Granulomatous lobular mastitis: report of a case with previously undescribed histopathological abnormalities.

PubMed

Axelsen, R A; Reasbeck, P

1988-10-01

A 41-yr-old multiparous woman presented with a discrete breast lump which proved histologically to be an example of granulomatous lobular mastitis. The clinical and histological features were similar to those noted in previous reports. Additional histological features in the present case were an intense mononuclear cell infiltration of lobular and ductal epithelium, associated with nuclear fragments morphologically suggestive of apoptosis. These appearances, which have not previously been described, are illustrated, together with the more classical features of the condition well demonstrated by the present case. The novel histological features noted here suggest that the development of granulomatous lobular mastitis may be at least in part immunologically mediated, and that the cellular infiltrates seen may be a manifestation of cell-mediated destruction of mammary epithelium.

WASp-dependent actin cytoskeleton stability at the dendritic cell immunological synapse is required for extensive, functional T cell contacts.

PubMed

Malinova, Dessislava; Fritzsche, Marco; Nowosad, Carla R; Armer, Hannah; Munro, Peter M G; Blundell, Michael P; Charras, Guillaume; Tolar, Pavel; Bouma, Gerben; Thrasher, Adrian J

2016-05-01

The immunological synapse is a highly structured and molecularly dynamic interface between communicating immune cells. Although the immunological synapse promotes T cell activation by dendritic cells, the specific organization of the immunological synapse on the dendritic cell side in response to T cell engagement is largely unknown. In this study, confocal and electron microscopy techniques were used to investigate the role of dendritic cell actin regulation in immunological synapse formation, stabilization, and function. In the dendritic cell-restricted absence of the Wiskott-Aldrich syndrome protein, an important regulator of the actin cytoskeleton in hematopoietic cells, the immunological synapse contact with T cells occupied a significantly reduced surface area. At a molecular level, the actin network localized to the immunological synapse exhibited reduced stability, in particular, of the actin-related protein-2/3-dependent, short-filament network. This was associated with decreased polarization of dendritic cell-associated ICAM-1 and MHC class II, which was partially dependent on Wiskott-Aldrich syndrome protein phosphorylation. With the use of supported planar lipid bilayers incorporating anti-ICAM-1 and anti-MHC class II antibodies, the dendritic cell actin cytoskeleton organized into recognizable synaptic structures but interestingly, formed Wiskott-Aldrich syndrome protein-dependent podosomes within this area. These findings demonstrate that intrinsic dendritic cell cytoskeletal remodeling is a key regulatory component of normal immunological synapse formation, likely through consolidation of adhesive interaction and modulation of immunological synapse stability. © The Author(s).

Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: A large patient cohort study.

PubMed

Coulter, Tanya I; Chandra, Anita; Bacon, Chris M; Babar, Judith; Curtis, James; Screaton, Nick; Goodlad, John R; Farmer, George; Steele, Cathal Laurence; Leahy, Timothy Ronan; Doffinger, Rainer; Baxendale, Helen; Bernatoniene, Jolanta; Edgar, J David M; Longhurst, Hilary J; Ehl, Stephan; Speckmann, Carsten; Grimbacher, Bodo; Sediva, Anna; Milota, Tomas; Faust, Saul N; Williams, Anthony P; Hayman, Grant; Kucuk, Zeynep Yesim; Hague, Rosie; French, Paul; Brooker, Richard; Forsyth, Peter; Herriot, Richard; Cancrini, Caterina; Palma, Paolo; Ariganello, Paola; Conlon, Niall; Feighery, Conleth; Gavin, Patrick J; Jones, Alison; Imai, Kohsuke; Ibrahim, Mohammad A A; Markelj, Gašper; Abinun, Mario; Rieux-Laucat, Frédéric; Latour, Sylvain; Pellier, Isabelle; Fischer, Alain; Touzot, Fabien; Casanova, Jean-Laurent; Durandy, Anne; Burns, Siobhan O; Savic, Sinisa; Kumararatne, D S; Moshous, Despina; Kracker, Sven; Vanhaesebroeck, Bart; Okkenhaug, Klaus; Picard, Capucine; Nejentsev, Sergey; Condliffe, Alison M; Cant, Andrew James

2017-02-01

Activated phosphoinositide 3-kinase δ syndrome (APDS) is a recently described combined immunodeficiency resulting from gain-of-function mutations in PIK3CD, the gene encoding the catalytic subunit of phosphoinositide 3-kinase δ (PI3Kδ). We sought to review the clinical, immunologic, histopathologic, and radiologic features of APDS in a large genetically defined international cohort. We applied a clinical questionnaire and performed review of medical notes, radiology, histopathology, and laboratory investigations of 53 patients with APDS. Recurrent sinopulmonary infections (98%) and nonneoplastic lymphoproliferation (75%) were common, often from childhood. Other significant complications included herpesvirus infections (49%), autoinflammatory disease (34%), and lymphoma (13%). Unexpectedly, neurodevelopmental delay occurred in 19% of the cohort, suggesting a role for PI3Kδ in the central nervous system; consistent with this, PI3Kδ is broadly expressed in the developing murine central nervous system. Thoracic imaging revealed high rates of mosaic attenuation (90%) and bronchiectasis (60%). Increased IgM levels (78%), IgG deficiency (43%), and CD4 lymphopenia (84%) were significant immunologic features. No immunologic marker reliably predicted clinical severity, which ranged from asymptomatic to death in early childhood. The majority of patients received immunoglobulin replacement and antibiotic prophylaxis, and 5 patients underwent hematopoietic stem cell transplantation. Five patients died from complications of APDS. APDS is a combined immunodeficiency with multiple clinical manifestations, many with incomplete penetrance and others with variable expressivity. The severity of complications in some patients supports consideration of hematopoietic stem cell transplantation for severe childhood disease. Clinical trials of selective PI3Kδ inhibitors offer new prospects for APDS treatment. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Immunological mechanisms of sublingual allergen-specific immunotherapy.

PubMed

Novak, Natalija; Bieber, T; Allam, J-P

2011-06-01

Within the last 100 years of allergen-specific immunotherapy, many clinical and scientific efforts have been made to establish alternative noninvasive allergen application strategies. Thus, intra-oral allergen delivery to the sublingual mucosa has been proven to be safe and effective. As a consequence, to date, sublingual immunotherapy (SLIT) is widely accepted by most allergists as an alternative to conventional subcutaneous immunotherapy. Although immunological mechanisms remain to be elucidated in detail, several studies in mice and humans within recent years provided deeper insights into local as well as systemic immunological features in response to SLIT. First of all, it was shown that the target organ, the oral mucosa, harbours a sophisticated immunological network as an important prerequisite for SLIT, which contains among other cells, local antigen-presenting cells (APC), such as dendritic cells (DCs), with a constitutive disposition to enforce tolerogenic mechanisms. Further on, basic research on local DCs within the oral mucosa gave rise to possible alternative strategies to deliver the allergens to other mucosal regions than sublingual tissue, such as the vestibulum oris. Moreover, characterization of oral DCs led to the identification of target structures for both allergens as well as adjuvants, which could be applied during SLIT. Altogether, SLIT came a long way since its very beginning in the last century and some, but not all questions about SLIT could be answered so far. However, recent research efforts as well as clinical approaches paved the way for another exciting 100 years of SLIT. © 2011 John Wiley & Sons A/S.

CD4 responses in the setting or suboptimal virological responses to antiretroviral therapy: features, outcomes, and associated factors.

PubMed

Collazos, Julio; Asensi, Víctor; Cartón, José Antonio

2009-07-01

The factors associated with discordant viroimmunological responses following antiretroviral therapy are unclear. We studied 1380 patients who initiated a protease inhibitor (PI)-based antiretroviral regimen and who fulfilled the criteria for inclusion. Of them, 255 (18.5%) had CD4 increases > or =100 cells/microl after 1 year of therapy despite detectable viral load (immunological responders); they were compared with 669 patients (48.5%) who had CD4 increases <100 cells/microl regardless of their final viral load (immunological nonresponders). Immunological responders had higher rates of sexual acquisition of HIV (p = 0.03), lower rates of clinical progression (p = 0.02), higher probabilities of being naive to antiretroviral therapy (p = 0.006) or to PI if antiretroviral experienced (p = 0.03), higher rates of receiving only nucleoside reverse transcriptase inhibitors in addition to the PI (p = 0.04), and lower baseline CD4 counts (p = 0.007) and higher viral loads (p = 0.009), as compared with nonresponders. Multivariate analysis revealed that sexual transmission of HIV (homosexual p = 0.004, heterosexual p = 0.03), no prior PI experience (p = 0.005), absence of clinical progression (p = 0.02), and lower baseline CD4 counts (p = 0.03) were independently associated with immunological response. However, these factors differed according to the patients' prior antiretroviral status, as higher baseline viral load was also associated with immunological response in antiretroviral-experienced patients (p = 0.02), whereas baseline CD4 count (p = 0.007) was the only predictive parameter in antiretroviral-naive patients. We conclude that immunological responses despite suboptimal viral suppression are common. Prior PI experience, HIV transmission category, baseline CD4 counts, and clinical progression were independently predictive of this condition, although the associated factors were different depending on the patient's prior antiretroviral history.

Paucity of CD4+CCR5+ T cells is a typical feature of natural SIV hosts

PubMed Central

Pandrea, Ivona; Apetrei, Cristian; Gordon, Shari; Barbercheck, Joseph; Dufour, Jason; Bohm, Rudolf; Sumpter, Beth; Roques, Pierre; Marx, Preston A.; Hirsch, Vanessa M.; Kaur, Amitinder; Lackner, Andrew A.; Veazey, Ronald S.; Silvestri, Guido

2007-01-01

In contrast to lentiviral infections of humans and macaques, simian immunodeficiency virus (SIV) infection of natural hosts is nonpathogenic despite high levels of viral replication. However, the mechanisms underlying this absence of disease are unknown. Here we report that natural hosts for SIV infection express remarkably low levels of CCR5 on CD4+ T cells isolated from blood, lymph nodes, and mucosal tissues. Given that this immunologic feature is found in 5 different species of natural SIV hosts (sooty mangabeys, African green monkeys, mandrills, sun-tailed monkeys, and chimpanzees) but is absent in 5 nonnatural/recent hosts (humans, rhesus, pigtail, cynomolgus macaques, and baboons), it may represent a key feature of the coevolution between the virus and its natural hosts that led to a nonpathogenic infection. Beneficial effects of low CCR5 expression on CD4+ T cells may include the reduction of target cells for viral replication and a decreased homing of activated CD4+ T cells to inflamed tissue. PMID:17003371

Desensitization for solid organ and hematopoietic stem cell transplantation.

PubMed

Zachary, Andrea A; Leffell, Mary S

2014-03-01

Desensitization protocols are being used worldwide to enable kidney transplantation across immunologic barriers, i.e. antibody to donor HLA or ABO antigens, which were once thought to be absolute contraindications to transplantation. Desensitization protocols are also being applied to permit transplantation of HLA mismatched hematopoietic stem cells to patients with antibody to donor HLA, to enhance the opportunity for transplantation of non-renal organs, and to treat antibody-mediated rejection. Although desensitization for organ transplantation carries an increased risk of antibody-mediated rejection, ultimately these transplants extend and enhance the quality of life for solid organ recipients, and desensitization that permits transplantation of hematopoietic stem cells is life saving for patients with limited donor options. Complex patient factors and variability in treatment protocols have made it difficult to identify, precisely, the mechanisms underlying the downregulation of donor-specific antibodies. The mechanisms underlying desensitization may differ among the various protocols in use, although there are likely to be some common features. However, it is likely that desensitization achieves a sort of immune detente by first reducing the immunologic barrier and then by creating an environment in which an autoregulatory process restricts the immune response to the allograft. © 2014 The Authors. Immunological Reviews Published by John Wiley & Sons Ltd.

Memory T cells maintain protracted protection against malaria.

PubMed

Krzych, Urszula; Zarling, Stasya; Pichugin, Alexander

2014-10-01

Immunologic memory is one of the cardinal features of antigen-specific immune responses, and the persistence of memory cells contributes to prophylactic immunizations against infectious agents. Adequately maintained memory T and B cell pools assure a fast, effective and specific response against re-infections. However, many aspects of immunologic memory are still poorly understood, particularly immunologic memory inducible by parasites, for example, Plasmodium spp., the causative agents of malaria. For example, memory responses to Plasmodium antigens amongst residents of malaria endemic areas appear to be either inadequately developed or maintained, because persons who survive episodes of childhood malaria remain vulnerable to intermittent malaria infections. By contrast, multiple exposures of humans and laboratory rodents to radiation-attenuated Plasmodium sporozoites (γ-spz) induce sterile and long-lasting protection against experimental sporozoite challenge. Multifactorial immune mechanisms maintain this protracted and sterile protection. While the presence of memory CD4 T cell subsets has been associated with lasting protection in humans exposed to multiple bites from Anopheles mosquitoes infected with attenuated Plasmodium falciparum, memory CD8 T cells maintain protection induced with Plasmodium yoelii and Plasmodium berghei γ-spz in murine models. In this review, we discuss our observations that show memory CD8 T cells specific for antigens expressed by P. berghei liver stage parasites as an indispensable component for the maintenance of protracted protective immunity against experimental malaria infection; moreover, the provision of an Ag-depot assures a quick recall of memory T cells as IFN-γ-producing effector CD8 T cells and IL-4- producing CD4 T cells that collaborate with B cells for an effective antibody response. Published by Elsevier B.V.

Immunology of malignant diseases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Byers, V.S.; Baldwin, R.W.

1987-01-01

This book contains 11 chapters. Some of the chapter titles are: Immunoscintigraphy: tumor detection with radiolabelled antitumor monoclonal antibodies; Bone marrow transplantation; Immunomodulating agents; Immunology in bowel cancer; Melanoma; and Immunological features of human bladder cancer.

Targeting Leukemia Stem Cells in the Bone Marrow Niche

PubMed Central

Bornhäuser, Martin

2018-01-01

The bone marrow (BM) niche encompasses multiple cells of mesenchymal and hematopoietic origin and represents a unique microenvironment that is poised to maintain hematopoietic stem cells. In addition to its role as a primary lymphoid organ through the support of lymphoid development, the BM hosts various mature lymphoid cell types, including naïve T cells, memory T cells and plasma cells, as well as mature myeloid elements such as monocyte/macrophages and neutrophils, all of which are crucially important to control leukemia initiation and progression. The BM niche provides an attractive milieu for tumor cell colonization given its ability to provide signals which accelerate tumor cell proliferation and facilitate tumor cell survival. Cancer stem cells (CSCs) share phenotypic and functional features with normal counterparts from the tissue of origin of the tumor and can self-renew, differentiate and initiate tumor formation. CSCs possess a distinct immunological profile compared with the bulk population of tumor cells and have evolved complex strategies to suppress immune responses through multiple mechanisms, including the release of soluble factors and the over-expression of molecules implicated in cancer immune evasion. This chapter discusses the latest advancements in understanding of the immunological BM niche and highlights current and future immunotherapeutic strategies to target leukemia CSCs and overcome therapeutic resistance in the clinic. PMID:29466292

Allergic conjunctivitis: a comprehensive review of the literature

PubMed Central

2013-01-01

Ocular allergy represents one of the most common conditions encountered by allergists and ophthalmologists. Allergic conjunctivitis is often underdiagnosed and consequently undertreated. Basic and clinical research has provided a better understanding of the cells, mediators, and immunologic events, which occur in ocular allergy. New pharmacological agents have improved the efficacy and safety of ocular allergy treatment. An understanding of the immunologic mechanisms, clinical features, differential diagnosis, and treatment of ocular allergy may be useful to all specialists who deal with these patients. The purpose of this review is to systematically review literature underlining all the forms classified as ocular allergy: seasonal allergic conjunctivitis, perennial allergic conjunctivitis, vernal keratoconjunctivitis, atopic keratocongiuntivitis, contact allergy, and giant papillary conjunctivitis. PMID:23497516

Is there a maternally induced immunological imprinting phase à la Konrad Lorenz?

PubMed

Lemke, H; Lange, H

1999-10-01

In mammals, IgG antibodies are transferred from mothers to the offspring. Since these maternal antibodies result mainly from thymus-dependent immune responses which have undergone immune maturation through somatic hypermutations, they represent the highest quality of the collective maternal immunological experience. Maternal antibodies not only confer passive immunity as long as the newborn's immune system has not fully developed, but also exert an active stimulation as indicated by their regulatory influence on isotype expression, long-term idiotypic alterations, determination of the adult B and T cell repertoire, induction of antigen reactive IgM as well as an affinity enhancement of a proportion of early primary antibodies. The fact that several of these features can only be induced during limited sensitive periods shortly after birth is reminiscent of the behavioural imprinting as defined by Konrad Lorenz. We therefore propose that during early ontogeny there is an immunological imprinting phase with characteristics analogous to behavioural imprinting: (i) the internal imprinting effect is induced by external signals, (ii) in contrast to normal learning, immunological imprinting is also only possible during certain development phases and (iii) it is characterised by an (almost) irreversible result. Hence, if particular immunological experiences are only possible during such sensitive phases, maternal immunoglobulins and consequently the mother's immunological experience is of prime importance for the start of the ontogenetic development of the immune system.

