Background In patients with chronic lymphoid leukemia (CLL) or small lymphocytic lymphoma (SLL), a short duration of response to therapy or adverse cytogenetic abnormalities are associated with a poor outcome. We evaluated the efficacy of ibrutinib, a covalent inhibitor of Bruton’s tyrosine kinase, in patients at risk for a poor outcome. Methods In this multicenter, open-label, phase 3 study, we randomly assigned 391 patients with relapsed or refractory CLL or SLL to receive daily ibrutinib or the anti-CD20 antibody ofatumumab. The primary end point was the duration of progression-free survival, with the duration of overall survival and the overall response rate as secondary end points. Results At a median follow-up of 9.4 months, ibrutinib significantly improved progression-free survival; the median duration was not reached in the ibrutinib group (with a rate of progression-free survival of 88% at 6 months), as compared with a median of 8.1 months in the ofatumumab group (hazard ratio for progression or death in the ibrutinib group, 0.22; P<0.001). Ibrutinib also significantly improved overall survival (hazard ratio for death, 0.43; P = 0.005). At 12 months, the overall survival rate was 90% in the ibrutinib group and 81% in the ofatumumab group. The overall response rate was significantly higher in the ibrutinib group than in the ofatumumab group (42.6% vs. 4.1%, P<0.001). An additional 20% of ibrutinib-treated patients had a partial response with lymphocytosis. Similar effects were observed regardless of whether patients had a chromosome 17p13.1 deletion or resistance to purine analogues. The most frequent nonhematologic adverse events were diarrhea, fatigue, pyrexia, and nausea in the ibrutinib group and fatigue, infusion-related reactions, and cough in the ofatumumab group. Conclusions Ibrutinib, as compared with ofatumumab, significantly improved progression-free survival, overall survival, and response rate among patients with previously treated CLL or SLL

  20. Progress towards eradication of lymphoid leukosis viruses--a review.

    PubMed

    Spencer, J L

    1984-10-01

    More than 20 years have now elapsed since technology was developed for producing chickens free of infection with exogenous lymphoid leukosis virus (LLV). However, it is only in recent years that commercial poultry breeders have initiated programmes to reduce the prevalence of infection in their stocks. This review considers advances that make large scale eradication feasible, even though methods for detecting infection and thus breaking the cycle of virus transmission are not completely effective. Congenital transmission of LLV occurs before eggs are incubated. Although chickens infected in this manner shed virus throughout their lives in faeces, saliva and remnants of cornified cells from skin, horizontal spread is slow. Nevertheless, horizontal transmission is important since it frequently results in persistent low level infections that are difficult to detect. Since horizontally infected dams are often erratic in congenitally transmitting virus, the prevalence of hens in a flock that have the potential for congenital transmission may be markedly higher than the actual rate of such transmission. Naturally infected chickens may have generalised infections, but even in these there are localised sites within certain organs that are prone to production of complete virus particles. While LLVs are usually considered avirulent at the cellular level, myocardial cells from some adult chickens may contain intracytoplasmic viral matrix inclusion bodies that are accompanied by swelling of these cells. Myocardial lesions may be one of many factors that contribute to reduced egg and meat production associated with subclinical LLV infections. While the enzyme-linked immunosorbent assay for group specific viral antigen in egg albumen appears to be the most efficient method for detecting dams that congenitally transmit virus, no combination of test procedures has proven 100% effective in identifying infected chickens. Rearing newly-hatched chickens in small isolated groups for 6

  1. T cell receptor gamma and delta rearrangements in hematologic malignancies. Relationship to lymphoid differentiation.

    PubMed Central

    Griesinger, F; Greenberg, J M; Kersey, J H

    1989-01-01

    We have studied recombinatorial events of the T cell receptor delta and gamma chain genes in hematopoietic malignancies and related these to normal stages of lymphoid differentiation. T cell receptor delta gene recombinatorial events were found in 91% of acute T cell lymphoblastic leukemia, 68% of non-T, non-B lymphoid precursor acute lymphoblastic leukemia (ALL) and 80% of mixed lineage acute leukemias. Mature B-lineage leukemias and acute nonlymphocytic leukemias retained the T-cell receptor delta gene in the germline configuration. The incidence of T cell receptor gamma and delta was particularly high in CD10+CD19+ non-T, non-B lymphoid precursor ALL. In lymphoid precursor ALL, T cell receptor delta was frequently rearranged while T cell receptor gamma was in the germline configuration. This suggests that TCR delta rearrangements may precede TCR gamma rearrangements in lymphoid ontogeny. In T-ALL, only concordant T cell receptor delta and gamma rearrangements were observed. Several distinct rearrangements were defined using a panel of restriction enzymes. Most of the rearrangements observed in T-ALL represented joining events of J delta 1 to upstream regions. In contrast, the majority of rearrangements in lymphoid precursor ALL most likely represented D-D or V-D rearrangements, which have been found to be early recombinatorial events of the TCR delta locus. We next analyzed TCR delta rearrangements in five CD3+TCR gamma/delta+ ALL and cell lines. One T-ALL, which demonstrated a different staining pattern with monoclonal antibodies against the products of the TCR gamma/delta genes than the PEER cell line, rearranges J delta 1 to a currently unidentified variable region. Images PMID:2547833

  2. Human Lymphoid Development in the Absence of Common Gamma Chain Receptor Signaling

    PubMed Central

    Kohn, Lisa A.; Seet, Christopher S.; Scholes, Jessica; Codrea, Felicia; Chan, Rebecca; Zaidi-Merchant, Sania; Zhu, Yuhua; De Oliveira, Satiro; Kapoor, Neena; Shah, Ami; Abdel-Azim, Hisham; Kohn, Donald B.; Crooks, Gay M.