A statistical mechanics approach to autopoietic immune networks

NASA Astrophysics Data System (ADS)

Barra, Adriano; Agliari, Elena

2010-07-01

In this work we aim to bridge theoretical immunology and disordered statistical mechanics. We introduce a model for the behavior of B-cells which naturally merges the clonal selection theory and the autopoietic network theory as a whole. From the analysis of its features we recover several basic phenomena such as low-dose tolerance, dynamical memory of antigens and self/non-self discrimination.

Characterization of clinical and immunological features in patients coinfected with dengue virus and HIV.

PubMed

Torrentes-Carvalho, Amanda; Hottz, Eugênio Damaceno; Marinho, Cintia Ferreira; da Silva, Jéssica Badolato-Corrêa; Pinto, Luzia Maria de Oliveira; Fialho, Luciana Gomes; Bozza, Fernando Augusto; Cunha, Rivaldo Venâncio; Damasco, Paulo Vieira; Kubelka, Claire Fernandes; de Azeredo, Elzinandes Leal

2016-03-01

The pathogenesis of dengue in subjects coinfected with HIV remains largely unknown. We investigate clinical and immunological parameters in coinfected DENV/HIV patients. According to the new dengue classification, most coinfected DENV/HIV patients presented mild clinical manifestations of dengue infection. Herein, we show that DENV/HIV coinfected patients had higher CD8 T cells percentages reflected as a lower CD4/CD8 ratio. Furthermore, CCR5 expression on CD4 T cells and CD107a expression on both T subsets were significantly higher in coinfected patients when compared with monoinfected DENV and HIV individuals respectively. Increased inflammatory response was observed in treated HAART coinfected patients despite undetectable HIV load. These data indicate that DENV infection may influence the clinical profile and immune response in individuals concomitantly infected with HIV. Copyright © 2016 Elsevier Inc. All rights reserved.

Immunological network signatures of cancer progression and survival

PubMed Central

2011-01-01

Background The immune contribution to cancer progression is complex and difficult to characterize. For example in tumors, immune gene expression is detected from the combination of normal, tumor and immune cells in the tumor microenvironment. Profiling the immune component of tumors may facilitate the characterization of the poorly understood roles immunity plays in cancer progression. However, the current approaches to analyze the immune component of a tumor rely on incomplete identification of immune factors. Methods To facilitate a more comprehensive approach, we created a ranked immunological relevance score for all human genes, developed using a novel strategy that combines text mining and information theory. We used this score to assign an immunological grade to gene expression profiles, and thereby quantify the immunological component of tumors. This immunological relevance score was benchmarked against existing manually curated immune resources as well as high-throughput studies. To further characterize immunological relevance for genes, the relevance score was charted against both the human interactome and cancer information, forming an expanded interactome landscape of tumor immunity. We applied this approach to expression profiles in melanomas, thus identifying and grading their immunological components, followed by identification of their associated protein interactions. Results The power of this strategy was demonstrated by the observation of early activation of the adaptive immune response and the diversity of the immune component during melanoma progression. Furthermore, the genome-wide immunological relevance score classified melanoma patient groups, whose immunological grade correlated with clinical features, such as immune phenotypes and survival. Conclusions The assignment of a ranked immunological relevance score to all human genes extends the content of existing immune gene resources and enriches our understanding of immune involvement in complex biological networks. The application of this approach to tumor immunity represents an automated systems strategy that quantifies the immunological component in complex disease. In so doing, it stratifies patients according to their immune profiles, which may lead to effective computational prognostic and clinical guides. PMID:21453479

Actin Engine in Immunological Synapse

PubMed Central

Piragyte, Indre

2012-01-01

T cell activation and function require physical contact with antigen presenting cells at a specialized junctional structure known as the immunological synapse. Once formed, the immunological synapse leads to sustained T cell receptor-mediated signalling and stabilized adhesion. High resolution microscopy indeed had a great impact in understanding the function and dynamic structure of immunological synapse. Trends of recent research are now moving towards understanding the mechanical part of immune system, expanding our knowledge in mechanosensitivity, force generation, and biophysics of cell-cell interaction. Actin cytoskeleton plays inevitable role in adaptive immune system, allowing it to bear dynamic and precise characteristics at the same time. The regulation of mechanical engine seems very complicated and overlapping, but it enables cells to be very sensitive to external signals such as surface rigidity. In this review, we focus on actin regulators and how immune cells regulate dynamic actin rearrangement process to drive the formation of immunological synapse. PMID:22916042

Sensitivity and specificity of clinical, histologic, and immunologic features in the diagnosis of paraneoplastic pemphigus.

PubMed

Joly, P; Richard, C; Gilbert, D; Courville, P; Chosidow, O; Roujeau, J C; Beylot-Barry, M; D'incan, M; Martel, P; Lauret, P; Tron, F

2000-10-01

Paraneoplastic pemphigus (PNP) is an autoimmune blistering disease characterized by the production of autoantibodies mainly directed against proteins of the plakin family. An overlapping distribution of autoantibody specificities has been recently reported between PNP, pemphigus vulgaris (PV), and pemphigus foliaceus (PF), which suggests a relationship between the different types of pemphigus. Our purpose was to evaluate the sensitivity and the specificity of clinical, histologic, and immunologic features in the diagnosis of PNP. The clinical, histologic, and immunologic features of 22 PNP patients were retrospectively reviewed and compared with those of 81 PV and PF patients without neoplasia and of 8 PV and 4 PF patients with various neoplasms. One clinical and 2 biologic features had both high sensitivity (82%-86%) and high specificity (83%-100%) whatever the control group considered: (1) association with a lymphoproliferative disorder, (2) indirect immunofluorescence (IIF) labeling of rat bladder, and (3) recognition of the envoplakin and/or periplakin bands in immunoblotting. Two clinicopathologic and two biologic features had high specificity (87%-100%) but poor sensitivity (27%-59%): (1) clinical presentation associating erosive oral lesions with erythema multiforme-like, bullous pemphigoid-like, or lichen planus-like cutaneous lesions; (2) histologic picture of suprabasal acantholysis with keratinocyte necrosis, interface changes, or lichenoid infiltrate; (3) presence of both anti-epithelial cell surface and anti-basement membrane zone antibodies by IIF; and (4) recognition of the desmoplakin I and/or BPAG1 bands in immunoblotting. Interestingly, 45% of patients with PNP presented initially with isolated oral erosions that were undistinguishable from those seen in PV patients, and 27% had histologic findings of only suprabasal acantholysis, which was in accordance with the frequent detection of anti-desmoglein 3 antibodies in PNP sera. The association with a lymphoproliferative disorder, the IIF labeling of rat bladder, and the immunoblotting recognition of envoplakin and/or periplakin are both sensitive and specific features in the diagnosis of PNP.

The Immunological Genome Project: networks of gene expression in immune cells.

PubMed

Heng, Tracy S P; Painter, Michio W

2008-10-01

The Immunological Genome Project combines immunology and computational biology laboratories in an effort to establish a complete 'road map' of gene-expression and regulatory networks in all immune cells.

Prevalence and Predictors of Immunological Failure among HIV Patients on HAART in Southern Ethiopia.

PubMed

Yirdaw, Kesetebirhan Delele; Hattingh, Susan

2015-01-01

Immunological monitoring is part of the standard of care for patients on antiretroviral treatment. Yet, little is known about the routine implementation of immunological laboratory monitoring and utilization in clinical care in Ethiopia. This study assessed the pattern of immunological monitoring, immunological response, level of immunological treatment failure and factors related to it among patients on antiretroviral therapy in selected hospitals in southern Ethiopia. A retrospective longitudinal analytic study was conducted using documents of patients started on antiretroviral therapy. Adequacy of timely immunological monitoring was assessed every six months the first year and every one year thereafter. Immunological response was assessed every six months at cohort level. Immunological failure was based on the criteria: fall of follow-up CD4 cell count to baseline (or below), or CD4 levels persisting below 100 cells/mm3, or 50% fall from on-treatment peak value. A total of 1,321 documents of patients reviewed revealed timely immunological monitoring were inadequate. There was adequate immunological response, with pediatric patients, females, those with less advanced illness (baseline WHO Stage I or II) and those with higher baseline CD4 cell count found to have better immunological recovery. Thirty-nine patients (3%) were not evaluated for immunological failure because they had frequent treatment interruption. Despite overall adequate immunological response at group level, the prevalence of those who ever experienced immunological failure was 17.6% (n=226), while after subsequent re-evaluation it dropped to 11.5% (n=147). Having WHO Stage III/IV of the disease or a higher CD4 cell count at baseline was identified as a risk for immunological failure. Few patients with confirmed failure were switched to second line therapy. These findings highlight the magnitude of the problem of immunological failure and the gap in management. Prioritizing care for high risk patients may help in effective utilization of meager resources.

Prevalence and Predictors of Immunological Failure among HIV Patients on HAART in Southern Ethiopia

PubMed Central

2015-01-01

Immunological monitoring is part of the standard of care for patients on antiretroviral treatment. Yet, little is known about the routine implementation of immunological laboratory monitoring and utilization in clinical care in Ethiopia. This study assessed the pattern of immunological monitoring, immunological response, level of immunological treatment failure and factors related to it among patients on antiretroviral therapy in selected hospitals in southern Ethiopia. A retrospective longitudinal analytic study was conducted using documents of patients started on antiretroviral therapy. Adequacy of timely immunological monitoring was assessed every six months the first year and every one year thereafter. Immunological response was assessed every six months at cohort level. Immunological failure was based on the criteria: fall of follow-up CD4 cell count to baseline (or below), or CD4 levels persisting below 100 cells/mm3, or 50% fall from on-treatment peak value. A total of 1,321 documents of patients reviewed revealed timely immunological monitoring were inadequate. There was adequate immunological response, with pediatric patients, females, those with less advanced illness (baseline WHO Stage I or II) and those with higher baseline CD4 cell count found to have better immunological recovery. Thirty-nine patients (3%) were not evaluated for immunological failure because they had frequent treatment interruption. Despite overall adequate immunological response at group level, the prevalence of those who ever experienced immunological failure was 17.6% (n=226), while after subsequent re-evaluation it dropped to 11.5% (n=147). Having WHO Stage III/IV of the disease or a higher CD4 cell count at baseline was identified as a risk for immunological failure. Few patients with confirmed failure were switched to second line therapy. These findings highlight the magnitude of the problem of immunological failure and the gap in management. Prioritizing care for high risk patients may help in effective utilization of meager resources. PMID:25961732

Orchestrating cytoskeleton and intracellular vesicle traffic to build functional immunological synapses.

PubMed

Soares, Helena; Lasserre, Rémi; Alcover, Andrés

2013-11-01

Immunological synapses are specialized cell-cell contacts formed between T lymphocytes and antigen-presenting cells. They are induced upon antigen recognition and are crucial for T-cell activation and effector functions. The generation and function of immunological synapses depend on an active T-cell polarization process, which results from a finely orchestrated crosstalk between the antigen receptor signal transduction machinery, the actin and microtubule cytoskeletons, and controlled vesicle traffic. Although we understand how some of these particular events are regulated, we still lack knowledge on how these multiple cellular elements are harmonized to ensure appropriate T-cell responses. We discuss here our view on how T-cell receptor signal transduction initially commands cytoskeletal and vesicle traffic polarization, which in turn sets the immunological synapse molecular design that regulates T-cell activation. We also discuss how the human immunodeficiency virus (HIV-1) hijacks some of these processes impairing immunological synapse generation and function. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Clustering of immunological, metabolic and genetic features in latent autoimmune diabetes in adults: evidence from principal component analysis.

PubMed

Pes, Giovanni Mario; Delitala, Alessandro Palmerio; Errigo, Alessandra; Delitala, Giuseppe; Dore, Maria Pina

2016-06-01

Latent autoimmune diabetes in adults (LADA) which accounts for more than 10 % of all cases of diabetes is characterized by onset after age 30, absence of ketoacidosis, insulin independence for at least 6 months, and presence of circulating islet-cell antibodies. Its marked heterogeneity in clinical features and immunological markers suggests the existence of multiple mechanisms underlying its pathogenesis. The principal component (PC) analysis is a statistical approach used for finding patterns in data of high dimension. In this study the PC analysis was applied to a set of variables from a cohort of Sardinian LADA patients to identify a smaller number of latent patterns. A list of 11 variables including clinical (gender, BMI, lipid profile, systolic and diastolic blood pressure and insulin-free time period), immunological (anti-GAD65, anti-IA-2 and anti-TPO antibody titers) and genetic features (predisposing gene variants previously identified as risk factors for autoimmune diabetes) retrieved from clinical records of 238 LADA patients referred to the Internal Medicine Unit of University of Sassari, Italy, were analyzed by PC analysis. The predictive value of each PC on the further development of insulin dependence was evaluated using Kaplan-Meier curves. Overall 4 clusters were identified by PC analysis. In component PC-1, the dominant variables were: BMI, triglycerides, systolic and diastolic blood pressure and duration of insulin-free time period; in PC-2: genetic variables such as Class II HLA, CTLA-4 as well as anti-GAD65, anti-IA-2 and anti-TPO antibody titers, and the insulin-free time period predominated; in PC-3: gender and triglycerides; and in PC-4: total cholesterol. These components explained 18, 15, 12, and 12 %, respectively, of the total variance in the LADA cohort. The predictive power of insulin dependence of the four components was different. PC-2 (characterized mostly by high antibody titers and presence of predisposing genetic markers) showed a faster beta-cells failure and PC-3 (characterized mostly by gender and high triglycerides) and PC-4 (high cholesterol) showed a slower beta-cells failure. PC-1 (including dislipidemia and other metabolic dysfunctions), showed a mild beta-cells failure. In conclusion variable clustering might be consistent with different pathogenic pathways and/or distinct immune mechanisms in LADA and could potentially help physicians improve the clinical management of these patients.

Single-Cell Genomics: Approaches and Utility in Immunology.

PubMed

Neu, Karlynn E; Tang, Qingming; Wilson, Patrick C; Khan, Aly A

2017-02-01

Single-cell genomics offers powerful tools for studying immune cells, which make it possible to observe rare and intermediate cell states that cannot be resolved at the population level. Advances in computer science and single-cell sequencing technology have created a data-driven revolution in immunology. The challenge for immunologists is to harness computing and turn an avalanche of quantitative data into meaningful discovery of immunological principles, predictive models, and strategies for therapeutics. Here, we review the current literature on computational analysis of single-cell RNA-sequencing data and discuss underlying assumptions, methods, and applications in immunology, and highlight important directions for future research. Copyright © 2016 Elsevier Ltd. All rights reserved.

Single Cell Genomics: Approaches and Utility in Immunology

PubMed Central

Neu, Karlynn E; Tang, Qingming; Wilson, Patrick C; Khan, Aly A

2017-01-01

Single cell genomics offers powerful tools for studying lymphocytes, which make it possible to observe rare and intermediate cell states that cannot be resolved at the population-level. Advances in computer science and single cell sequencing technology have created a data-driven revolution in immunology. The challenge for immunologists is to harness computing and turn an avalanche of quantitative data into meaningful discovery of immunological principles, predictive models, and strategies for therapeutics. Here, we review the current literature on computational analysis of single cell RNA-seq data and discuss underlying assumptions, methods, and applications in immunology, and highlight important directions for future research. PMID:28094102

Theoretical immunology, Part 2: Proceedings

DOE Office of Scientific and Technical Information (OSTI.GOV)

Perelson, A.S.

1988-01-01

This document contains 43 papers on current topics in immunology. Topics include cell chemotaxis, killer cells, AIDS, antigen reactivity, t-cells, crosslinking, cell-cell adhesion, immune response, and the regulation of lymphocyte proliferation. (TEM)

Human immunophenotyping via low-variance, low-bias, interpretive regression modeling of small, wide data sets: Application to aging and immune response to influenza vaccination.