    2014-01-01

    Despite the power of model systems to reveal basic immunologic mechanisms, critical differences exist between species that necessitate the direct study of human cells. Illustrating this point is the difference in phenotype between patients with Severe Combined Immune Deficiency (SCID) caused by mutations affecting the common gamma chain (γc) cytokine signaling pathway and mice with similar mutations. Although in both species, null mutations in either IL2RG (which encodes γc), or its direct downstream signaling partner JAK3, result in T and NK cell deficiency, an associated B cell deficiency is seen in mice but not in humans with these genetic defects. In this study, we applied recent data that have revised our understanding of the earliest stages of lymphoid commitment in human bone marrow (BM), to determine the requirement for signaling through IL2RG and JAK3 in normal development of human lymphoid progenitors. BM samples from SCID patients with IL2RG (n=3) or JAK3 deficiency (n=2), which produce similar “T-NK-B+” clinical phenotypes, were compared to normal BM and umbilical cord blood as well as BM from children on enzyme treatment for adenosine deaminase deficient SCID (n=2). In both IL2RG- and JAK3-SCID patients, the early stages of lymphoid commitment from HSC were present with development of Lymphoid-primed Multipotent Progenitors, common lymphoid progenitors and B cell progenitors, and normal expression patterns of IL7RA and TLSPR, and the DNA recombination genes DNTT and RAG1. Thus, in humans, signaling through the γc pathway is not required for pre-thymic lymphoid commitment or for DNA rearrangement. PMID:24771849

  3. Susceptibility of chicken lymphoid cells to infectious bursal disease virus does not correlate with the presence of specific binding sites.

    PubMed

    Nieper, H; Müller, H

    1996-06-01

    Pathogenic serotype 1 strains of infectious bursal disease virus (IBDV) replicate efficiently in lymphoid cells of the bursa of Fabricius of chicken. Lymphoid cells in other organs are not susceptible. Apathogenic serotype 2 strains do not replicate in lymphoid bursa cells or in other lymphoid cells. Chicken embryo fibroblasts (CEF), however, efficiently replicate strains of either serotype. Binding studies showed that strains of both IBDV serotypes bind to lymphoid cells isolated from the bursa, thymus or spleen, indicating that restriction of IBDV replication to lymphoid B cells is not determined by the presence of specific receptor sites. The specificity of binding was demonstrated by saturation and competition experiments. These revealed the presence of different receptors: CEF had receptors common to both serotypes and specific ones for each serotype. Receptor sites common to both serotypes were also present on lymphoid cells; however, additional serotype-specific sites were only demonstrated for the apathogenic serotype 2 strain. Strains of both serotypes specifically bound to proteins with molecular masses of 40 kDa and 46 kDa, exposed on the surface of CEF and lymphoid cells. Competition experiments indicated that these proteins might represent the common receptor sites of IBDV. PMID:8683211

  4. A novel lymphoid progenitor cell population (LSK(low)) is restricted by p18(INK4c).

    PubMed

    Dong, Fang; Hao, Sha; Ma, Shihui; Cheng, Hui; Wang, Yajie; Zhou, Wen; Yuan, Weiping; Ema, Hideo; Cheng, Tao

    2016-09-01

    The cyclin-dependent kinase inhibitor CDKN2C (p18(INK4c)) restrains self-renewal in hematopoietic stem cells (HSCs) and participates in the development and maturation of lymphoid cells. Deficiency in p18 predisposes mice and humans to hematopoietic lymphoid malignancies such as T-cell leukemia and multiple myeloma. However, the mechanism by which p18 regulates differentiation from HSCs to lymphoid cells is poorly understood. In this study, we found that a progenitor population characterized by its expression of surface markers, Lin(-) Sca-1(+) c-Kit(low) (LSK(low)), was markedly expanded in the bone marrow of p18 knock-out (p18(-/-)) mice. This novel population possessed lymphoid differentiation potential, but not myeloid differentiation potential, both in vitro and in vivo. Whereas LSK(low) cells and common lymphoid progenitors (CLPs) overlapped functionally in generating lymphoid cells, they were distinct cell populations, because they had different gene expression profiles. Unlike CLPs, LSK(low) cells did not express the interleukin-7 receptor. LSK(low) cells were derived from HSCs and were independent of the p18-deleted microenvironment. This cell population may represent a previously unappreciated transitional stage from HSCs to lymphoid progenitors that is strictly restricted by p18 under physiological conditions. Likewise, LSK(low) might serve as a new cellular target of lymphoid malignances in the absence of p18. PMID:27287689

  5. Long-term followup of rheumatoid arthritis patients treated with total lymphoid irradiation

    SciTech Connect

    Tanay, A.; Field, E.H.; Hoppe, R.T.; Strober, S.

    1987-01-01

    Total lymphoid irradiation was administered to 32 patients with intractable rheumatoid arthritis. Twenty-four patients showed at least a 25% improvement in 3 of 4 disease activity parameters, which persisted during the followup period of up to 48 months. Eight of the 32 patients required adjunctive immunosuppressive drug therapy to maintain improvement. Four patients died after total lymphoid irradiation; the causes of death were acute myocardial infarction (1 patient), pulmonary embolism (1 patient), and rheumatoid lung disease complicated by respiratory infection (2 patients). After therapy, patients exhibited a prolonged reduction in the number and function of circulating T helper cells.

  6. Dissection of the mechanisms of immune injury in rheumatoid arthritis, using total lymphoid irradiation

    SciTech Connect

    Gaston, J.S.; Strober, S.; Solovera, J.J.; Gandour, D.; Lane, N.; Schurman, D.; Hoppe, R.T.; Chin, R.C.; Eugui, E.M.; Vaughan, J.H.

    1988-01-01

    Eleven patients with intractable rheumatoid arthritis were treated with total lymphoid irradiation. After radiotherapy, there was a marked decrease in the number and function of peripheral blood helper/inducer (Leu-3+) T lymphocytes, in the spontaneous secretion of interleukin-1 by synovial biopsy specimens, and in the activity of the joint disease. In contrast, levels of IgM, IgA, and IgG rheumatoid factors and C3 concentrations in blood and synovial fluid samples did not change significantly after therapy with total lymphoid irradiation.

  7. Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia or Chronic Myeloid Leukemia in Lymphoid Blast Crisis.

    PubMed

    Kolenova, Alexandra; Maloney, Kelly W; Hunger, Stephen P

    2016-08-01

    The clinical characteristics of chronic myeloid leukemia (CML) in lymphoid blast crisis (BC) can resemble those of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph ALL). Because of this, there can be concern as to whether a patient with newly diagnosed Ph leukemia has Ph ALL or CML in lymphoid BC. This distinction has significant potential therapeutic implications because most children with Ph ALL are now treated with chemotherapy plus a tyrosine kinase inhibitor, whereas allogeneic stem cell transplant is usually recommended for any patient with CML that presents in or later develops BC. PMID:27164534

  8. Identity, regulation and in vivo function of gut NKp46+RORγt+ and NKp46+RORγt- lymphoid cells.

    PubMed

    Reynders, Ana; Yessaad, Nadia; Vu Manh, Thien-Phong; Dalod, Marc; Fenis, Aurore; Aubry, Camille; Nikitas, Georgios; Escalière, Bertrand; Renauld, Jean Christophe; Dussurget, Olivier; Cossart, Pascale; Lecuit, Marc; Vivier, Eric; Tomasello, Elena

    2011-07-20

    The gut is a major barrier against microbes and encloses various innate lymphoid cells (ILCs), including two subsets expressing the natural cytotoxicity receptor NKp46. A subset of NKp46(+) cells expresses retinoic acid receptor-related orphan receptor γt (RORγt) and produces IL-22, like lymphoid tissue inducer (LTi) cells. Other NKp46(+) cells lack RORγt and produce IFN-γ, like conventional Natural Killer (cNK) cells. The identity, the regulation and the in vivo functions of gut NKp46(+) ILCs largely remain to be unravelled. Using pan-genomic profiling, we showed here that small intestine (SI) NKp46(+)RORγt(-) ILCs correspond to SI NK cells. Conversely, we identified a transcriptional programme conserved in fetal LTi cells and adult SI NKp46(+)RORγt(+) and NKp46(-)RORγt(+) ILCs. We also demonstrated that the IL-1β/IL-1R1/MyD88 pathway, but not the commensal flora, drove IL-22 production by NKp46(+)RORγt(+) ILCs. Finally, oral Listeria monocytogenes infection induced IFN-γ production in SI NK and IL-22 production in NKp46(+)RORγt(+) ILCs, but only IFN-γ contributed to control bacteria dissemination. NKp46(+) ILC heterogeneity is thus associated with subset-specific transcriptional programmes and effector functions that govern their implication in gut innate immunity. PMID:21685873

  9. Identity, regulation and in vivo function of gut NKp46+RORγt+ and NKp46+RORγt− lymphoid cells

    PubMed Central

    Reynders, Ana; Yessaad, Nadia; Vu Manh, Thien-Phong; Dalod, Marc; Fenis, Aurore; Aubry, Camille; Nikitas, Georgios; Escalière, Bertrand; Renauld, Jean Christophe; Dussurget, Olivier; Cossart, Pascale; Lecuit, Marc; Vivier, Eric; Tomasello, Elena

    2011-01-01

    The gut is a major barrier against microbes and encloses various innate lymphoid cells (ILCs), including two subsets expressing the natural cytotoxicity receptor NKp46. A subset of NKp46+ cells expresses retinoic acid receptor-related orphan receptor γt (RORγt) and produces IL-22, like lymphoid tissue inducer (LTi) cells. Other NKp46+ cells lack RORγt and produce IFN-γ, like conventional Natural Killer (cNK) cells. The identity, the regulation and the in vivo functions of gut NKp46+ ILCs largely remain to be unravelled. Using pan-genomic profiling, we showed here that small intestine (SI) NKp46+RORγt− ILCs correspond to SI NK cells. Conversely, we identified a transcriptional programme conserved in fetal LTi cells and adult SI NKp46+RORγt+ and NKp46−RORγt+ ILCs. We also demonstrated that the IL-1β/IL-1R1/MyD88 pathway, but not the commensal flora, drove IL-22 production by NKp46+RORγt+ ILCs. Finally, oral Listeria monocytogenes infection induced IFN-γ production in SI NK and IL-22 production in NKp46+RORγt+ ILCs, but only IFN-γ contributed to control bacteria dissemination. NKp46+ ILC heterogeneity is thus associated with subset-specific transcriptional programmes and effector functions that govern their implication in gut innate immunity. PMID:21685873

  10. A High-Dimensional Atlas of Human T Cell Diversity Reveals Tissue-Specific Trafficking and Cytokine Signatures.

    PubMed

    Wong, Michael Thomas; Ong, David Eng Hui; Lim, Frances Sheau Huei; Teng, Karen Wei Weng; McGovern, Naomi; Narayanan, Sriram; Ho, Wen Qi; Cerny, Daniela; Tan, Henry Kun Kiaang; Anicete, Rosslyn; Tan, Bien Keem; Lim, Tony Kiat Hon; Chan, Chung Yip; Cheow, Peng Chung; Lee, Ser Yee; Takano, Angela; Tan, Eng-Huat; Tam, John Kit Chung; Tan, Ern Yu; Chan, Jerry Kok Yen; Fink, Katja; Bertoletti, Antonio; Ginhoux, Florent; Curotto de Lafaille, Maria Alicia; Newell, Evan William