PubMed

Holmes, Tyson H; He, Xiao-Song

2016-10-01

Small, wide data sets are commonplace in human immunophenotyping research. As defined here, a small, wide data set is constructed by sampling a small to modest quantity n,1

Human Immunophenotyping via Low-Variance, Low-Bias, Interpretive Regression Modeling of Small, Wide Data Sets: Application to Aging and Immune Response to Influenza Vaccination

PubMed Central

Holmes, Tyson H.; He, Xiao-Song

2016-01-01

Small, wide data sets are commonplace in human immunophenotyping research. As defined here, a small, wide data set is constructed by sampling a small to modest quantity n, 1 < n < 50, of human participants for the purpose of estimating many parameters p, such that n < p < 1,000. We offer a set of prescriptions that are designed to facilitate low-variance (i.e. stable), low-bias, interpretive regression modeling of small, wide data sets. These prescriptions are distinctive in their especially heavy emphasis on minimizing use of out-of-sample information for conducting statistical inference. That allows the working immunologist to proceed without being encumbered by imposed and often untestable statistical assumptions. Problems of unmeasured confounders, confidence-interval coverage, feature selection, and shrinkage/denoising are defined clearly and treated in detail. We propose an extension of an existing nonparametric technique for improved small-sample confidence-interval tail coverage from the univariate case (single immune feature) to the multivariate (many, possibly correlated immune features). An important role for derived features in the immunological interpretation of regression analyses is stressed. Areas of further research are discussed. Presented principles and methods are illustrated through application to a small, wide data set of adults spanning a wide range in ages and multiple immunophenotypes that were assayed before and after immunization with inactivated influenza vaccine (IIV). Our regression modeling prescriptions identify some potentially important topics for future immunological research. 1) Immunologists may wish to distinguish age-related differences in immune features from changes in immune features caused by aging. 2) A form of the bootstrap that employs linear extrapolation may prove to be an invaluable analytic tool because it allows the working immunologist to obtain accurate estimates of the stability of immune parameter estimates with a bare minimum of imposed assumptions. 3) Liberal inclusion of immune features in phenotyping panels can facilitate accurate separation of biological signal of interest from noise. In addition, through a combination of denoising and potentially improved confidence interval coverage, we identify some candidate immune correlates (frequency of cell subset and concentration of cytokine) with B cell response as measured by quantity of IIV-specific IgA antibody-secreting cells and quantity of IIV-specific IgG antibody-secreting cells. PMID:27196789

Immunological Demyelination Triggers Macrophage/Microglial Cells Activation without Inducing Astrogliosis

PubMed Central

Sears-Kraxberger, Ilse; Keirstead, Hans S.

2013-01-01

The glial scar formed by reactive astrocytes and axon growth inhibitors associated with myelin play important roles in the failure of axonal regeneration following central nervous system (CNS) injury. Our laboratory has previously demonstrated that immunological demyelination of the CNS facilitates regeneration of severed axons following spinal cord injury. In the present study, we evaluate whether immunological demyelination is accompanied with astrogliosis. We compared the astrogliosis and macrophage/microglial cell responses 7 days after either immunological demyelination or a stab injury to the dorsal funiculus. Both lesions induced a strong activated macrophage/microglial cells response which was significantly higher within regions of immunological demyelination. However, immunological demyelination regions were not accompanied by astrogliosis compared to stab injury that induced astrogliosis which extended several millimeters above and below the lesions, evidenced by astroglial hypertrophy, formation of a glial scar, and upregulation of intermediate filaments glial fibrillary acidic protein (GFAP). Moreover, a stab or a hemisection lesion directly within immunological demyelination regions did not induced astrogliosis within the immunological demyelination region. These results suggest that immunological demyelination creates a unique environment in which astrocytes do not form a glial scar and provides a unique model to understand the putative interaction between astrocytes and activated macrophage/microglial cells. PMID:24319469

Opsoclonus: clinical and immunological features.

PubMed

Jen, Joanna C; Lopez, Ivan; Baloh, Robert W

2012-09-15

Opsoclonus is felt to be a saccadic oscillation disorder but the neuroanatomical substrate for generating the abnormal eye movements is poorly understood. We recorded eye movements and studied serum samples from 7 patients who presented with opsoclonus and with either myoclonus or generalized tremor. Anti neuronal antibodies were detected by immunohistochemestry using rat and human cerebellar sections. In all patients but one the opsoclonus resolved within 2weeks (after immunosuppression in 4, resection of the underlying neoplasm in 1 and spontaneously in 1). Opsoclonus was arrhythmic and multidirectional with a wide frequency range (4-10Hz). No known paraneoplastic antibodies were found in the initial commercial screen. Three patients had antiPurkinje cell antibodies with a characteristic punctate staining in the molecular layer. The clinical and immunological findings are consistent with the hypothesis, that in some patients, opsoclonus results from antibodies directed at the parallel fiber-Purkinje cell synapse. The antibodies block parallel fiber input to Purkinje cells allowing spontaneous oscillating activity generated in the inferior olives to be passed on to the oculomotor nuclei via the flocculus. Copyright © 2012 Elsevier B.V. All rights reserved.

Food allergens: molecular and immunological aspects, allergen databases and cross-reactivity.

PubMed

Lorenz, Anne-Regine; Scheurer, Stephan; Vieths, Stefan

2015-01-01

The currently known food allergens are assigned to a relatively small number of protein families. Food allergens grouped into protein families share common functional and structural features that can be attributed to the allergenic potency and potential cross-reactivity of certain proteins. Molecular data, in terms of structural information, biochemical characteristics and clinical relevance for each known allergen, including isoforms and variants, are mainly compiled into four open-access databases. Allergens are designated according to defined criteria by the World Health Organization and the International Union of Immunological Societies Allergen Nomenclature Sub-committee. Food allergies are caused by primary sensitisation to the disease-eliciting food allergens (class I food allergen), or they can be elicited as a consequence of a primary sensitisation to inhalant allergens and subsequent IgE cross-reaction to homologous proteins in food (class II food allergens). Class I and class II allergens display different clinical significance in children and adults and are characterised by different molecular features. In line with this, high stability when exposed to gastrointestinal digestion and heat treatment is attributed to many class I food allergens that frequently induce severe reactions. The stability of a food allergen is determined by its molecular characteristics and can be influenced by structural (chemical) modifications due to thermal processing. Moreover, the immunogenicity and allergenicity of food allergens further depends on specific T cell and B cell epitopes. Although the T cell epitope pattern can be highly diverse for individual patients, several immuno-prominent T cell epitopes have been identified. Such conserved T cell epitopes and IgE cross-reactive B cell epitopes contribute to cross-reactivity between food allergens of the same family and to clinical cross-reactivity, similar to the birch pollen-food syndrome. © 2015 S. Karger AG, Basel.

Immunological classification of high grade non-Hodgkin's lymphomas (NHL) in children.

PubMed

Pituch-Noworolska, A; Miezyński, W

1994-01-01

The immunological classification of 28 high grade non-Hodgkin's lymphomas (NHL) in children was shown. The morphological classification was based on Working Formulation, the immunological classification--on acute lymphoblastic leukemia subtypes. The phenotypes were assayed cytofluorometrically with monoclonal antibodies and compared to ontogenic stages in B and T cell development. Small non-cleaved cell lymphoma (Burkitt's type) was seen in 13 patients, lymphoblastic lymphoma in 12 patients, low differentiated in 3 patients. Immunological classification showed B-lymphocyte origin of blast cells in 15 patients including 11 small non-cleaved Burkitt's lymphoma (mature B and cALL phenotype), 3 undifferentiated cases (pro-B and mature B cell) and 1 case of lymphoblastic lymphoma (cALL type). T-cell origin of blast cells was demonstrated in 13 patients. The immunological classification used routinely was helpful in selection of patients with unfavourable prognosis. The more precise description of blast cells was valuable for better adjustment of therapy and better prognosis.

The Clinical and Immunologic Features of Patients With Combined Anti-GBM Disease and Castleman Disease.

PubMed

Gu, Qiu-Hua; Jia, Xiao-Yu; Hu, Shui-Yi; Wang, Su-Xia; Zou, Wan-Zhong; Cui, Zhao; Zhao, Ming-Hui

2018-06-01

Patients with both anti-glomerular basement membrane (anti-GBM) disease and Castleman disease have been rarely reported. In this study, we report 3 patients with this combination. They had immunologic features similar to patients with classic anti-GBM disease. Sera from the 3 patients recognized the noncollagenous (NC) domain of the α3 chain of type IV collagen (α3(IV)NC1) and its 2 major epitopes, EA and EB. All 4 immunogloblin G (IgG) subclasses against α3(IV)NC1 were detectable, with predominance of IgG1. In one patient with lymph node biopsy specimens available, sporadic plasma cells producing α3(IV)NC1-IgG were found, suggesting a causal relationship between the 2 diseases. One patient, who achieved remission with antibody clearance and normalization of serum creatinine and interleukin 6 concentrations after plasma exchange and 3 cycles of chemotherapy, experienced recurrence of anti-GBM antibodies and an increase in interleukin 6 concentration after chemotherapy discontinuation because of adverse effects, but both returned to normal after another cycle of chemotherapy. This clinical course and the pathologic findings support the hypothesis that the Castleman disease-associated tumor cells are the source of the anti-GBM autoantibodies. Copyright © 2018 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

T cells' immunological synapses induce polarization of brain astrocytes in vivo and in vitro: a novel astrocyte response mechanism to cellular injury.

PubMed

Barcia, Carlos; Sanderson, Nicholas S R; Barrett, Robert J; Wawrowsky, Kolja; Kroeger, Kurt M; Puntel, Mariana; Liu, Chunyan; Castro, Maria G; Lowenstein, Pedro R

2008-08-20

Astrocytes usually respond to trauma, stroke, or neurodegeneration by undergoing cellular hypertrophy, yet, their response to a specific immune attack by T cells is poorly understood. Effector T cells establish specific contacts with target cells, known as immunological synapses, during clearance of virally infected cells from the brain. Immunological synapses mediate intercellular communication between T cells and target cells, both in vitro and in vivo. How target virally infected astrocytes respond to the formation of immunological synapses established by effector T cells is unknown. Herein we demonstrate that, as a consequence of T cell attack, infected astrocytes undergo dramatic morphological changes. From normally multipolar cells, they become unipolar, extending a major protrusion towards the immunological synapse formed by the effector T cells, and withdrawing most of their finer processes. Thus, target astrocytes become polarized towards the contacting T cells. The MTOC, the organizer of cell polarity, is localized to the base of the protrusion, and Golgi stacks are distributed throughout the protrusion, reaching distally towards the immunological synapse. Thus, rather than causing astrocyte hypertrophy, antiviral T cells cause a major structural reorganization of target virally infected astrocytes. Astrocyte polarization, as opposed to hypertrophy, in response to T cell attack may be due to T cells providing a very focused attack, and thus, astrocytes responding in a polarized manner. A similar polarization of Golgi stacks towards contacting T cells was also detected using an in vitro allogeneic model. Thus, different T cells are able to induce polarization of target astrocytes. Polarization of target astrocytes in response to immunological synapses may play an important role in regulating the outcome of the response of astrocytes to attacking effector T cells, whether during antiviral (e.g. infected during HIV, HTLV-1, HSV-1 or LCMV infection), anti-transplant, autoimmune, or anti-tumor immune responses in vivo and in vitro.

Immunobiography and the Heterogeneity of Immune Responses in the Elderly: A Focus on Inflammaging and Trained Immunity

PubMed Central

Franceschi, Claudio; Salvioli, Stefano; Garagnani, Paolo; de Eguileor, Magda; Monti, Daniela; Capri, Miriam

2017-01-01

Owing to its memory and plasticity, the immune system (IS) is capable of recording all the immunological experiences and stimuli it was exposed to. The combination of type, dose, intensity, and temporal sequence of antigenic stimuli that each individual is exposed to has been named “immunobiography.” This immunological history induces a lifelong continuous adaptation of the IS, which is responsible for the capability to mount strong, weak or no response to specific antigens, thus determining the large heterogeneity of immunological responses. In the last years, it is becoming clear that memory is not solely a feature of adaptive immunity, as it has been observed that also innate immune cells are provided with a sort of memory, dubbed “trained immunity.” In this review, we discuss the main characteristics of trained immunity as a possible contributor to inflammaging within the perspective of immunobiography, with particular attention to the phenotypic changes of the cell populations known to be involved in trained immunity. In conclusion, immunobiography emerges as a pervasive and comprehensive concept that could help in understanding and interpret the individual heterogeneity of immune responses (to infections and vaccinations) that becomes particularly evident at old age and could affect immunosenescence and inflammaging. PMID:28861086

From Hayflick to Walford: the role of T cell replicative senescence in human aging.

PubMed

Effros, Rita B

2004-06-01

The immunologic theory of aging, proposed more than 40 years ago by Roy Walford, suggests that the normal process of aging in man and in animals is pathogenetically related to faulty immunological processes. Since that time, research on immunological aging has undergone extraordinary expansion, leading to new information in areas spanning from molecular biology and cell signaling to large-scale clinical studies. Investigation in this area has also provided unexpected insights into HIV disease, many aspects of which represent accelerated immunological aging. This article describes the initial insights and vision of Roy Walford into one particular facet of human immunological aging, namely, the potential relevance of the well-studied human fibroblast replicative senescence model, initially developed by Leonard Hayflick, to cells of the immune system. Extensive research on T cell senescence in cell culture has now documented changes in vitro that closely mirror alterations occurring during in vivo aging in humans, underscoring the biological significance of T cell replicative senescence. Moreover, the inclusion of high proportions of putatively senescent T cells in the 'immune risk phenotype' that is associated with early mortality in octogenarians provides initial clinical confirmation of both the immunologic theory of aging and the role of the T cell Hayflick Limit in human aging, two areas of gerontological research pioneered by Roy Walford.

Immunology of the gastrointestinal tract and liver

DOE Office of Scientific and Technical Information (OSTI.GOV)

Heyworth, M.F.; Jones, A.L.

1988-01-01

This book contains 11 chapters. Some of the chapter titles are: T cells and Other Non-B Lymphocytes; Mucosal Mast Cells and IgE; Genetic Aspects of Gastrointestinal Immunology; Immunological Functions of the Liver; Lymphocyte Migration and Mucosal Immunity; and Immunoglobulin Circulation and Secretion.

Histological and immunological features of appendix in patients with ulcerative colitis.

PubMed

Jo, Yukihiko; Matsumoto, Takayuki; Yada, Shinichiro; Nakamura, Shotaro; Yao, Takashi; Hotokezaka, Masayuki; Mibu, Ryuichi; Iida, Mitsuo

2003-01-01

Patients with ulcerative colitis (UC) have a less frequent prior history of appendectomy than the general population. The aim of the present investigation was to elucidate histological and immunological characteristics of the appendix in UC and to assess the effect of appendectomy on the disease. Nine subjects with mildly active UC were treated by surgical appendectomy. In four subjects, the histological findings of the appendix were compatible with ulcerative appendicitis. CD3+CD4+CD25+, CD3+CD4+CD45RO+, and CD3+CD8+CD45RO+ appendiceal mononuclear cells were significantly higher in UC than in acute appendicitis and in normal appendix. There was a trend towards higher mRNA transcripts of IFN-gamma in the appendix of UC than those in other two groups. Clinical activity index decreased significantly four weeks after the appendectomy, although the effect was transient. The appendix is a site of involvement in UC, where mononuclear cells are presumed to be at a state of basal activation.

Characterization of B cell lymphoma in patients with Sjögren's syndrome and hepatitis C virus infection.

PubMed

Ramos-Casals, Manuel; la Civita, Luca; de Vita, Salvatore; Solans, Roser; Luppi, Mario; Medina, Francisco; Caramaschi, Paola; Fadda, Patrizia; de Marchi, Ginevra; Lopez-Guillermo, Armando; Font, Josep

2007-02-15

To characterize the clinical and immunologic patterns of expression, response to therapy, and outcome of patients with Sjögren's syndrome (SS) and associated hepatitis C virus (HCV) infection who developed B cell lymphoma. Various international reference centers constituted a multicenter study group with the purpose of creating a registry of patients with SS-HCV who developed B cell lymphoma. A protocol form was used to record the main characteristics of SS, chronic HCV infection, and B cell lymphoma. Twenty-five patients with SS-HCV with B cell lymphoma were included in the registry. There were 22 (88%) women and 3 (12%) men (mean age 55, 58, and 61 years at SS, HCV infection, and lymphoma diagnosis, respectively). The main extraglandular SS manifestations were cutaneous vasculitis in 15 (60%) patients and peripheral neuropathy in 12 (48%); the main immunologic features were positive rheumatoid factor (RF) in 24 (96%) and type II cryoglobulins in 20 (80%). The main histologic subtypes were mucosa-associated lymphoid tissue (MALT) lymphoma in 11 (44%) patients, diffuse large B cell lymphoma in 6 (24%), and follicular center cell lymphoma in 6 (24%). Fifteen (60%) patients had an extranodal primary location, most frequently in the parotid gland (5 patients), liver (4 patients), and stomach (4 patients). Twelve (52%) of 23 patients died after a median followup from the time of lymphoma diagnosis of 4 years, with lymphoma progression being the most frequent cause of death. Survival differed significantly between the main types of B cell lymphoma. Patients with SS-HCV and B cell lymphoma are clinically characterized by a high frequency of parotid enlargement and vasculitis, an immunologic pattern overwhelmingly dominated by the presence of RF and mixed type II cryoglobulins, a predominance of MALT lymphomas, and an elevated frequency of primary extranodal involvement in organs in which HCV replicates (exocrine glands, liver, and stomach).

Phenotypic variations of cartilage hair hypoplasia: granulomatous skin inflammation and severe T cell immunodeficiency as initial clinical presentation in otherwise well child with short stature.

PubMed

McCann, Liza J; McPartland, Jo; Barge, Dawn; Strain, Lisa; Bourn, David; Calonje, Eduardo; Verbov, Julian; Riordan, Andrew; Kokai, George; Bacon, Chris M; Wright, Michael; Abinun, Mario

2014-01-01

We report a child with short stature since birth who was otherwise well, presenting at 2.8 years with progressive granulomatous skin lesions when diagnosed with severe T cell immunodeficiency. When previously investigated for short stature, and at the time of current investigations, she had no radiological skeletal features characteristics for cartilage hair hypoplasia, but we found a disease causing RMRP (RNase mitochondrial RNA processing endoribonuclease) gene mutation. Whilst search for HLA matched unrelated donor for haematopoietic stem cell transplantation (HSCT) was underway, she developed rapidly progressive EBV-related lymphoproliferative disorder requiring laparotomy and small bowel resection, and was treated with anti-B cell monoclonal antibody and eventually curative allogeneic HSCT. Screening for RMRP gene mutations should be part of immunological evaluation of patients with 'severe and/or combined' T cell immunodeficiency of unknown origin, especially when associated with short stature and regardless of presence or absence of radiological skeletal features.

21 CFR 866.5470 - Hemoglobin immunological test system.

Code of Federal Regulations, 2011 CFR

2011-04-01

... hemoglobin (the oxygen-carrying pigment in red blood cells) in blood, urine, plasma, or other body fluids... Hemoglobin immunological test system. (a) Indentification. A hemoglobin immunological test system is a device... blood cells), and leukemia (cancer of the blood-forming organs). (b) Classification. Class II...

21 CFR 866.5470 - Hemoglobin immunological test system.

Code of Federal Regulations, 2013 CFR

2013-04-01

... hemoglobin (the oxygen-carrying pigment in red blood cells) in blood, urine, plasma, or other body fluids... Hemoglobin immunological test system. (a) Indentification. A hemoglobin immunological test system is a device... blood cells), and leukemia (cancer of the blood-forming organs). (b) Classification. Class II...

21 CFR 866.5470 - Hemoglobin immunological test system.

Code of Federal Regulations, 2012 CFR

2012-04-01

... hemoglobin (the oxygen-carrying pigment in red blood cells) in blood, urine, plasma, or other body fluids... Hemoglobin immunological test system. (a) Indentification. A hemoglobin immunological test system is a device... blood cells), and leukemia (cancer of the blood-forming organs). (b) Classification. Class II...

21 CFR 866.5470 - Hemoglobin immunological test system.

Code of Federal Regulations, 2014 CFR

2014-04-01

... hemoglobin (the oxygen-carrying pigment in red blood cells) in blood, urine, plasma, or other body fluids... Hemoglobin immunological test system. (a) Indentification. A hemoglobin immunological test system is a device... blood cells), and leukemia (cancer of the blood-forming organs). (b) Classification. Class II...

Mechanism study of tumor-specific immune responses induced by laser immunotherapy

NASA Astrophysics Data System (ADS)

Li, Xiaosong; Zhou, Feifan; Le, Henry; Wolf, Roman F.; Howard, Eric; Nordquist, Robert E.; Hode, Tomas; Liu, Hong; Chen, Wei R.

2011-03-01

Laser immunotherapy (LIT) has shown its efficacy against late-stage, metastatic cancers, both in pre-clinical studies and clinical pilot trials. However, the possible mechanism of LIT is still not fully understood. In our previous studies, we have shown that LIT induces tumor-specific antibodies that strongly bind to the target tumors. Tumor resistance in cured animals demonstrated long-term immunological effect of LIT. Successful transfer of adoptive immunity using spleen cells from LIT-cured animals indicated a long-term immunological memory of the host system. In clinical trials for the treatment of late-stage melanoma patients and breast cancer patients, the similar long-term, systemic effects have also been observed. To further study the immunological mechanism of LIT, immuno-histochemical analysis of patient tumor samples has performed before and after LIT treatment. Our results showed strong evidence that LIT significantly increases the infiltration of immune cells in the target tumors. Specifically, LIT appeared to drive the infiltrating immune cell populations in the direction of CD4, CD8 and CD68 T-cells. It is possible that activation and enhancement of both humeral and cellular arms of the host immune system are achievable by the treatment of LIT. These special features of LIT have contributed to the success of patient treatment. The underlying mechanism of LIT appears to be an in-situ autologous whole-cell cancer vaccination, using all components of tumors as sources of tumor antigens. Our preliminary mechanistic studies and future in-depth studies will contribute to the understanding and development of LIT as an effective modality for the treatment of late stage cancer patients who are facing severely limited options.

Cell biology and immunology lessons taught by Legionella pneumophila.

PubMed

Zhu, Wenhan; Luo, Zhao-Qing

2016-01-01

Legionella pneumophila is a facultative intracellular pathogen capable of replicating within a broad range of hosts. One unique feature of this pathogen is the cohort of ca. 300 virulence factors (effectors) delivered into host cells via its Dot/Icm type IV secretion system. Study of these proteins has produced novel insights into the mechanisms of host function modulation by pathogens, the regulation of essential processes of eukaryotic cells and of immunosurveillance. In this review, we will briefly discuss the roles of some of these effectors in the creation of a niche permissive for bacterial replication in phagocytes and recent advancements in the dissection of the innate immune detection mechanisms by challenging immune cells with L. pneumophila.

21 CFR 866.5460 - Haptoglobin immunological test system.

Code of Federal Regulations, 2014 CFR

2014-04-01

... that binds hemoglobin, the oxygen-carrying pigment in red blood cells) in serum. Measurement of haptoglobin may aid in the diagnosis of hemolytic diseases (diseases in which the red blood cells rupture and... Haptoglobin immunological test system. (a) Identification. A haptoglobin immunological test system is a device...

21 CFR 866.5490 - Hemopexin immunological test system.

Code of Federal Regulations, 2012 CFR

2012-04-01

... survival of mature red blood cells and inability of the bone marrow to compensate for their decreased life span) and sickle cell anemia. (b) Classification. Class II (special controls). The device is exempt... Hemopexin immunological test system. (a) Indentification. A hemopexin immunological test system is a device...

21 CFR 866.5460 - Haptoglobin immunological test system.

Code of Federal Regulations, 2012 CFR

2012-04-01

... that binds hemoglobin, the oxygen-carrying pigment in red blood cells) in serum. Measurement of haptoglobin may aid in the diagnosis of hemolytic diseases (diseases in which the red blood cells rupture and... Haptoglobin immunological test system. (a) Identification. A haptoglobin immunological test system is a device...

21 CFR 866.5490 - Hemopexin immunological test system.

Code of Federal Regulations, 2011 CFR

2011-04-01

... survival of mature red blood cells and inability of the bone marrow to compensate for their decreased life span) and sickle cell anemia. (b) Classification. Class II (special controls). The device is exempt... Hemopexin immunological test system. (a) Indentification. A hemopexin immunological test system is a device...

21 CFR 866.5490 - Hemopexin immunological test system.

Code of Federal Regulations, 2013 CFR

2013-04-01

... survival of mature red blood cells and inability of the bone marrow to compensate for their decreased life span) and sickle cell anemia. (b) Classification. Class II (special controls). The device is exempt... Hemopexin immunological test system. (a) Indentification. A hemopexin immunological test system is a device...

21 CFR 866.5490 - Hemopexin immunological test system.

Code of Federal Regulations, 2014 CFR

2014-04-01

... survival of mature red blood cells and inability of the bone marrow to compensate for their decreased life span) and sickle cell anemia. (b) Classification. Class II (special controls). The device is exempt... Hemopexin immunological test system. (a) Indentification. A hemopexin immunological test system is a device...

21 CFR 866.5460 - Haptoglobin immunological test system.

Code of Federal Regulations, 2013 CFR

2013-04-01

... that binds hemoglobin, the oxygen-carrying pigment in red blood cells) in serum. Measurement of haptoglobin may aid in the diagnosis of hemolytic diseases (diseases in which the red blood cells rupture and... Haptoglobin immunological test system. (a) Identification. A haptoglobin immunological test system is a device...

21 CFR 866.5460 - Haptoglobin immunological test system.

Code of Federal Regulations, 2011 CFR

2011-04-01

... that binds hemoglobin, the oxygen-carrying pigment in red blood cells) in serum. Measurement of haptoglobin may aid in the diagnosis of hemolytic diseases (diseases in which the red blood cells rupture and... Haptoglobin immunological test system. (a) Identification. A haptoglobin immunological test system is a device...

Immunological responses induced by the combination of phototherapy and immunotherapy in the treatment of metastatic tumors

NASA Astrophysics Data System (ADS)

Chen, Wei R.; Naylor, Mark F.; Nordquist, Robert E.; Teague, T. Kent; Liu, Hong

2008-02-01

Combination therapy using laser photothermal interaction and immunological stimulation has demonstrated its ability to induce immunological responses. Glycated chitosan (GC), an immunological stimulant, and imiquimod, a new type of immune response modifier (IRM), when used in conjunction with laser phototherapy, have shown to have a great immunological stimulation function. Specifically, imiquimod can help release cytokines from immunocompetent cells, stimulate TH1 lymphocyte responses (CD8+ T-cells), and recruit additional dendritic cells. To study the effects of immunoadjuvnats in combination of laser photo-irradiation, we treated animal tumors with laser-ICG-GC combination and late-stage melanoma patients with laser-ICG-imiquimod combination. At designated times, tumors, blood, and spleens in both treated and untreated animals were colleted for analysis. The major immunological indicators, such as IL-6, IL-12, IFN-gamma, CD4, and CD8 were analyzed. The same immunological analysis was also performed for melanoma patients treated by the laser-imiquimod combination.

HIV Envelope gp120 Alters T Cell Receptor Mobilization in the Immunological Synapse of Uninfected CD4 T Cells and Augments T Cell Activation

PubMed Central

Deng, Jing; Mitsuki, Yu-ya; Shen, Guomiao; Ray, Jocelyn C.; Cicala, Claudia; Arthos, James; Dustin, Michael L.

2016-01-01

ABSTRACT HIV is transmitted most efficiently from cell to cell, and productive infection occurs mainly in activated CD4 T cells. It is postulated that HIV exploits immunological synapses formed between CD4 T cells and antigen-presenting cells to facilitate the targeting and infection of activated CD4 T cells. This study sought to evaluate how the presence of the HIV envelope (Env) in the CD4 T cell immunological synapse affects synapse formation and intracellular signaling to impact the downstream T cell activation events. CD4 T cells were applied to supported lipid bilayers that were reconstituted with HIV Env gp120, anti-T cell receptor (anti-TCR) monoclonal antibody, and ICAM-1 to represent the surface of HIV Env-bearing antigen-presenting cells. The results showed that the HIV Env did not disrupt immunological synapse formation. Instead, the HIV Env accumulated with TCR at the center of the synapse, altered the kinetics of TCR recruitment to the synapse and affected synapse morphology over time. The HIV Env also prolonged Lck phosphorylation at the synapse and enhanced TCR-induced CD69 upregulation, interleukin-2 secretion, and proliferation to promote virus infection. These results suggest that HIV uses the immunological synapse as a conduit not only for selective virus transmission to activated CD4 T cells but also for boosting the T cell activation state, thereby increasing its likelihood of undergoing productive replication in targeted CD4 T cells. IMPORTANCE There are about two million new HIV infections every year. A better understanding of how HIV is transmitted to susceptible cells is critical to devise effective strategies to prevent HIV infection. Activated CD4 T cells are preferentially infected by HIV, although how this is accomplished is not fully understood. This study examined whether HIV co-opts the normal T cell activation process through the so-called immunological synapse. We found that the HIV envelope is recruited to the center of the immunological synapse together with the T cell receptor and enhances the T cell receptor-induced activation of CD4 T cells. Heightened cellular activation promotes the capacity of CD4 T cells to support productive HIV replication. This study provides evidence of the exploitation of the normal immunological synapse and T cell activation process by HIV to boost the activation state of targeted CD4 T cells and promote the infection of these cells. PMID:27630246

Magnetic Labeling of Activated Microglia in Experimental Gliomas1

PubMed Central

Fleige, Gerrit; Nolte, Christiane; Synowitz, Michael; Seeberger, Florian; Kettenmann, Helmut; Zimmer, Claus

2001-01-01

Abstract Microglia, as intrinsic immunoeffector cells of the central nervous system (CNS), play a very sensitive, crucial role in the response to almost any brain pathology where they are activated to a phagocytic state. Based on the characteristic features of activated microglia, we investigated whether these cells can be visualized with magnetic resonance imaging (MRI) using ultrasmall superparamagnetic iron oxides (USPIOs). The hypothesis of this study was that MR microglia visualization could not only reveal the extent of the tumor, but also allow for assessing the status of immunologic defense. Using USPIOs in cell culture experiments and in a rat glioma model, we showed that microglia can be labeled magnetically. Labeled microglia are detected by confocal microscopy within and around tumors in a typical border-like pattern. Quantitative in vitro studies revealed that microglia internalize amounts of USPIOs that are significantly higher than those incorporated by tumor cells and astrocytes. Labeled microglia can be detected and quantified with MRI in cell phantoms, and the extent of the tumor can be seen in glioma-bearing rats in vivo. We conclude that magnetic labeling of microglia provides a potential tool for MRI of gliomas, which reflects tumor morphology precisely. Furthermore, the results suggest that MRI may yield functional data on the immunologic reaction of the CNS. PMID:11774031

Current Features of Secondary (Acquired) Types of Immune Deficiency.

PubMed

Kovalchuk, Leonid V.; Pinegin, Boris V.

1999-12-01

Secondary (acquired) types of immune deficiencies (SID) take a leading place in practice of modern clinical immunology. The causes for SID development are extremely variable. Special attention is concerned with accumulating facts about target action of microorganisms, and first of all viruses, on certain processes in immune system. Damageable action of HIV-1 on cell elements expressing CD4 molecules is known in most precise manner. It is noteworthy that the search of real molecular defects, induced by microorganisms in immune system is required. It is not to be ruled out that the increased level of apoptosis of immune system cells is one of the causes of SID. The basis of it is disbalance between positive and negative activation processes of immunocompetent cells. Multiple factors may serve as apoptogens, including drugs (glucocorticoids etc.), xenobiotics, physical factors (radiation) and many others. In practice of clinical laboratories a certain spectrum of immunological investigations is recommended that allows to diagnose the degree of immunopathology. At present, in clinical practice these methods are focused around flow cytometry (immunophenotyping), immunodiffusion and immunoenzyme tests (determination of immunoglobulins, cytokines, other soluble components of immune system), tests of estimation of immunocompetent cell activation, proliferation and differentiation. As a prospective, some methods, based on identification of molecular defects in cells and soluble factors of immune system, may be taken into consideration.

Cytoskeletal actin dynamics shape a ramifying actin network underpinning immunological synapse formation

PubMed Central

Fritzsche, Marco; Fernandes, Ricardo A.; Chang, Veronica T.; Colin-York, Huw; Clausen, Mathias P.; Felce, James H.; Galiani, Silvia; Erlenkämper, Christoph; Santos, Ana M.; Heddleston, John M.; Pedroza-Pacheco, Isabela; Waithe, Dominic; de la Serna, Jorge Bernardino; Lagerholm, B. Christoffer; Liu, Tsung-li; Chew, Teng-Leong; Betzig, Eric; Davis, Simon J.; Eggeling, Christian

2017-01-01

T cell activation and especially trafficking of T cell receptor microclusters during immunological synapse formation are widely thought to rely on cytoskeletal remodeling. However, important details on the involvement of actin in the latter transport processes are missing. Using a suite of advanced optical microscopes to analyze resting and activated T cells, we show that, following contact formation with activating surfaces, these cells sequentially rearrange their cortical actin across the entire cell, creating a previously unreported ramifying actin network above the immunological synapse. This network shows all the characteristics of an inward-growing transportation network and its dynamics correlating with T cell receptor rearrangements. This actin reorganization is accompanied by an increase in the nanoscale actin meshwork size and the dynamic adjustment of the turnover times and filament lengths of two differently sized filamentous actin populations, wherein formin-mediated long actin filaments support a very flat and stiff contact at the immunological synapse interface. The initiation of immunological synapse formation, as highlighted by calcium release, requires markedly little contact with activating surfaces and no cytoskeletal rearrangements. Our work suggests that incipient signaling in T cells initiates global cytoskeletal rearrangements across the whole cell, including a stiffening process for possibly mechanically supporting contact formation at the immunological synapse interface as well as a central ramified transportation network apparently directed at the consolidation of the contact and the delivery of effector functions. PMID:28691087

The immunological synapse

PubMed Central

Dustin, Michael L.