    2016-08-16

    Depending on the tissue microenvironment, T cells can differentiate into highly diverse subsets expressing unique trafficking receptors and cytokines. Studies of human lymphocytes have primarily focused on a limited number of parameters in blood, representing an incomplete view of the human immune system. Here, we have utilized mass cytometry to simultaneously analyze T cell trafficking and functional markers across eight different human tissues, including blood, lymphoid, and non-lymphoid tissues. These data have revealed that combinatorial expression of trafficking receptors and cytokines better defines tissue specificity. Notably, we identified numerous T helper cell subsets with overlapping cytokine expression, but only specific cytokine combinations are secreted regardless of tissue type. This indicates that T cell lineages defined in mouse models cannot be clearly distinguished in humans. Overall, our data uncover a plethora of tissue immune signatures and provide a systemic map of how T cell phenotypes are altered throughout the human body. PMID:27521270

  11. Development of tertiary lymphoid structures in the kidneys of pigs with chronic leptospiral nephritis.

    PubMed

    Pezzolato, M; Maina, E; Lonardi, S; Bozzetta, E; Grassi, F; Scanziani, E; Radaelli, E

    2012-01-15

    Tertiary lymphoid organs (TLOs) are structures that are morphologically and functionally similar to secondary lymphoid organs. TLOs usually arise in a background of chronic inflammation. Several histological patterns of interstitial nephritis have been documented in porcine leptospirosis. Among them the lympho-follicular pattern is characterized by infiltrates of mononuclear cells organized in lymphoid follicle-like structures. Immunohistological analysis of 5 cases of porcine lympho-follicular nephritis associated with Leptospira Pomona infection demonstrated the presence of inflammatory cell populations, including B cells, T cells, macrophages and follicular dendritic cells (FDCs), which were compartmentalized as in TLOs. Immunohistochemistry for Leptospira Pomona revealed an intimate association between leptospiral antigen and FDCs. Overexpression of MHCII in different populations of both professional and non-professional antigen presenting cells was also demonstrated. FDCs play role during TLOs induction for their ability to retain non-self antigens in the form of immune complexes, thus causing persistent T cell activation, generation of a complex cytokine network and stimulation of humoral immunity. Sustained bacterial antigen presentation in the context of chronic leptospiral nephritis, may also lead to autoimmune mechanisms involved in the generation of TLOs. Whether lymphoid neogenesis and TLOs play a protective role in porcine leptospiral nephritis is still unclear. PMID:22227076

  12. Effect of cyclosporine, total lymphoid irradiation, and cobra venom factor on hyperacute rejection

    SciTech Connect

    Knechtle, S.J.; Halperin, E.C.; Murphy, C.E.; Saad, T.; Abernethy, K.; Miller, D.; Bollinger, R.R.

    1985-09-01

    Transplantation into sensitized recipients is contraindicated due to the potential for hyperacute rejection. In order to study the mechanism of hyperacute rejection and the role of immunosuppression in the face of presensitization, we evaluated the effect of total lymphoid irradiation, cyclosporine, and cobra venom factor, alone and in combination, on hyperacute rejection of heterotopic rat heart allografts. Lewis rats were sensitized to strongly RT-1-incompatible ACI rats by three successive skin grafts. Heart allografts were then performed, and survived for a mean period of 15.7 +/- 7.4 hours. Neither preoperative treatment of hypersensitized rats with total lymphoid irradiation alone nor with cyclosporine (5 mg/kg/day) resulted in a prolongation of survival (20.4 +/- 16.6 hours and 35.6 +/- 6.2 hours, respectively). However, complement depletion using cobra venom factor significantly prolonged mean graft survival time to 114.4 +/- 31.0 hours (p less than 0.05). Cyclosporine (10 mg/kg/day) also significantly prolonged survival to 149 +/- 29 hours (p less than 0.01), but did not lower the antibody or complement levels. The addition of total lymphoid irradiation or cyclosporine to treatment with cobra venom factor did not result in longer survival than cobra venom factor alone. In conclusion, cobra venom factor and cyclosporine delay but do not prevent hyperacute rejection, while total lymphoid irradiation has no observable effect on hyperacute rejection.

  13. Total lymphoid irradiation in heart transplantation: Adjunctive treatment for recurrent rejection

    SciTech Connect

    Frist, W.H.; Winterland, A.W.; Gerhardt, E.B.; Merrill, W.H.; Atkinson, J.B.; Eastburn, T.E.; Stewart, J.R.; Eisert, D.R. )

    1989-12-01

    In the face of recurrent heart transplant graft rejection refractory to all conventional immunotherapy, retransplantation is customary treatment. The case of a heart transplant recipient unsuitable for retransplantation whose recurrent rejection was successfully treated with postoperative total lymphoid irradiation is described.