2015-01-01

The molecular interactions underlying regulation of the immune response take place in a nano-scale gap between T cells and antigen presenting cells, termed the immunological synapse. If these interactions are regulated appropriately, the host is defended against a wide range of pathogens and deranged host cells. If these interactions are dis-regulated, the host is susceptible to pathogens or tumor escape at one extreme and autoimmunity at the other. Treatments targeting the synapse have helped to establish immunotherapy as a mainstream element in cancer treatment. This Masters primer will cover the basics of the immunological synapse and some of the applications to tumor immunology. PMID:25367977

How understanding immunology contributes to managing CMV disease in immunosuppressed patients: now and in future.

PubMed

Sissons, J G Patrick; Wills, Mark R

2015-06-01

Several decades of research on human cytomegalovirus (HCMV) and the principal mammalian cytomegaloviruses which to varying degrees act as models of HCMV infection, particularly murine, guinea pig and rhesus CMV, have led to the recognition of the CMVs as interesting models of persistent infection with a large and complex DNA virus, which have been highly informative of the immunology and molecular pathogenesis of the virus-host relationship in the normal host. However, it is appropriate to ask how this relative wealth of knowledge has influenced the understanding and management of clinical disease due to HCMV. This article considers the immunology of cytomegalovirus in the normal human host, and the interrelated issue of the sites of HCMV latency and mechanisms of reactivation in the myeloid cell lineage, and in related in vitro model systems. The way in which this site of latency conditions the immune response, and emerging information on the special features of the adaptive immune response to HCMV during latency are also considered. Examples of HCMV disease associated with acquired immunosuppression, principally in the context of transplantation, but also as a consequence of HIV/AIDS and immune reconstitution inflammatory syndrome, are then discussed, with a particular emphasis on how understanding the immunology of persistent infection may contribute to managing CMV disease now and in future.

Immunopathology of immune reconstitution inflammatory syndrome in Whipple's disease.

PubMed

Moos, Verena; Feurle, Gerhard E; Schinnerling, Katina; Geelhaar, Anika; Friebel, Julian; Allers, Kristina; Moter, Annette; Kikhney, Judith; Loddenkemper, Christoph; Kühl, Anja A; Erben, Ulrike; Fenollar, Florence; Raoult, Didier; Schneider, Thomas

2013-03-01

During antimicrobial treatment of classic Whipple's disease (CWD), the chronic systemic infection with Tropheryma whipplei, immune reconstitution inflammatory syndrome (IRIS), is a serious complication. The aim of our study was to characterize the immunological processes underlying IRIS in CWD. Following the definition of IRIS, we describe histological features of IRIS and immunological parameters of 24 CWD IRIS patients, 189 CWD patients without IRIS, and 89 healthy individuals. T cell reconstitution, Th1 reactivity, and the phenotype of T cells were described in the peripheral blood, and infiltration of CD4(+) T cells and regulatory T cells in the duodenal mucosa was determined. During IRIS, tissues were heavily infiltrated by CD3(+), predominantly CD45RO(+)CD4(+) T cells. In the periphery, initial reduction of CD4(+) cell counts and their reconstitution on treatment was more pronounced in CWD patients with IRIS than in those without IRIS. The ratio of activated and regulatory CD4(+) T cells, nonspecific Th1 reactivity, and the proportion of naive among CD4(+) T cells was high, whereas serum IL-10 was low during IRIS. T. whipplei-specific Th1 reactivity remained suppressed before and after emergence of IRIS. The findings that IRIS in CWD mainly are mediated by nonspecific activation of CD4(+) T cells and that it is not sufficiently counterbalanced by regulatory T cells indicate that flare-up of pathogen-specific immunoreactivity is not instrumental in the pathogenesis of IRIS in CWD.

The effects of laser immunotherapy on cancer cell migration

NASA Astrophysics Data System (ADS)

Bahavar, Cody F.; Zhou, Feifan; Hasanjee, Aamr M.; Layton, Elivia; Lam, Anh; Chen, Wei R.; Vaughan, Melville B.

2016-03-01

Laser immunotherapy (LIT) uses laser irradiation and immunological stimulation to target all types of metastases and creates a long-term tumor resistance. Glycated chitosan (GC) is the immunological stimulant used in LIT. Interestingly, GC can act as a surfactant for single-walled carbon nanotubes (SWNTs) to immunologically modify SWNTs. SWNT-GC retains the optical properties of SWNTs and the immunological functions of GC to help increase the selectivity of the laser and create a more optimal immune response. One essential aspect of understanding this immune response is knowing how laser irradiation affects cancer cells' ability to metastasize. In this experiment, a cell migration assay was performed. A 2mm circular elastomer plugs were placed at the bottom of multi-well dishes. Pre-cancerous keratinocytes, different tumor cells, and fibroblasts were then plated separately in treated wells. Once the cells reached 100% confluence, they were irradiated by either a 980nm or 805nm wavelength laser. The goal was to determine the effects of laser irradiation and immunological stimulation on cancer cell migration in vitro, paying the way to understand the mechanism of LIT in treating metastatic tumors in cancer patients.

Antiretroviral Therapy in Simian Immunodeficiency Virus-Infected Sooty Mangabeys: Implications for AIDS Pathogenesis

PubMed Central

Calascibetta, Francesca; Micci, Luca; Carnathan, Diane; Lawson, Benton; Vanderford, Thomas H.; Bosinger, Steven E.; Easley, Kirk; Chahroudi, Ann; Mackel, Joseph; Keele, Brandon F.; Long, Samuel; Lifson, Jeffrey; Paiardini, Mirko

2016-01-01

ABSTRACT Simian immunodeficiency virus (SIV)-infected sooty mangabeys (SMs) do not develop AIDS despite high levels of viremia. Key factors involved in the benign course of SIV infection in SMs are the absence of chronic immune activation and low levels of infection of CD4+ central memory (TCM) and stem cell memory (TSCM) T cells. To better understand the role of virus replication in determining the main features of SIV infection in SMs, we treated 12 SMs with a potent antiretroviral therapy (ART) regimen for 2 to 12 months. We observed that ART suppressed viremia to <60 copies/ml of plasma in 10 of 12 animals and induced a variable decrease in the level of cell-associated SIV DNA in peripheral blood (average changes of 0.9-, 1.1-, 1.5-, and 3.7-fold for CD4+ transitional memory [TTM], TCM, effector memory [TEM], and TSCM cells, respectively). ART-treated SIV-infected SMs showed (i) increased percentages of circulating CD4+ TCM cells, (ii) increased levels of CD4+ T cells in the rectal mucosa, and (iii) significant declines in the frequencies of HLA-DR+ CD8+ T cells in the blood and rectal mucosa. In addition, we observed that ART interruption resulted in rapid viral rebound in all SIV-infected SMs, indicating that the virus reservoir persists for at least a year under ART despite lower infection levels of CD4+ TCM and TSCM cells than those seen in pathogenic SIV infections of macaques. Overall, these data indicate that ART induces specific immunological changes in SIV-infected SMs, thus suggesting that virus replication affects immune function even in the context of this clinically benign infection. IMPORTANCE Studies of natural, nonpathogenic simian immunodeficiency virus (SIV) infection of African monkeys have provided important insights into the mechanisms responsible for the progression to AIDS during pathogenic human immunodeficiency virus (HIV) infection of humans and SIV infection of Asian macaques. In this study, for the first time, we treated SIV-infected sooty mangabeys, a natural host for the infection, with a potent antiretroviral therapy (ART) regimen for periods ranging from 2 to 12 months and monitored in detail how suppression of virus replication affected the main virological and immunological features of this nonpathogenic infection. The observed findings provide novel information on both the pathogenesis of residual immunological disease under ART during pathogenic infection and the mechanisms involved in virus persistence during primate lentiviral infections. PMID:27279614

The immunological synapse: the gateway to the HIV reservoir

PubMed Central

Kulpa, Deanna A; Brehm, Jessica H; Fromentin, Rémi; Cooper, Anthony; Cooper, Colleen; Ahlers, Jeffrey; Chomont, Nicolas; Sékaly, Rafick-Pierre

2013-01-01

A major challenge in the development of a cure for human immunodeficiency virus (HIV) has been the incomplete understanding of the basic mechanisms underlying HIV persistence during antiretroviral therapy. It is now realized that the establishment of a latently infected reservoir refractory to immune system recognition has thus far hindered eradication efforts. Recent investigation into the innate immune response has shed light on signaling pathways downstream of the immunological synapse critical for T-cell activation and establishment of T-cell memory. This has led to the understanding that the cell-to-cell contacts observed in an immunological synapse that involve the CD4+ T cell and antigen-presenting cell or T-cell–T-cell interactions enhance efficient viral spread and facilitate the induction and maintenance of latency in HIV-infected memory T cells. This review focuses on recent work characterizing the immunological synapse and the signaling pathways involved in T-cell activation and gene regulation in the context of HIV persistence. PMID:23772628

Polarized release of T-cell-receptor-enriched microvesicles at the immunological synapse.

PubMed

Choudhuri, Kaushik; Llodrá, Jaime; Roth, Eric W; Tsai, Jones; Gordo, Susana; Wucherpfennig, Kai W; Kam, Lance C; Stokes, David L; Dustin, Michael L

2014-03-06

The recognition events that mediate adaptive cellular immunity and regulate antibody responses depend on intercellular contacts between T cells and antigen-presenting cells (APCs). T-cell signalling is initiated at these contacts when surface-expressed T-cell receptors (TCRs) recognize peptide fragments (antigens) of pathogens bound to major histocompatibility complex molecules (pMHC) on APCs. This, along with engagement of adhesion receptors, leads to the formation of a specialized junction between T cells and APCs, known as the immunological synapse, which mediates efficient delivery of effector molecules and intercellular signals across the synaptic cleft. T-cell recognition of pMHC and the adhesion ligand intercellular adhesion molecule-1 (ICAM-1) on supported planar bilayers recapitulates the domain organization of the immunological synapse, which is characterized by central accumulation of TCRs, adjacent to a secretory domain, both surrounded by an adhesive ring. Although accumulation of TCRs at the immunological synapse centre correlates with T-cell function, this domain is itself largely devoid of TCR signalling activity, and is characterized by an unexplained immobilization of TCR-pMHC complexes relative to the highly dynamic immunological synapse periphery. Here we show that centrally accumulated TCRs are located on the surface of extracellular microvesicles that bud at the immunological synapse centre. Tumour susceptibility gene 101 (TSG101) sorts TCRs for inclusion in microvesicles, whereas vacuolar protein sorting 4 (VPS4) mediates scission of microvesicles from the T-cell plasma membrane. The human immunodeficiency virus polyprotein Gag co-opts this process for budding of virus-like particles. B cells bearing cognate pMHC receive TCRs from T cells and initiate intracellular signals in response to isolated synaptic microvesicles. We conclude that the immunological synapse orchestrates TCR sorting and release in extracellular microvesicles. These microvesicles deliver transcellular signals across antigen-dependent synapses by engaging cognate pMHC on APCs.

Polarized release of T-cell-receptor-enriched microvesicles at the immunological synapse

NASA Astrophysics Data System (ADS)

Choudhuri, Kaushik; Llodrá, Jaime; Roth, Eric W.; Tsai, Jones; Gordo, Susana; Wucherpfennig, Kai W.; Kam, Lance C.; Stokes, David L.; Dustin, Michael L.

2014-03-01

The recognition events that mediate adaptive cellular immunity and regulate antibody responses depend on intercellular contacts between T cells and antigen-presenting cells (APCs). T-cell signalling is initiated at these contacts when surface-expressed T-cell receptors (TCRs) recognize peptide fragments (antigens) of pathogens bound to major histocompatibility complex molecules (pMHC) on APCs. This, along with engagement of adhesion receptors, leads to the formation of a specialized junction between T cells and APCs, known as the immunological synapse, which mediates efficient delivery of effector molecules and intercellular signals across the synaptic cleft. T-cell recognition of pMHC and the adhesion ligand intercellular adhesion molecule-1 (ICAM-1) on supported planar bilayers recapitulates the domain organization of the immunological synapse, which is characterized by central accumulation of TCRs, adjacent to a secretory domain, both surrounded by an adhesive ring. Although accumulation of TCRs at the immunological synapse centre correlates with T-cell function, this domain is itself largely devoid of TCR signalling activity, and is characterized by an unexplained immobilization of TCR-pMHC complexes relative to the highly dynamic immunological synapse periphery. Here we show that centrally accumulated TCRs are located on the surface of extracellular microvesicles that bud at the immunological synapse centre. Tumour susceptibility gene 101 (TSG101) sorts TCRs for inclusion in microvesicles, whereas vacuolar protein sorting 4 (VPS4) mediates scission of microvesicles from the T-cell plasma membrane. The human immunodeficiency virus polyprotein Gag co-opts this process for budding of virus-like particles. B cells bearing cognate pMHC receive TCRs from T cells and initiate intracellular signals in response to isolated synaptic microvesicles. We conclude that the immunological synapse orchestrates TCR sorting and release in extracellular microvesicles. These microvesicles deliver transcellular signals across antigen-dependent synapses by engaging cognate pMHC on APCs.

T cell costimulation by chemokine receptors.

PubMed

Molon, Barbara; Gri, Giorgia; Bettella, Monica; Gómez-Moutón, Concepción; Lanzavecchia, Antonio; Martínez-A, Carlos; Mañes, Santos; Viola, Antonella

2005-05-01

Signals mediated by chemokine receptors may compete with T cell receptor stop signals and determine the duration of T cell-antigen-presenting cell interactions. Here we show that during T cell stimulation by antigen-presenting cells, T cell chemokine receptors coupled to G(q) and/or G(11) protein were recruited to the immunological synapse by a G(i)-independent mechanism. When chemokine receptors were sequestered at the immunological synapse, T cells became insensitive to chemotactic gradients, formed more stable conjugates and finally responded with enhanced proliferation and cytokine production. We suggest that chemokine receptor trapping at the immunological synapse enhances T cell activation by improving T cell-antigen-presenting cell attraction and impeding the 'distraction' of successfully engaged T cells by other chemokine sources.

Genetic and demographic features of X-linked agammaglobulinemia in Eastern and Central Europe: a cohort study.

PubMed

Tóth, Beáta; Volokha, Alla; Mihas, Alexander; Pac, Malgorzata; Bernatowska, Ewa; Kondratenko, Irina; Polyakov, Alexander; Erdos, Melinda; Pasic, Srdjan; Bataneant, Michaela; Szaflarska, Anna; Mironska, Kristina; Richter, Darko; Stavrik, Katarina; Avcin, Tadej; Márton, Gabriella; Nagy, Kálmán; Dérfalvi, Beáta; Szolnoky, Miklós; Kalmár, Agnes; Belevtsev, Michael; Guseva, Marina; Rugina, Aurica; Kriván, Gergely; Timár, László; Nyul, Zoltán; Mosdósi, Bernadett; Kareva, Lidija; Peova, Sonja; Chernyshova, Liudmyla; Gherghina, Ioan; Serban, Margit; Conley, Mary Ellen; Notarangelo, Luigi D; Smith, C I Edvard; van Dongen, Jacques; van der Burg, Mirjam; Maródi, László

2009-06-01

Primary immunodeficiency disorders are a recognized public health problem worldwide. The prototype of these conditions is X-linked agammaglobulinemia (XLA) or Bruton's disease. XLA is caused by mutations in Bruton's tyrosine kinase gene (BTK), preventing B cell development and resulting in the almost total absence of serum immunoglobulins. The genetic profile and prevalence of XLA have not previously been studied in Eastern and Central European (ECE) countries. We studied the genetic and demographic features of XLA in Belarus, Croatia Hungary, Poland, Republic of Macedonia, Romania, Russia, Serbia, Slovenia, and Ukraine. We collected clinical, immunological, and genetic information for 122 patients from 109 families. The BTK gene was sequenced from the genomic DNA of patients with a high susceptibility to infection, almost no CD19(+) peripheral blood B cells, and low or undetectable levels of serum immunoglobulins M, G, and A, compatible with a clinical and immunological diagnosis of XLA. BTK sequence analysis revealed 98 different mutations, 46 of which are reported for the first time here. The mutations included single nucleotide changes in the coding exons (35 missense and 17 nonsense), 23 splicing defects, 13 small deletions, 7 large deletions, and 3 insertions. The mutations were scattered throughout the BTK gene and most frequently concerned the SH1 domain; no missense mutation was detected in the SH3 domain. The prevalence of XLA in ECE countries (total population 145,530,870) was found to be 1 per 1,399,000 individuals. This report provides the first comprehensive overview of the molecular genetic and demographic features of XLA in Eastern and Central Europe.

Antibody response against Betaferon® in immune tolerant mice: involvement of marginal zone B-cells and CD4+ T-cells and apparent lack of immunological memory.

PubMed

Sauerborn, Melody; van Beers, Miranda M C; Jiskoot, Wim; Kijanka, Grzegorz M; Boon, Louis; Schellekens, Huub; Brinks, Vera

2013-01-01

The immunological processes underlying immunogenicity of recombinant human therapeutics are poorly understood. Using an immune tolerant mouse model we previously demonstrated that aggregates are a major trigger of the antidrug antibody (ADA) response against recombinant human interferon beta (rhIFNβ) products including Betaferon®, and that immunological memory seems to be lacking after a rechallenge with non-aggregated rhIFNβ. The apparent absence of immunological memory indicates a CD4+ T-cell independent (Tind) immune response underlying ADA formation against Betaferon®. This hypothesis was tested. Using the immune tolerant mouse model we first validated that rechallenge with highly aggregated rhIFNβ (Betaferon®) does not lead to a subsequent fast increase in ADA titers, suggesting a lack of immunological memory. Next we assessed whether Betaferon® could act as Tind antigen by inactivation of marginal zone (MZ) B-cells during treatment. MZ B-cells are major effector cells involved in a Tind immune response. In a following experiment we depleted the mice from CD4+ T-cells to test their involvement in the ADA response against Betaferon®. Inactivation of MZ B-cells at the start of Betaferon® treatment drastically lowered ADA levels, suggesting a Tind immune response. However, persistent depletion of CD4+ T-cells before and during Betaferon® treatment abolished the ADA response in almost all mice. The immune response against rhIFNβ in immune tolerant mice is neither a T-cell independent nor a classical T-cell dependent immune response. Further studies are needed to confirm absence of immunological memory (cells).

Postdoctoral Fellow | Center for Cancer Research

Cancer.gov

Highly motivated postdoctoral fellows sought to work on tumor immunology with a strong background in biology preferentially cellular immunology. The tumor immunology group in the laboratory is exploring mechanisms of improving vaccines and immunotherapy for cancer, especially by discovering new principles to enhance and steer T cell immune responses. The group is focusing on negative immunoregulatory mechanisms used for immune evasion by cancer cells. The postdoctoral fellow will work on a project to understand the negative regulatory mechanisms of tumor immunity especially the mechanisms initiated by NKT cells. Group members also have an opportunity to gain knowledge of HIV/mucosal immunology by interacting with the HIV research group in the lab.

Desensitization for solid organ and hematopoietic stem cell transplantation

PubMed Central

Zachary, Andrea A; Leffell, Mary S

2014-01-01

Desensitization protocols are being used worldwide to enable kidney transplantation across immunologic barriers, i.e. antibody to donor HLA or ABO antigens, which were once thought to be absolute contraindications to transplantation. Desensitization protocols are also being applied to permit transplantation of HLA mismatched hematopoietic stem cells to patients with antibody to donor HLA, to enhance the opportunity for transplantation of non-renal organs, and to treat antibody-mediated rejection. Although desensitization for organ transplantation carries an increased risk of antibody-mediated rejection, ultimately these transplants extend and enhance the quality of life for solid organ recipients, and desensitization that permits transplantation of hematopoietic stem cells is life saving for patients with limited donor options. Complex patient factors and variability in treatment protocols have made it difficult to identify, precisely, the mechanisms underlying the downregulation of donor-specific antibodies. The mechanisms underlying desensitization may differ among the various protocols in use, although there are likely to be some common features. However, it is likely that desensitization achieves a sort of immune detente by first reducing the immunologic barrier and then by creating an environment in which an autoregulatory process restricts the immune response to the allograft. PMID:24517434

Stem Cell Niche, the Microenvironment and Immunological Crosstalk

PubMed Central

Sujata, Law; Chaudhuri, S

2008-01-01

The concept of stem cells, their physiological existence, the intricate anatomical localization, the known and the unknown functions, and their exclusive utility for the purpose of regenerative medicine, are all now encompassed within an emergent question, ‘how compatible these cells are immunologically?' Indeed, the medical aspects of stem cells are dependent on a large number of queries based on the basic properties of the cells. It has greatly been emphasized to probe into the basic research on stem cells before any successful therapeutic attempts are made. One of the intricate aspects of the adult stem cells is its immunological behavior in relation to the microenvironmental associates, the stromal cells in the presence of a suitable target. PMID:18445340

Stem cell niche, the microenvironment and immunological crosstalk.

PubMed

Sujata, Law; Chaudhuri, S

2008-04-01

The concept of stem cells, their physiological existence, the intricate anatomical localization, the known and the unknown functions, and their exclusive utility for the purpose of regenerative medicine, are all now encompassed within an emergent question, 'how compatible these cells are immunologically?' Indeed, the medical aspects of stem cells are dependent on a large number of queries based on the basic properties of the cells. It has greatly been emphasized to probe into the basic research on stem cells before any successful therapeutic attempts are made. One of the intricate aspects of the adult stem cells is its immunological behavior in relation to the microenvironmental associates, the stromal cells in the presence of a suitable target.

Perfluorocarbon Particle Size Influences Magnetic Resonance Signal and Immunological Properties of Dendritic Cells

PubMed Central

Waiczies, Helmar; Lepore, Stefano; Janitzek, Nicole; Hagen, Ulrike; Seifert, Frank; Ittermann, Bernd; Purfürst, Bettina; Pezzutto, Antonio; Paul, Friedemann; Niendorf, Thoralf; Waiczies, Sonia

2011-01-01

The development of cellular tracking by fluorine (19F) magnetic resonance imaging (MRI) has introduced a number of advantages for following immune cell therapies in vivo. These include improved signal selectivity and a possibility to correlate cells labeled with fluorine-rich particles with conventional anatomic proton (1H) imaging. While the optimization of the cellular labeling method is clearly important, the impact of labeling on cellular dynamics should be kept in mind. We show by 19F MR spectroscopy (MRS) that the efficiency in labeling cells of the murine immune system (dendritic cells) by perfluoro-15-crown-5-ether (PFCE) particles increases with increasing particle size (560>365>245>130 nm). Dendritic cells (DC) are professional antigen presenting cells and with respect to impact of PFCE particles on DC function, we observed that markers of maturation for these cells (CD80, CD86) were also significantly elevated following labeling with larger PFCE particles (560 nm). When labeled with these larger particles that also gave an optimal signal in MRS, DC presented whole antigen more robustly to CD8+ T cells than control cells. Our data suggest that increasing particle size is one important feature for optimizing cell labeling by PFCE particles, but may also present possible pitfalls such as alteration of the immunological status of these cells. Therefore depending on the clinical scenario in which the 19F-labeled cellular vaccines will be applied (cancer, autoimmune disease, transplantation), it will be interesting to monitor the fate of these cells in vivo in the relevant preclinical mouse models. PMID:21811551

Dissecting the human immunologic memory for pathogens.

PubMed

Zielinski, Christina E; Corti, Davide; Mele, Federico; Pinto, Dora; Lanzavecchia, Antonio; Sallusto, Federica

2011-03-01

Studies on immunologic memory in animal models and especially in the human system are instrumental to identify mechanisms and correlates of protection necessary for vaccine development. In this article, we provide an overview of the cellular basis of immunologic memory. We also describe experimental approaches based on high throughput cell cultures, which we have developed to interrogate human memory T cells, B cells, and plasma cells. We discuss how these approaches can provide new tools and information for vaccine design, in a process that we define as 'analytic vaccinology'. © 2011 John Wiley & Sons A/S.

T cell-B cell interactions in primary immunodeficiencies.

PubMed

Tangye, Stuart G; Deenick, Elissa K; Palendira, Umaimainthan; Ma, Cindy S

2012-02-01

Regulated interactions between cells of the immune system facilitate the generation of successful immune responses, thereby enabling efficient neutralization and clearance of pathogens and the establishment of both cell- and humoral-mediated immunological memory. The corollary of this is that impediments to efficient cell-cell interactions, normally necessary for differentiation and effector functions of immune cells, underly the clinical features and disease pathogenesis of primary immunodeficiencies. In affected individuals, these defects manifest as impaired long-term humoral immunity and susceptibility to infection by specific pathogens. In this review, we discuss the importance of, and requirements for, effective interactions between B cells and T cells during the formation of CD4(+) T follicular helper cells and the elicitation of cytotoxic function of virus-specific CD8(+) T cells, as well as how these processes are abrogated in primary immunodeficiencies due to loss-of-function mutations in defined genes. © 2012 New York Academy of Sciences.

Actin polymerization‐dependent activation of Cas‐L promotes immunological synapse stability

PubMed Central

Santos, Luís C; Blair, David A; Kumari, Sudha; Cammer, Michael; Iskratsch, Thomas; Herbin, Olivier; Alexandropoulos, Konstantina

2016-01-01

The immunological synapse formed between a T‐cell and an antigen‐presenting cell is important for cell–cell communication during T‐cell‐mediated immune responses. Immunological synapse formation begins with stimulation of the T‐cell receptor (TCR). TCR microclusters are assembled and transported to the center of the immunological synapse in an actin polymerization‐dependent process. However, the physical link between TCR and actin remains elusive. Here we show that lymphocyte‐specific Crk‐associated substrate (Cas‐L), a member of a force sensing protein family, is required for transport of TCR microclusters and for establishing synapse stability. We found that Cas‐L is phosphorylated at TCR microclusters in an actin polymerization‐dependent fashion. Furthermore, Cas‐L participates in a positive feedback loop leading to amplification of Ca2+ signaling, inside–out integrin activation, and actomyosin contraction. We propose a new role for Cas‐L in T‐cell activation as a mechanical transducer linking TCR microclusters to the underlying actin network and coordinating multiple actin‐dependent structures in the immunological synapse. Our studies highlight the importance of mechanotransduction processes in T‐cell‐mediated immune responses. PMID:27359298

Integration of immunological aspects in the European Human Embryonic Stem Cell Registry.

PubMed

Borstlap, Joeri; Kurtz, Andreas

2008-05-01

The immunological properties of stem cells are of increasing importance in regenerative medicine. Immunomodulatory mechanisms seem to play an important role not only with respect to the understanding of underlying mechanisms of autologous versus allogenic therapeutic approaches, but also for endogeneous tissue regeneration. The newly established European human embryonic stem cell registry (hESCreg) offers an international database for the registration, documentation and characterisation of human embryonic stem cells (hESC) and their use. By doing so, hESCreg aims to develop a model procedure for further standardisation efforts in the field of stem cell research and regenerative medicine, and eventually the registry may lead to a repository of therapy-related information. Currently the stem cell characterisation data acquired by the registry are divided into several categories such as cell derivation, culture conditions, genetic constitution, stem cell marker expression and degree of modification. This article describes immunological aspects of stem cell characterisation and explores the layout and relevance of a possible additional section to the hESCreg repository to include immunological characteristics of human embryonic stem cells.

Design of three-component vaccines against group A streptococcal infections: importance of spatial arrangement of vaccine components.

PubMed

Abdel-Aal, Abu-Baker M; Zaman, Mehfuz; Fujita, Yoshio; Batzloff, Michael R; Good, Michael F; Toth, Istvan

2010-11-25

Immunological assessment of group A streptococcal (GAS) branched lipopeptides demonstrated the impact of spatial arrangement of vaccine components on both the quality and quantity of their immune responses. Each lipopeptide was composed of three components: a GAS B-cell epitope (J14), a universal CD4(+) T-cell helper epitope (P25), and an immunostimulant lipid moiety that differs only in its spatial arrangement. The best systemic immune responses were demonstrated by a lipopeptide featuring the lipid moiety at the lipopeptide C-terminus. However, this candidate did not achieve protection against bacterial challenge. The best protection (100%) was shown by a lipopeptide featuring a C-terminal J14, conjugated through a lysine residue to P25 at the N-terminus, and a lipid moiety on the lysine side chain. The former candidate features α-helical conformation required to produce protective J14-specific antibodies. Our results highlight the importance of epitope orientation and lipid position in the design of three-component synthetic vaccines.

Immunological Characterization of Intraocular Lymphoid Follicles in a Spontaneous Recurrent Uveitis Model.

PubMed

Kleinwort, Kristina J H; Amann, Barbara; Hauck, Stefanie M; Feederle, Regina; Sekundo, Walter; Deeg, Cornelia A

2016-08-01

Recently, formation of tertiary lymphoid structures was demonstrated and further characterized in the R161H mouse model of spontaneous autoimmune uveitis. In the horse model of spontaneous recurrent uveitis, intraocular lymphoid follicle formation is highly characteristic, and found in all stages and scores of disease, but in depth analyses of immunologic features of these structures are lacking to date. Paraffin-embedded eye sections of cases with equine spontaneous recurrent uveitis (ERU) were characterized with immunohistochemistry to gain insight into the distribution, localization, and signaling of immune cells in intraocular tertiary lymphoid tissues. Ectopic lymphoid tissues were located preferentially in the iris, ciliary body, and retina at the ora serrata of horses with naturally-occurring ERU. The majority of cells in the tertiary lymphoid follicles were T cells with a scattered distribution of B cells and PNA+ cells interspersed. A fraction of T cells was additionally positive for memory cell marker CD45RO. Almost all cells coexpressed CD166, a molecule associated with activation and transmigration of T cells into inflamed tissues. Several transcription factors that govern immune cell responses were detectable in the tertiary lymphoid follicles, among them Zap70, TFIIB, GATA3, and IRF4. A high expression of the phosphorylated signal transducers and activators of transcription (STAT) proteins 1 and 5 were found at the margin of the structures. Cellular composition and structural organization of these inflammation-associated tertiary lymphoid tissue structures and the expression of markers of matured T and B cells point to highly organized adaptive immune responses in these follicles in spontaneous recurrent uveitis.

21 CFR 866.5880 - Transferrin immunological test system.

Code of Federal Regulations, 2011 CFR

2011-04-01

... transferrin levels aids in the diagnosis of malnutrition, acute inflammation, infection, and red blood cell... Transferrin immunological test system. (a) Identification. A transferrin immunological test system is a device...

21 CFR 866.5880 - Transferrin immunological test system.

Code of Federal Regulations, 2013 CFR

2013-04-01

... transferrin levels aids in the diagnosis of malnutrition, acute inflammation, infection, and red blood cell... Transferrin immunological test system. (a) Identification. A transferrin immunological test system is a device...

21 CFR 866.5880 - Transferrin immunological test system.

Code of Federal Regulations, 2014 CFR

2014-04-01

... transferrin levels aids in the diagnosis of malnutrition, acute inflammation, infection, and red blood cell... Transferrin immunological test system. (a) Identification. A transferrin immunological test system is a device...

21 CFR 866.5880 - Transferrin immunological test system.

Code of Federal Regulations, 2012 CFR

2012-04-01

... transferrin levels aids in the diagnosis of malnutrition, acute inflammation, infection, and red blood cell... Transferrin immunological test system. (a) Identification. A transferrin immunological test system is a device...

[The distribution of B-lymphocytes in lymphoepithelial tissues as well as in tumors of the neck-, nose-, and throat region derived from lymphoreticular and lymphoepithelial tissues (author's transl)].

PubMed

Uhlmann, C; Krüger, G R; Sesterhenn, K; Wustrow, F; Fisher, R

1975-08-28

B-Lymphocytes carrying IgG-, IgM,- and IgA-surface receptors were estimated by fluorescence microscopy in the palatine tonsil of 50 patients aged 3 to 18 years as well as in 44 patients with various types of malignant lymphoms and lymphoepithelial carcinomas. Hyperplastic tonsillartissue contains large numbers of B-cells with a marked variability in concentration (4-30% IgG-cells, medium 12,9%;6-36 IgM-cells, medium 23.4%;3-38% IgA cells, medium 20.8%). There appears to exist an age-dependent increase in IgM-cells and an increase in IgG-and IgA-cells in patients with numerous recurrent infections of the upper respiratory tract. Malignant lymphomas can be grouped into three main categories: Such with a predominance of one B-cell line (above 75-80% of one immunological cell type); these include primarily malignant lymphomas of the well differentiated lymphocytic type (IgM and IgA receptors). Secondly, such with a significant decrease in B-cells (below 10%) which include primarily malignant lymphomas of the poorly differentiated lymphocytic type. Thirdly, such with an increased B-cell content but with more than one cell line participating in cell proliferation. The latter ones comprise certain cases of Hodkin's lymphomas. Lymphoepithial carcinomas are charactersized by a significant decrease in total B-cell content, except for IgE- and IgD-cells which were not investigated. The results show that the immunologic classification of malignant lymphomas correlates only to a certain degree with the morphologic classification; i.e. the same morphologic type of tumor may possess different immunologic characteristics. Since the immunologic characteristics may reflect a certain functional potential of these tumors as well as probably a certain kind of immunologic incompetence prior to tumor development, it is suggested, that future morphologic investigations of malignant lymphomas and lymphoepithelial carcinomas are combined with immunologic classifications.