  14. CXCR5-mediated shaping of the lymphoid follicle in chronic lymphocytic leukemia.

    PubMed

    López-Guerra, Mònica; Xargay-Torrent, Sílvia; Colomer, Dolors

    2014-12-01

    Heinig and colleagues, using the Eμ-Tcl1 mouse model of chronic lymphocytic leukemia (CLL), shed light on the trafficking routes of CLL cells into the protective microenvironmental niches in secondary lymphoid organs. The authors propose a crucial role of the resident follicular dendritic cells for leukemia pathogenesis that is essentially orchestrated by the chemokine receptor CXCR5. PMID:25477106

  15. Case of CML lymphoid blast crisis presenting as bilateral breast masses.

    PubMed

    Hossain, Aneesha; Gupta, Kanika; Mener, Andrew; Tabbara, Imad

    2016-01-01

    A woman aged 42 years with a 1-month history of rapidly expanding bilateral breast masses presented with severe leucocytosis, anaemia, blurry vision, headaches and shortness of breath. Evaluation revealed chronic myeloid leukaemia in lymphoid blast crisis with extramedullary leukaemia involving her breasts. PMID:27511749

  16. Lymphoid-rich effusions. Diagnosis by morphometry using the CAS 200 System.

    PubMed

    Walts, A E; Svidler, R; Tolmachoff, T; Marchevsky, A M

    1994-04-01

    Lymphoid-rich effusions frequently present diagnostic problems in clinical cytology. In the authors' previous studies, most lymphoid-rich effusions had been correctly classified as benign lymphocytosis or malignant lymphoma by an experimental computerized interactive morphometry system, in which randomly selected lymphoid nuclear profile images were measured in Papanicolaou fixed and stained cytospin smears. The present study used the CAS 200 System and criteria from the previously described rule-based expert system to classify similar preparations of 134 lymphoid rich pleural, peritoneal, and pericardial effusions (90 benign lymphocytoses, 36 malignant lymphomas, and 8 chronic lymphocytic leukemias). A total of 98.9% of the benign lymphocytoses and 88.9% of the malignant lymphomas were correctly classified (predictive values of correct diagnoses 95.7% and 97.3%, respectively). Chronic lymphocytic leukemias could not be distinguished from benign lymphocytoses by nuclear profile areas. Optical density histograms of benign, lymphomatous, and chronic lymphocytic leukemias effusions are described. Advantages and limitations of image analysis and immunocytochemistry are discussed. PMID:8160646

  17. Expression Profiles of Cloned Channel Catfish (Ictalurus punctatus) Lymphoid Cell Lines and Mixed Lymphocyte Cultures

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Clonal channel catfish lymphoid cell lines and mixed lymphocyte cultures (MLC) have proven extremely useful in examining immune responses at the cellular and molecular levels. To date clonal catfish cell lines and MLC have been biologically and phenotypically characterized using a variety of techniq...

  18. Synovial cytokine expression in psoriatic arthritis and associations with lymphoid neogenesis and clinical features

    PubMed Central

    2012-01-01

    Introduction Psoriatic arthritis (PsA) is an autoantibody-negative immune-mediated disease in which synovial lymphoid neogenesis (LN) occurs. We determined whether LN is associated with specific patterns of inflammatory cytokine expression in paired synovial tissue (ST) and fluid (SF) samples and their potential correlation with the clinical characteristics of PsA. Methods ST and paired SF samples were obtained from the inflamed knee of PsA patients. ST samples were immunostained with CD3 (T cell), CD20 (B cell), and MECA-79 (high endothelial vessels). Total ST mRNA was extracted, and the gene expression of 21 T-cell-derived and proinflammatory cytokines were measured with quantitative real-time PCR. SF concentrations of Th1, Th2, Th17, and proinflammatory cytokines were determined with the Quantibody Human Th17 Array. Clinical and biologic data were collected at inclusion and after a median of 27 months of follow-up. Results Twenty (43.5%) of 46 patients had LN. Only two genes showed differences (Wilcoxon test, P < 0.06) in ST between LN-positive and LN-negative patients: interleukin-23A (IL-23A) (P = 0.058) and transforming growth factor-beta (TGF-β1) (P = 0.050). IL-23A expression was higher, and TGF-β1 expression was lower in LN-positive patients. ST IL-15 mRNA showed a nonsignificant trend toward higher expression in LN-positive patients, and SF IL-15 protein levels were significantly higher in LN-positive patients (P = 0.002). In all PsA patients, IL-23A mRNA expression correlated with C-reactive protein (CRP) (r = 0.471; P = 0.001) and swollen-joint count (SJC) (r = 0.350; P = 0.018), whereas SF levels of IL-6 and CC chemokine-ligand 20 (CCL-20) correlated with CRP levels (r = 0.377; P = 0.014 and r = 0.501; P < 0.0001, respectively). Conclusions These findings suggest differences in the cytokine profile of PsA patients with LN, with a higher expression of IL-23A and IL-15 and a lower expression of TGF-β1. In the entire group of patients, IL-23 ST

  19. Expression of gene, protein and immunohistochemical localization of the estrogen receptor isoform ERα1 in male rainbow trout lymphoid organs; indication of the role of estrogens in the regulation of immune mechanisms.

    PubMed

    Massart, Sophie; Milla, Sylvain; Kestemont, Patrick

    2014-08-01

    In vertebrates, estrogens act on the reproductive system but also affect the functioning of non-reproductive tissues such as the immune system. In teleost fish, effects of estrogens and xenoestrogens have been reported extensively, but the available information on targeted tissues and cells is still scarce. Moreover, a better knowledge of the distinct ER subtypes is required to find out the mechanistic pathways by which estrogen compounds are able to disrupt endogenous estrogen signaling in fish immunity. The present study aimed at characterizing, in male rainbow trout juveniles, multi-tissue gene expression pattern of one isoform of estrogen receptor (ER), ERα1, at the mRNA and protein levels. The mRNA levels for ERα1 were measured in various lymphoid organs by real-time RT-PCR and ERα1 protein level by Western blot. Furthermore, this protein was located by immunohistochemistry in the same organs. The transcripts were ubiquitously expressed, but at a higher level in testis and liver, while the protein was more abundant in testis and skin. Moreover, the ERα1 was detected in endothelial, Kupffer, mucous and chloride cells, hematopoietic tissues, proximal tubule, epithelia of the skin and intestine, in the lamina propria and in the stratum granulosum. This distribution backs the idea that, in male rainbow trout, estrogeno-mimetic compounds could be involved in different immune mechanisms such as inflammatory response, transport of Ig, mucus production, regulation of cellular immunity and development and maturation of lymphoid and myeloid cells. PMID:24937418