Aging increases cell-to-cell transcriptional variability upon immune stimulation.

PubMed

Martinez-Jimenez, Celia Pilar; Eling, Nils; Chen, Hung-Chang; Vallejos, Catalina A; Kolodziejczyk, Aleksandra A; Connor, Frances; Stojic, Lovorka; Rayner, Timothy F; Stubbington, Michael J T; Teichmann, Sarah A; de la Roche, Maike; Marioni, John C; Odom, Duncan T

2017-03-31

Aging is characterized by progressive loss of physiological and cellular functions, but the molecular basis of this decline remains unclear. We explored how aging affects transcriptional dynamics using single-cell RNA sequencing of unstimulated and stimulated naïve and effector memory CD4 + T cells from young and old mice from two divergent species. In young animals, immunological activation drives a conserved transcriptomic switch, resulting in tightly controlled gene expression characterized by a strong up-regulation of a core activation program, coupled with a decrease in cell-to-cell variability. Aging perturbed the activation of this core program and increased expression heterogeneity across populations of cells in both species. These discoveries suggest that increased cell-to-cell transcriptional variability will be a hallmark feature of aging across most, if not all, mammalian tissues. Copyright © 2017, American Association for the Advancement of Science.

[Immunological background and pathomechanisms of food allergies].

PubMed

Schülke, Stefan; Scheurer, Stephan

2016-06-01

Recent advances in immunology have greatly improved our understanding of the pathomechanisms of food allergies. Food allergies are caused and maintained by complex interactions of the innate and adaptive immune system involving antigen-presenting cells (APC), T cells, group 2 innate lymphoid cells (ILC2), epithelial cells (EC) and effectors cells. Additionally, epigenetic factors, the intestinal microbiome and nutritional factors modulating the gastrointestinal lymphatic tissue probably have a significant impact on allergy development. However, why certain individuals develop tolerance while others mount allergic responses, the factors defining the allergenicity of food proteins, as well as the immunological mechanisms triggering allergy development have yet to be analyzed in detail.

Predictors of immunological failure of antiretroviral therapy among HIV infected patients in Ethiopia: a matched case-control study.

PubMed

Teshome, Wondu; Asefa, Anteneh; Assefa, Anteneh

2014-01-01

In resource constrained settings, immunological assessment through CD4 count is used to assess response to first line Highly Active Antiretroviral Therapy (HAART). In this study, we aim to investigate factors associated with immunological treatment failure. A matched case-control study design was used. Cases were subjects who already experienced immunological treatment failure and controls were those without immunological failure after an exactly or approximately equivalent duration of first line treatment with cases. Data were analyzed using SPSS v16.0. Conditional logistic regression was carried out. A total of 134 cases and 134 controls were included in the study. At baseline, the mean age ± 1 SD of cases was 37.5 ± 9.7 years whereas it was 36.9 ± 9.2 years among controls. The median baseline CD4 counts of cases and controls were 121.0 cells/µl (IQR: 47-183 cells/µl) and 122.0 cells/µl (IQR: 80.0-189.8 cells/µl), respectively. The median rate of CD4 cells increase was comparable for the two groups in the first six months of commencing HAART (P = 0.442). However, the median rate of CD4 increase was significantly different for the two groups in the next 6 months period (M6 to M12). The rate of increment was 8.8 (IQR: 0.5, 14.6) and 1.8 (IQR: 8.8, 11.3) cells/µl/month for controls and cases, respectively (Mann-Whitney U test, P = 0.003). In conditional logistic regressions grouped baseline CD4 count (P = 0.028), old age group and higher educational status (P<0.001) were significant predictors of immunological treatment failure. Subjects with immunological treatment failure have an optimal rate of immunological recovery in the first 6 months of treatment with first line HAART, but relative to the non-failing group the rate declines at a later period, notably between 6 and 12 months. Low baseline CD4 count, old age and higher educational status were associated with immunological treatment failure.

Long survival and immunologic reconstitution following transplantation with syngeneic or allogeneic fetal liver and neonatal spleen cells. [X radiation, mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yunis, E.J.; Fernandes, G.; Smith, J.

1976-12-01

Spleen cells from newborn syngeneic and allogeneic mice that lack fully differentiated T lymphocytes can be used as a hematopoietic source to reconstitute both hematopoietic and lymphoid systems of lethally irradiated mice without producing a GVHR. Fetal liver cells from syngeneic and allogeneic mice that lack postthymic T lymphocytes can also be used for hematopoietic and immunologic reconstitution of lethally irradiated mice without producing GVHR. Immunologic deficiency is observed in some experiments in mice given supralethal irradiation (1000 R) and fetal liver as reconstituting hematopoietic tissue. The findings suggest that T cells, at an early stage of differentiation, are moremore » susceptible to tolerance induction than are T lymphocytes at later stages of differentiation and do not, in general, produce GVHR. It is postulated that hematopoietic cells, free of postthymic lymphoid cells, can be used for hematopoietic or immunologic reconstitution and celular engineering without producing GVHD.« less

Phosphatidylserine externalization, “necroptotic bodies” release, and phagocytosis during necroptosis

PubMed Central

Erlich, Ziv; Hourizadeh, Aria; Ofir-Birin, Yifat; Croker, Ben A.; Regev-Rudzki, Neta; Edry-Botzer, Liat

2017-01-01

Necroptosis is a regulated, nonapoptotic form of cell death initiated by receptor-interacting protein kinase-3 (RIPK3) and mixed lineage kinase domain-like (MLKL) proteins. It is considered to be a form of regulated necrosis, and, by lacking the “find me” and “eat me” signals that are a feature of apoptosis, necroptosis is considered to be inflammatory. One such “eat me” signal observed during apoptosis is the exposure of phosphatidylserine (PS) on the outer plasma membrane. Here, we demonstrate that necroptotic cells also expose PS after phosphorylated mixed lineage kinase-like (pMLKL) translocation to the membrane. Necroptotic cells that expose PS release extracellular vesicles containing proteins and pMLKL to their surroundings. Furthermore, inhibition of pMLKL after PS exposure can reverse the process of necroptosis and restore cell viability. Finally, externalization of PS by necroptotic cells drives recognition and phagocytosis, and this may limit the inflammatory response to this nonapoptotic form of cell death. The exposure of PS to the outer membrane and to extracellular vesicles is therefore a feature of necroptotic cell death and may serve to provide an immunologically-silent window by generating specific “find me” and “eat me” signals. PMID:28650960

Anti-tumor response with immunologically modified carbon nanotubes and phototherapy

NASA Astrophysics Data System (ADS)

Acquaviva, Joseph T.; Zhou, Feifan; Boarman, Ellen; Chen, Wei R.

2013-02-01

While successes of different cancer therapies have been achieved in various degrees a systemic immune response is needed to effectively treat late-stage, metastatic cancers, and to establish long-term tumor resistance in the patients. A novel method for combating metastatic cancers has been developed using immunologically modified carbon nanotubes in conjunction with phototherapy. Glycated chitosan (GC) is a potent immunological adjuvant capable of increasing host immune responses, including antigen presentation by activation of dendritic cells (DCs) and causing T cell proliferation. GC is also an effective surfactant for nanomaterials. By combining single-walled carbon nanotubes (SWNTs) and GC, immunologically modified carbon nanotubes (SWNT-GC) were constructed. The SWNT-GC suspension retains the enhanced light absorption properties in the near infrared (NIR) region and the ability to enter cells, which are characteristic of SWNTs. The SWNT-GC also retains the immunological properties of GC. Cellular SWNT-GC treatments increased macrophage activity, DC activation and T cell proliferation. When cellular SWNT-GC was irradiated with a laser of an appropriate wavelength, these immune activities could be enhanced. The combination of laser irradiation and SWNT-GC induced cellular toxicity in targeted tumor cells, leading to a systemic antitumor response. Immunologically modified carbon nanotubes in conjunction with phototherapy is a novel and promising method to produce a systemic immune response for the treatment of metastatic cancers.

Cancer immunotherapy and immunological memory.

PubMed

Murata, Kenji; Tsukahara, Tomohide; Torigoe, Toshihiko

2016-01-01

Human immunological memory is the key distinguishing hallmark of the adaptive immune system and plays an important role in the prevention of morbidity and the severity of infection. The differentiation system of T cell memory has been clarified using mouse models. However, the human T cell memory system has great diversity induced by natural antigens derived from many pathogens and tumor cells throughout life, and profoundly differs from the mouse memory system constructed using artificial antigens and transgenic T cells. We believe that only human studies can elucidate the human immune system. The importance of immunological memory in cancer immunotherapy has been pointed out, and the trafficking properties and long-lasting anti-tumor capacity of memory T cells play a crucial role in the control of malignant tumors. Adoptive cell transfer of less differentiated T cells has consistently demonstrated superior anti-tumor capacity relative to more differentiated T cells. Therefore, a human T cell population with the characteristics of stem cell memory is thought to be attractive for peptide vaccination and adoptive cell transfer. A novel human memory T cell population that we have identified is closer to the naive state than previous memory T cells in the T cell differentiation lineage, and has the characteristics of stem-like chemoresistance. Here we introduce this novel population and describe the fundamentals of immunological memory in cancer immunotherapy.

Effects of lead shot ingestion on selected cells of the mallard immune system

USGS Publications Warehouse

Rocke, T.E.; Samuel, M.D.

1991-01-01

The immunologic effects of lead were measured in game-farm mallards (Anas platyrhynchos) that ingested lead shot while foraging naturally, mallards intubated with lead shot, and unexposed controls. Circulating white blood cells (WBC) declined significantly in male mallards exposed to lead by either natural ingestion or intubation, but not females. Spleen plaque-forming cell (SPFC) counts were significantly lower in mallards intubated with lead pellets compared to controls. Declines in WBC and SPFC means with increasing tissue lead concentrations provide further evidence that lead exposure reduced immunologic cell numbers. Hormonal activity and diet may have influenced the immunologic effects of lead exposure in this study.

A CD4+ cell count <200 cells per cubic millimeter at 2 years after initiation of combination antiretroviral therapy is associated with increased mortality in HIV-infected individuals with viral suppression.

PubMed

Loutfy, Mona R; Genebat, Miguel; Moore, David; Raboud, Janet; Chan, Keith; Antoniou, Tony; Milan, David; Shen, Anya; Klein, Marina B; Cooper, Curtis; Machouf, Nima; Rourke, Sean B; Rachlis, Anita; Tsoukas, Chris; Montaner, Julio S G; Walmsley, Sharon L; Smieja, Marek; Bayoumi, Ahmed; Mills, Edward; Hogg, Robert S

2010-12-01

To determine the long-term impact of immunologic discordance (viral load <50 copies/mL and CD4+ count <=200 cells/mm3) in antiretroviral-naive patients initiating combination antiretroviral therapy (cART). Our analysis included antiretroviral-naive individuals from a population-based Canadian Observational Cohort that initiated cART after January 1, 2000, and achieved virologic suppression. Multivariable Cox proportional hazards regression was used to examine the association between 1-year and 2-year immunologic discordance and time to death from all-causes. Correlates of immunologic discordance were assessed with logistic regression. Immunologic discordance was observed in 19.9% (404 of 2028) and 10.2% (176 of 1721) of individuals at 1 and 2 years after cART initiation, respectively. Two-year immunologic discordance was associated with an increased risk of death [adjusted hazard ratio = 2.69; 95% confidence interval (CI): 1.26 to 5.78]. One-year immunologic discordance was not associated with death (adjusted hazard ratio = 1.12; 95% CI: 0.54 to 2.30). Two-year immunologic discordance was associated with older age (aOR per decade = 1.23; 95% CI: 1.03 to 1.48), male gender (aOR = 1.86; 95% CI: 1.09 to 3.16), injection drug use (aOR = 2.75; 95% CI: 1.81 to 4.17), and lower baseline CD4+ count (aOR per 100 cells = 0.24; 95% CI: 0.19 to 0.31) and viral load (aOR per log10 copies/mL = 0.46; 95% CI: 0.33 to 0.65). Immunologic discordance after 2 years of cART in antiretroviral-naive individuals was significantly associated with an increased risk of mortality.

Differential Activation of Human Monocytes and Lymphocytes by Distinct Strains of Trypanosoma cruzi.

PubMed

Magalhães, Luísa M D; Viana, Agostinho; Chiari, Egler; Galvão, Lúcia M C; Gollob, Kenneth J; Dutra, Walderez O

2015-01-01

Trypanosoma cruzi strains are currently classified into six discrete typing units (DTUs) named TcI to VI. It is known that these DTUs have different geographical distribution, as well as biological features. TcI and TcII are major DTUs found in patients from northern and southern Latin America, respectively. Our hypothesis is that upon infection of human peripheral blood cells, Y strain (Tc II) and Col cl1.7 (Tc I), cause distinct immunological changes, which might influence the clinical course of Chagas disease. We evaluated the infectivity of CFSE-stained trypomastigotes of Col cl1.7 and Y strain in human monocytes for 15 and 72 hours, and determined the immunological profile of lymphocytes and monocytes exposed to the different isolates using multiparameter flow cytometry. Our results showed a similar percentage and intensity of monocyte infection by Y and Col cl1.7. We also observed an increased expression of CD80 and CD86 by monocytes infected with Col cl1.7, but not Y strain. IL-10 was significantly higher in monocytes infected with Col cl1.7, as compared to Y strain. Moreover, infection with Col cl1.7, but not Y strain, led to an increased expression of IL-17 by CD8+ T cells. On the other hand, we observed a positive correlation between the expression of TNF-alpha and granzyme A only after infection with Y strain. Our study shows that while Col cl1.7 induces higher monocyte activation and, at the same time, production of IL-10, infection with Y strain leads to a lower monocyte activation but higher inflammatory profile. These results show that TcI and TcII have a distinct immunological impact on human cells during early infection, which might influence disease progression.

Anergic CD4+ T cells form mature immunological synapses with enhanced accumulation of c-Cbl and Cbl-b1

PubMed Central

Doherty, Melissa; Osborne, Douglas G.; Browning, Diana L.; Parker, David C.; Wetzel, Scott A.

2010-01-01

CD4+ T cell recognition of MHC:peptide complexes in the context of a costimulatory signal results in the large-scale redistribution of molecules at the T-APC interface to form the immunological synapse. The immunological synapse is the location of sustained TCR signaling and delivery of a subset of effector functions. T cells activated in the absence of costimulation are rendered anergic and are hyporesponsive when presented with antigen in the presence of optimal costimulation. Several previous studies have looked at aspects of immunological synapses formed by anergic T cells, but it remains unclear whether there are differences in the formation or composition of anergic immunological synapses. In this study we anergized primary murine CD4+ T cells by incubation of costimulation-deficient, transfected fibroblast APC. Using a combination of TCR, MHC:peptide, and ICAM-1 staining, we found that anergic T cells make mature immunological synapses with characteristic cSMAC and pSMAC domains that were indistinguishable from control synapses. There were small increases in total phosphotyrosine at the anergic synapse along with significant decreases in phosphorylated ERK 1/2 accumulation. Most striking, there was specific accumulation of c-Cbl and Cbl-b to the anergic synapses. Cbl-b, previously shown to be essential in anergy induction, was found in both the pSMAC and the cSMAC of the anergic synapse. This Cbl-b (and c-Cbl) accumulation at the anergic synapse may play an important role in anergy maintenance and/or induction. PMID:20207996

Search for biomarkers of asbestos exposure and asbestos-induced cancers in investigations of the immunological effects of asbestos.

PubMed

Matsuzaki, Hidenori; Kumagai-Takei, Naoko; Lee, Suni; Maeda, Megumi; Sada, Nagisa; Hatayama, Tamayo; Yamamoto, Shoko; Ikeda, Miho; Yoshitome, Kei; Min, Yu; Nishimura, Yasumitsu; Otsuki, Takemi

2017-06-09

The immunological effects of asbestos exposure on various lymphocytes such as the regulatory T cell (Treg), responder CD4+ T helper cell (Tresp), CD8+ cytotoxic T lymphocytes (CTL), and natural killer (NK) cells were investigated. Results show that asbestos exposure impairs antitumor immunity through enhancement of regulatory T cell function and volume, reduction of CXCR3 chemokine receptor in responder CD4+ T helper cells, and impairment of the killing activities of CD8+ cytotoxic T lymphocytes (CTL) and NK cells. These findings were used to explore biological markers associated with asbestos exposure and asbestos-induced cancers and suggested the usefulness of serum/plasma IL-10 and TGF-β, surface CXCR3 expression in Tresp, the secreting potential of IFN-γ in Tresp, intracellular perforin level in CTL, and surface expression NKp46 in NK cells. Although other unexplored cytokines in serum/plasma and molecules in these immunological cells, including Th17, should be investigated by experimental procedures in addition to a comprehensive analysis of screening methods, biomarkers based on immunological alterations may be helpful in clinical situations to screen the high-risk population exposed to asbestos and susceptible to asbestos-related cancers such as mesothelioma.