  20. Body size in early life and risk of lymphoid malignancies and histological subtypes in adulthood

    PubMed Central

    Cairns, Benjamin J.; Kroll, Mary E.; Reeves, Gillian K.; Green, Jane; Beral, Valerie

    2016-01-01

    Risk of adult lymphoid malignancy is associated with recent adiposity. Some have reported apparent associations with adiposity in childhood or early adulthood, but whether these associations are independent of recent adiposity is unknown. Birth weight, body size at age 10 years, clothes size at age 20 years, and recent body mass index (BMI) were recorded in 745,273 UK women, mean age 60.1 (SD 4.9) at baseline, without prior cancer. They were followed for 11 years, during which time 5,765 lymphoid malignancies occurred. Using Cox regression, a higher risk of lymphoid malignancy was strongly associated with higher recent BMI (RR=1.33, 95%CI 1.17‐1.51, for BMI 35+ vs <22.5 kg/m2), and this association remained essentially unchanged after adjustment for birth weight and body size at 10. Higher lymphoid malignancy risk was also associated with large size at birth, at age 10, and at age 20 years, but after adjustment for recent BMI, the significance of the associations with large size at birth and at age 10 years was sufficiently reduced that residual confounding by adult BMI could not be excluded; a weak association with large size at 20 years remained (adjusted RR =1.17, 95%CI 1.10–1.24 for large size at age 20 vs. medium or small size). We found no strong evidence of histological specificity in any of these associations. In conclusion, our findings suggest a possible role of adiposity throughout adulthood in the risk of lymphoid malignancy, but the independent contribution of body size at birth and during childhood appears to be small. PMID:26888490

  1. Body size in early life and risk of lymphoid malignancies and histological subtypes in adulthood.

    PubMed

    Yang, TienYu Owen; Cairns, Benjamin J; Kroll, Mary E; Reeves, Gillian K; Green, Jane; Beral, Valerie

    2016-07-01

    Risk of adult lymphoid malignancy is associated with recent adiposity. Some have reported apparent associations with adiposity in childhood or early adulthood, but whether these associations are independent of recent adiposity is unknown. Birth weight, body size at age 10 years, clothes size at age 20 years, and recent body mass index (BMI) were recorded in 745,273 UK women, mean age 60.1 (SD 4.9) at baseline, without prior cancer. They were followed for 11 years, during which time 5,765 lymphoid malignancies occurred. Using Cox regression, a higher risk of lymphoid malignancy was strongly associated with higher recent BMI (RR=1.33, 95%CI 1.17-1.51, for BMI 35+ vs <22.5 kg/m(2) ), and this association remained essentially unchanged after adjustment for birth weight and body size at 10. Higher lymphoid malignancy risk was also associated with large size at birth, at age 10, and at age 20 years, but after adjustment for recent BMI, the significance of the associations with large size at birth and at age 10 years was sufficiently reduced that residual confounding by adult BMI could not be excluded; a weak association with large size at 20 years remained (adjusted RR =1.17, 95%CI 1.10-1.24 for large size at age 20 vs. medium or small size). We found no strong evidence of histological specificity in any of these associations. In conclusion, our findings suggest a possible role of adiposity throughout adulthood in the risk of lymphoid malignancy, but the independent contribution of body size at birth and during childhood appears to be small. PMID:26888490

  2. Effects of xenogeneic, allogeneic and isogeneic thymus grafts on lymphocyte populations in peripheral lymphoid organs of the nude rat.

    PubMed

    Hougen, H P; Klausen, B; Stenvang, J P; Kraemmer, J; Rygaard, J

    1987-04-01

    In order to gain information about the effect of xenografted, allografted and isografted thymic tissue on peripheral lymphoid organs of immune-deficient rats, athymic nude LEW rats of ninth backcross-intercross were grafted with fetal calf and neonatal BDIX and LEW thymus. Adrenalectomy was also performed in some animals in order to obtain a possible enhancement of the immunological reconstitution. Both groups of isogeneic-thymus-grafted animals had more T helper cells than the nude controls. Furthermore, they had more densely populated paracortical areas in the inguinal lymph nodes and higher lymphocyte counts in the thoracic duct lymph. Finally, the inguinal lymph nodes contained germinal centres. Xenogeneic and allogeneic thymus transplants did not induce constant changes in the parameters observed compared with the untreated nudes. No clear difference was observed between the adrenalectomized and non-adrenalectomized thymic-isografted animals. We therefore conclude that of all the experimental animals examined the isografted nude rats show by far the best response and that adrenalectomy seems unnecessary for the success of neonatal isogeneic thymus grafts. We also conclude that the isogeneic-thymus-grafted nude rat is a suitable tool for immunological reconstitution studies. PMID:3496487

  3. Modulation of tumor response to photodynamic therapy in severe combined immunodeficient (SCID) mice by adoptively transferred lymphoid cells

    NASA Astrophysics Data System (ADS)

    Korbelik, Mladen; Krosl, Gorazd; Krosl, Jana; Dougherty, Graeme J.

    1996-04-01

    Photodynamic treatment, consisting of intravenous injection of PhotofrinR (10 mg/kg) followed by exposure to 110 J/cm2 of 630 plus or minus 10 nm light 24 hours later, cured 100% of EMT6 tumors (murine mammary sarcoma) growing in syngeneic immunocompetent BALB/C mice. In contrast, the same treatment produced no cures of EMT6 tumors growing in either nude or SCID mice (immunodeficient strains). EMT6 tumors growing in BALB/C and SCID mice showed no difference in either the level of PhotofrinR accumulated per gram of tumor tissue, or the extent of tumor cell killing during the first 24 hours post photodynamic therapy (PDT). In an attempt to improve the sensitivity to PDT of EMT6 tumors growing in SCID mice, these hosts were given either splenic T lymphocytes or whole bone marrow from BALB/C mice. The adoptive transfer of lymphocytes 9 days before PDT was successful in delaying tumor recurrence but produced no cures. A better improvement in PDT response was obtained with tumors growing in SCID mice reconstituted with BALB/C bone marrow (tumor cure rate of 63%). The results of this study demonstrate that, at least with the EMT6 tumor model, antitumor immune activity mediated by lymphoid cell populations makes an important contribution to the curative effect of PDT.

  4. Bimodal Expansion of the Lymphatic Vessels Is Regulated by the Sequential Expression of IL-7 and Lymphotoxin α1β2 in Newly Formed Tertiary Lymphoid Structures.

    PubMed

    Nayar, Saba; Campos, Joana; Chung, Ming May; Navarro-Núñez, Leyre; Chachlani, Menka; Steinthal, Nathalie; Gardner, David H; Rankin, Philip; Cloake, Thomas; Caamaño, Jorge H; McGettrick, Helen M; Watson, Steve P; Luther, Sanjiv; Buckley, Christopher D; Barone, Francesca

    2016-09-01

    Lymphangiogenesis associated with tertiary lymphoid structure (TLS) has been reported in numerous studies. However, the kinetics and dynamic changes occurring to the lymphatic vascular network during TLS development have not been studied. Using a viral-induced, resolving model of TLS formation in the salivary glands of adult mice we demonstrate that the expansion of the lymphatic vascular network is tightly regulated. Lymphatic vessel expansion occurs in two distinct phases. The first wave of expansion is dependent on IL-7. The second phase, responsible for leukocyte exit from the glands, is regulated by lymphotoxin (LT)βR signaling. These findings, while highlighting the tight regulation of the lymphatic response to inflammation, suggest that targeting the LTα1β2/LTβR pathway in TLS-associated pathologies might impair a natural proresolving mechanism for lymphocyte exit from the tissues and account for the failure of therapeutic strategies that target these molecules in diseases such as rheumatoid arthritis. PMID:27474071

  5. Bimodal Expansion of the Lymphatic Vessels Is Regulated by the Sequential Expression of IL-7 and Lymphotoxin α1β2 in Newly Formed Tertiary Lymphoid Structures

    PubMed Central

    Nayar, Saba; Campos, Joana; Chung, Ming May; Navarro-Núñez, Leyre; Chachlani, Menka; Steinthal, Nathalie; Gardner, David H.; Rankin, Philip; Cloake, Thomas; Caamaño, Jorge H.; McGettrick, Helen M.; Watson, Steve P.; Luther, Sanjiv; Buckley, Christopher D.

    2016-01-01

    Lymphangiogenesis associated with tertiary lymphoid structure (TLS) has been reported in numerous studies. However, the kinetics and dynamic changes occurring to the lymphatic vascular network during TLS development have not been studied. Using a viral-induced, resolving model of TLS formation in the salivary glands of adult mice we demonstrate that the expansion of the lymphatic vascular network is tightly regulated. Lymphatic vessel expansion occurs in two distinct phases. The first wave of expansion is dependent on IL-7. The second phase, responsible for leukocyte exit from the glands, is regulated by lymphotoxin (LT)βR signaling. These findings, while highlighting the tight regulation of the lymphatic response to inflammation, suggest that targeting the LTα1β2/LTβR pathway in TLS-associated pathologies might impair a natural proresolving mechanism for lymphocyte exit from the tissues and account for the failure of therapeutic strategies that target these molecules in diseases such as rheumatoid arthritis. PMID:27474071

  6. The lymphoid chemokine, CXCL13, is dispensable for the initial recruitment of B cells to the acutely inflamed central nervous system

    PubMed Central

    Rainey-Barger, Emily K; Rumble, Julie M; Lalor, Stephen J.; Esen, Nilufer; Segal, Benjamin M; Irani, David N

    2010-01-01

    Cases of progressive multifocal leukoencephalopathy can occur in patients treated with the B cell depleting anti-CD20 antibody, rituximab, highlighting the importance of B cell surveillance of the central nervous system (CNS). The lymphoid chemokine, CXCL13, is critical for B cell recruitment and functional organization of peripheral lymphoid tissues, and CXCL13 levels are often elevated in the inflamed CNS. To more directly investigate the role of CXCL13 in CNS B cell migration, its role in animal models of infectious and inflammatory demyelinating disease was examined. During acute alphavirus encephalitis where viral clearance depends on the local actions of anti-viral antibodies, CXCL13 levels and B cell numbers increased in brain tissue over time. Surprisingly, however, CXCL13-deficient animals showed normal CNS B cell recruitment, unaltered CNS virus replication and clearance, and intact peripheral anti-viral antibody responses. During experimental autoimmune encephalomyelitis (EAE), CNS levels of CXCL13 increased as symptoms emerged and equivalent numbers of B cells were identified among the CNS infiltrates of CXCL13-deficient mice compared to control animals. However, CXCL13-deficient mice did not sustain pathogenic anti-myelin T cell responses, consistent with their known propensity to develop more self-limited EAE. These data show that CXCL13 is dispensable for CNS B cell recruitment in both models. The disease course is unaffected by CXCL13 in a CNS infection paradigm that depends on a pathogen-specific B cell response, while it is heightened and prolonged by CXCL13 when myelin-specific CD4+ T cells drive CNS pathology. Thus, CXCL13 could be a therapeutic target in certain neuroinflammatory diseases, but not by blocking B cell recruitment to the CNS. PMID:20933590

  7. Lymphoid organisation in labial salivary gland biopsies is a possible predictor for the development of malignant lymphoma in primary Sjögren's syndrome

    PubMed Central

    Theander, Elke; Vasaitis, Lilian; Baecklund, Eva; Nordmark, Gunnel; Warfvinge, Gunnar; Liedholm, Rolf; Brokstad, Karl; Jonsson, Roland; Jonsson, Malin V

    2011-01-01

    Objective The development of non-Hodgkin's lymphoma (NHL) confers a high risk of mortality in primary Sjögren's syndrome (pSS) patients, but the sensitivity and specificity of proposed lymphoma predictors are insufficient for practical use. The performance of lymphoid organisation in the form of germinal centre (GC)-like lesions was evaluated in labial salivary gland biopsies taken at pSS diagnosis as a potential lymphoma-predicting biomarker. Methods Labial salivary gland tissue biopsies available from two Swedish pSS research cohorts (n=175) were re-evaluated by light microscopy in a blind study in order to identify GC-like structures as a sign of ectopic lymphoid tissue formation and organisation. A linkage study was performed with the Swedish Cancer Registry for lymphoma identification. The risk of developing NHL in GC-positive patients in comparison with GC-negative patients was evaluated using Kaplan–Meier statistics and log-rank test. Associations between GC-like structures and clinical and/or laboratory disease markers were also determined using χ2 or Fisher's exact tests. Results At diagnosis, 25% of pSS patients had GC-like structures in their salivary glands. Seven of the 175 patients studied (14% GC+ and 0.8% GC−) developed NHL during 1855 patient-years at risk, with a median onset of 7 years following the initial diagnostic salivary gland biopsy. Six of the seven patients had GC-like structures at diagnosis; the remaining patient was GC negative at the time of diagnosis (p=0.001). Conclusions The detection of GC-like structures by light microscopy in pSS diagnostic salivary biopsies is proposed as a highly predictive and easy-to-obtain marker for NHL development. This allows for risk stratification of patients and the possibility to initiate preventive B-cell-directed therapy. PMID:21715359

  8. In Vitro and In Vivo Infectivity and Pathogenicity of the Lymphoid Cell-Derived Woodchuck Hepatitis Virus

    PubMed Central

    Lew, Yuan-Yee; Michalak, Tomasz I.

    2001-01-01

    Woodchuck hepatitis virus (WHV) and human hepatitis B virus are closely related, highly hepatotropic mammalian DNA viruses that also replicate in the lymphatic system. The infectivity and pathogenicity of hepadnaviruses propagating in lymphoid cells are under debate. In this study, hepato- and lymphotropism of WHV produced by naturally infected lymphoid cells was examined in specifically established woodchuck hepatocyte and lymphoid cell cultures and coculture systems, and virus pathogenicity was tested in susceptible animals. Applying PCR-based assays discriminating between the total pool of WHV genomes and covalently closed circular DNA (cccDNA), combined with enzymatic elimination of extracellular viral sequences potentially associated with the cell surface, our study documents that virus replicating in woodchuck lymphoid cells is infectious to homologous hepatocytes and lymphoid cells in vitro. The productive replication of WHV from lymphoid cells in cultured hepatocytes was evidenced by the appearance of virus-specific DNA, cccDNA, and antigens, transmissibility of the virus through multiple passages in hepatocyte cultures, and the ability of the passaged virus to infect virus-naive animals. The data also revealed that WHV from lymphoid cells can initiate classical acute viral hepatitis in susceptible animals, albeit small quantities (∼103 virions) caused immunovirologically undetectable (occult) WHV infection that engaged the lymphatic system but not the liver. Our results provide direct in vitro and in vivo evidence that lymphoid cells in the infected host support propagation of infectious hepadnavirus that has the potential to induce hepatitis. They also emphasize a principal role of the lymphatic system in the maintenance and dissemination of hepadnavirus infection, particularly when infection is induced by low virus doses. PMID:11160675

  9. Lymphocyte culture: induction of colonies by conditioned medium from human lymphoid cell lines.

    PubMed

    Galbraith, R M; Goust, J M; Fudenberg, H H

    1977-12-01

    The presence of phytohemagglutinin or pokeweed mitogen in cultures of human peripheral blood mononuclear cells in agar is known to stimulate the formation of lymphoid colonies. We now report that similar colonies can be induced in the absence of plant lectins upon addition of filtered and ultracentrifuged conditioned medium (CM) obtained from certain human lymphoblastoid cell lines. Colony formation required at least 6 X 10(5) mononuclear cells per milliliter, and optimum results were obtained at concentrations of 1 X 10(6) cells/ml in the presence of 20% CM (50-500 colonies per 10(6) cells cultured). Individual cells within colonies displayed uniform morphological characteristics of lymphoid cells, and the majority formed rosettes with sheep erythrocytes, suggesting that they were of T-cell type. PMID:303689

  10. The induction of human peripheral blood lymphoid colonies by conditioned media from human tumour cell lines.

    PubMed Central

    Vesole, D H; Moore, G E

    1980-01-01

    Conditioned medium (CM) from 29 human tumour cell lines and 3 malignant pleural fluids were tested for their ability to stimulate lymphoid colony formation in semi-solid agar; 9 of 14 malignant melanomas, 3 of 6 colonic carcinomas, 2 of 5 ovarian carcinomas, 3 of 4 breast carcinomas and 1 of 3 pleural fluids from breast cancer patients contained colony-stimulating activity (CSA) for human peripheral blood <