Cytokines profile and peripheral blood mononuclear cells morphology in Rett and autistic patients.

PubMed

Pecorelli, Alessandra; Cervellati, Franco; Belmonte, Giuseppe; Montagner, Giulia; Waldon, PhiAnh; Hayek, Joussef; Gambari, Roberto; Valacchi, Giuseppe

2016-01-01

A potential role for immune dysfunction in autism spectrum disorders (ASD) has been well established. However, immunological features of Rett syndrome (RTT), a genetic neurodevelopmental disorder closely related to autism, have not been well addressed yet. By using multiplex Luminex technology, a panel of 27 cytokines and chemokines was evaluated in serum from 10 RTT patients with confirmed diagnosis of MECP2 mutation (typical RTT), 12 children affected by classic autistic disorder and 8 control subjects. The cytokine/chemokine gene expression was assessed by real time PCR on mRNA of isolated peripheral blood mononuclear cells (PBMCs). Moreover, ultrastructural analysis of PBMCs was performed using transmission electron microscopy (TEM). Significantly higher serum levels of interleukin-8 (IL-8), IL-9, IL-13 were detected in RTT compared to control subjects, and IL-15 shows a trend toward the upregulation in RTT. In addition, IL-1β and VEGF were the only down-regulated cytokines in autistic patients with respect to RTT. No difference in cytokine/chemokine profile between autistic and control groups was detected. These data were also confirmed by ELISA real time PCR. At the ultrastructural level, the most severe morphological abnormalities were observed in mitochondria of both RTT and autistic PBMCs. In conclusion, our study shows a deregulated cytokine/chemokine profile together with morphologically altered immune cells in RTT. Such abnormalities were not quite as evident in autistic subjects. These findings indicate a possible role of immune dysfunction in RTT making the clinical features of this pathology related also to the immunology aspects, suggesting, therefore, novel possible therapeutic interventions for this disorder. Copyright © 2015 Elsevier Ltd. All rights reserved.

Immunological compatibility status of placenta-derived stem cells is mediated by scaffold 3D structure.

PubMed

Azizian, Sara; Khatami, Fatemeh; Modaresifar, Khashayar; Mosaffa, Nariman; Peirovi, Habibollah; Tayebi, Lobat; Bahrami, Soheyl; Redl, Heinz; Niknejad, Hassan

2018-02-23

Placenta-derived amniotic epithelial cells (AECs), a great cell source for tissue engineering and stem cell therapy, are immunologically inert in their native state; however, immunological changes in these cells after culture and differentiation have challenged their applications. The aim of this study was to investigate the effect of 2D and 3D scaffolds on human lymphocyte antigens (HLA) expression by AECs. The effect of different preparation parameters including pre-freezing time and temperature was evaluated on 3D chitosan-gelatine scaffolds properties. Evaluation of MHC class I, HLA-DR and HLA-G expression in AECs after 7 d culture on 2D bed and 3D scaffold of chitosan-gelatine showed that culture of AECs on the 2D substrate up-regulated MHC class I and HLA-DR protein markers on AECs surface and down-regulated HLA-G protein. In contrast, 3D scaffold did not increase protein expression of MHC class I and HLA-DR. Moreover, HLA-G protein expression remained unchanged in 3D culture. These results confirm that 3D scaffold can remain AECs in their native immunological state and modification of physical properties of the scaffold is a key regulator of immunological markers at the gene and protein expression levels; a strategy which circumvents rejection challenge of amniotic stem cells to be translated into the clinic.

Immunological implications of pregnancy-induced microchimerism

PubMed Central

Kinder, Jeremy M.; Stelzer, Ina A.; Arck, Petra C.; Way, Sing Sing

2017-01-01

Immunological identity is traditionally defined by genetically encoded antigens, with equal maternal and paternal contributions as a result of Mendelian inheritance. However, vertically transferred maternal cells also persist in individuals at very low levels throughout postnatal development. Reciprocally, mothers are seeded during pregnancy with genetically foreign fetal cells that persist long after parturition. Recent findings suggest that these microchimeric cells expressing noninherited familially relevant antigenic traits are not accidental souvenirs of pregnancy, but are purposefully retained within mothers and their offspring to promote genetic fitness by improving the outcome of future pregnancies. Here, we discuss the immunological implications, benefits and potential consequences of individuals being constitutively chimeric with a biologically active ‘microchiome’ of genetically foreign cells. PMID:28480895

[Quantitative variations of lymphocyte subsets in various kinds of cancer patients in the terminal stage].

PubMed

Nakajima, Y; Akimoto, M; Iwasaki, H; Matano, S; Hirakawa, H; Kimura, M

1986-12-01

Immunological studies of the peripheral blood were made in terminal breast cancer and terminal abdominal cancer patients. Two immunological parameters were studied: (1) lymphocyte subsets and (2) proliferative response to PHA. A decrease in the number of OKT-3(+) cells and an increase in that of OKT-8(+) cells were observed in abdominal cancer. It was suggested that the immunological status in abdominal cancer is more suppressive than in breast cancer. Increases in the number of OK-M1(+) cells and Leu-7(+) cells were observed in breast cancer. It is suggested that cytotoxic lymphocytes increase in number in breast cancer more than in abdominal cancer.

Practical immunology

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hudson, L.; Hay, F.C.

1989-01-01

This book covers the advances in contemporary molecular and cellular immunology which have provided the experimentalist with tools of unparalleled reproducibility and precision. Techniques for the propagation and manipulation of cells, genes and gene products have a central place in the new edition, reflecting their role in modern immunology.

Heterogeneity of colon cancer: from bench to bedside

PubMed Central

Merlano, Marco C; Granetto, Cristina; Fea, Elena; Ricci, Vincenzo; Garrone, Ornella

2017-01-01

The large bowel shows biomolecular, anatomical and bacterial changes that proceed from the proximal to the distal tract. These changes account for the different behaviour of colon cancers arising from the diverse sides of the colon–rectum as well as for the sensitivity to the therapy, including immunotherapy. The gut microbiota plays an important role in the modulation of the immune response and differs between the right colon cancer and the left colorectal cancer. The qualitative and quantitative difference of the commensal bacteria between the right side and the left side induces epigenetic changes in the intestinal epithelial cells as well as in the resident immune population. The second player in the pathological homeostasis of colorectal cancer is the differences of the genetic features of cancer cells and the different effects that microsatellite instability, chromosomal instability and the CpG island methylator phenotype induce on the immunological organisation of the tumour microenvironment. The third player is the immunological composition of the tumour microenvironment, which changes under the influence of both genetic structures and gut microbiota. All these three players influence each other. This review describes these three aspects, highlights their interactions and discusses data from reported clinical trials. Click here to listen to the Podcast PMID:29209524

Comparative immunogenomics of molluscs.

PubMed

Schultz, Jonathan H; Adema, Coen M

2017-10-01

Comparative immunology, studying both vertebrates and invertebrates, provided the earliest descriptions of phagocytosis as a general immune mechanism. However, the large scale of animal diversity challenges all-inclusive investigations and the field of immunology has developed by mostly emphasizing study of a few vertebrate species. In addressing the lack of comprehensive understanding of animal immunity, especially that of invertebrates, comparative immunology helps toward management of invertebrates that are food sources, agricultural pests, pathogens, or transmit diseases, and helps interpret the evolution of animal immunity. Initial studies showed that the Mollusca (second largest animal phylum), and invertebrates in general, possess innate defenses but lack the lymphocytic immune system that characterizes vertebrate immunology. Recognizing the reality of both common and taxon-specific immune features, and applying up-to-date cell and molecular research capabilities, in-depth studies of a select number of bivalve and gastropod species continue to reveal novel aspects of molluscan immunity. The genomics era heralded a new stage of comparative immunology; large-scale efforts yielded an initial set of full molluscan genome sequences that is available for analyses of full complements of immune genes and regulatory sequences. Next-generation sequencing (NGS), due to lower cost and effort required, allows individual researchers to generate large sequence datasets for growing numbers of molluscs. RNAseq provides expression profiles that enable discovery of immune genes and genome sequences reveal distribution and diversity of immune factors across molluscan phylogeny. Although computational de novo sequence assembly will benefit from continued development and automated annotation may require some experimental validation, NGS is a powerful tool for comparative immunology, especially increasing coverage of the extensive molluscan diversity. To date, immunogenomics revealed new levels of complexity of molluscan defense by indicating sequence heterogeneity in individual snails and bivalves, and members of expanded immune gene families are expressed differentially to generate pathogen-specific defense responses. Copyright © 2017 Elsevier Ltd. All rights reserved.

White matter microstructure alterations correlate with terminally differentiated CD8+ effector T cell depletion in the peripheral blood in mania: Combined DTI and immunological investigation in the different phases of bipolar disorder.

PubMed

Magioncalda, Paola; Martino, Matteo; Tardito, Samuele; Sterlini, Bruno; Conio, Benedetta; Marozzi, Valentina; Adavastro, Giulia; Capobianco, Laura; Russo, Daniel; Parodi, Alessia; Kalli, Francesca; Nasi, Giorgia; Altosole, Tiziana; Piaggio, Niccolò; Northoff, Georg; Fenoglio, Daniela; Inglese, Matilde; Filaci, Gilberto; Amore, Mario

2018-05-01

White matter (WM) microstructural abnormalities and, independently, signs of immunological activation were consistently demonstrated in bipolar disorder (BD). However, the relationship between WM and immunological alterations as well as their occurrence in the various phases of BD remain unclear. In 60 type I BD patients - 20 in manic, 20 in depressive, 20 in euthymic phases - and 20 controls we investigated: (i) diffusion tensor imaging (DTI)-derived fractional anisotropy (FA), radial diffusivity (RD) and axial diffusivity (AD) using a tract-based spatial statistics (TBSS) approach; (ii) circulating T cell subpopulations frequencies, as well as plasma levels of different cytokines; (iii) potential relationships between WM and immunological data. We found: (i) a significant widespread combined FA-RD alteration mainly in mania, with involvement of the body of corpus callosum (BCC) and superior corona radiata (SCR); (ii) significant increase in CD4+ T cells as well as significant decrease in CD8+ T cells and their subpopulations effector memory (CD8+ CD28-CD45RA-), terminal effector memory (CD8+ CD28-CD45RA+) and CD8+ IFNγ+ in mania; (iii) a significant relationship between WM and immunological alterations in the whole cohort, and a significant correlation of FA-RD abnormalities in the BCC and SCR with reduced frequencies of CD8+ terminal effector memory and CD8+ IFNγ+ T cells in mania only. Our data show a combined occurrence of WM and immunological alterations in mania. WM abnormalities highly correlated with reduction in circulating CD8+ T cell subpopulations that are terminally differentiated effector cells prone to tissue migration, suggesting that these T cells could play a role in WM alteration in BD. Copyright © 2018 Elsevier Inc. All rights reserved.

Selenium Pretreatment Alleviated LPS-Induced Immunological Stress Via Upregulation of Several Selenoprotein Encoding Genes in Murine RAW264.7 Cells.

PubMed

Wang, Longqiong; Jing, Jinzhong; Yan, Hui; Tang, Jiayong; Jia, Gang; Liu, Guangmang; Chen, Xiaoling; Tian, Gang; Cai, Jingyi; Shang, Haiying; Zhao, Hua

2018-04-18

This study was conducted to profile selenoprotein encoding genes in mouse RAW264.7 cells upon lipopolysaccharide (LPS) challenge and integrate their roles into immunological regulation in response to selenium (Se) pretreatment. LPS was used to develop immunological stress in macrophages. Cells were pretreated with different levels of Se (0, 0.5, 1.0, 1.5, 2.0 μmol Se/L) for 2 h, followed by LPS (100 ng/mL) stimulation for another 3 h. The mRNA expression of 24 selenoprotein encoding genes and 9 inflammation-related genes were investigated. The results showed that LPS (100 ng/mL) effectively induced immunological stress in RAW264.7 cells with induced inflammation cytokines, IL-6 and TNF-α, mRNA expression, and cellular secretion. LPS increased (P < 0.05) mRNA profiles of 9 inflammation-related genes in cells, while short-time Se pretreatment modestly reversed (P < 0.05) the LPS-induced upregulation of 7 genes (COX-2, ICAM-1, IL-1β, IL-6, IL-10, iNOS, and MCP-1) and further increased (P < 0.05) expression of IFN-β and TNF-α in stressed cells. Meanwhile, LPS decreased (P < 0.05) mRNA levels of 18 selenoprotein encoding genes and upregulated mRNA levels of TXNRD1 and TXNRD3 in cells. Se pretreatment recovered (P < 0.05) expression of 3 selenoprotein encoding genes (GPX1, SELENOH, and SELENOW) in a dose-dependent manner and increased (P < 0.05) expression of another 5 selenoprotein encoding genes (SELENOK, SELENOM, SELENOS, SELENOT, and TXNRD2) only at a high level (2.0 μmol Se/L). Taken together, LPS-induced immunological stress in RAW264.7 cells accompanied with the global downregulation of selenoprotein encoding genes and Se pretreatment alleviated immunological stress via upregulation of a subset of selenoprotein encoding genes.

Migration and Tissue Tropism of Innate Lymphoid Cells

PubMed Central

Kim, Chang H.; Hashimoto-Hill, Seika; Kim, Myunghoo

2016-01-01

Innate lymphoid cell (ILCs) subsets differentially populate various barrier and non-barrier tissues, where they play important roles in tissue homeostasis and tissue-specific responses to pathogen attack. Recent findings have provided insight into the molecular mechanisms that guide ILC migration into peripheral tissues, revealing common features among different ILC subsets as well as important distinctions. Recent studies have also highlighted the impact of tissue-specific cues on ILC migration, and the importance of the local immunological milieu. We review these findings here and discuss how the migratory patterns and tissue tropism of different ILC subsets relate to the development and differentiation of these cells, and to ILC-mediated tissue-specific regulation of innate and adaptive immune responses. In this context we outline open questions and important areas of future research. PMID:26708278

Antiretroviral therapy suppressed participants with low CD4+ T-cell counts segregate according to opposite immunological phenotypes

PubMed Central

Pérez-Santiago, Josué; Ouchi, Dan; Urrea, Victor; Carrillo, Jorge; Cabrera, Cecilia; Villà-Freixa, Jordi; Puig, Jordi; Paredes, Roger; Negredo, Eugènia; Clotet, Bonaventura; Massanella, Marta; Blanco, Julià

2016-01-01

Background: The failure to increase CD4+ T-cell counts in some antiretroviral therapy suppressed participants (immunodiscordance) has been related to perturbed CD4+ T-cell homeostasis and impacts clinical evolution. Methods: We evaluated different definitions of immunodiscordance based on CD4+ T-cell counts (cutoff) or CD4+ T-cell increases from nadir value (ΔCD4) using supervised random forest classification of 74 immunological and clinical variables from 196 antiretroviral therapy suppressed individuals. Unsupervised clustering was performed using relevant variables identified in the supervised approach from 191 individuals. Results: Cutoff definition of CD4+ cell count 400 cells/μl performed better than any other definition in segregating immunoconcordant and immunodiscordant individuals (85% accuracy), using markers of activation, nadir and death of CD4+ T cells. Unsupervised clustering of relevant variables using this definition revealed large heterogeneity between immunodiscordant individuals and segregated participants into three distinct subgroups with distinct production, programmed cell-death protein-1 (PD-1) expression, activation and death of T cells. Surprisingly, a nonnegligible number of immunodiscordant participants (22%) showed high frequency of recent thymic emigrants and low CD4+ T-cell activation and death, very similar to immunoconcordant participants. Notably, human leukocyte antigen - antigen D related (HLA-DR) PD-1 and CD45RA expression in CD4+ T cells allowed reproducing subgroup segregation (81.4% accuracy). Despite sharp immunological differences, similar and persistently low CD4+ values were maintained in these participants over time. Conclusion: A cutoff value of CD4+ T-cell count 400 cells/μl classified better immunodiscordant and immunoconcordant individuals than any ΔCD4 classification. Immunodiscordance may present several, even opposite, immunological patterns that are identified by a simple immunological follow-up. Subgroup classification may help clinicians to delineate diverse approaches that may be needed to boost CD4+ T-cell recovery. PMID:27427875

Cutaneous defenses against dermatophytes and yeasts.

PubMed Central

Wagner, D K; Sohnle, P G

1995-01-01

Predispositions to the superficial mycoses include warmth and moisture, natural or iatrogenic immunosuppression, and perhaps some degree of inherited susceptibility. Some of these infections elicit a greater inflammatory response than others, and the noninflammatory ones are generally more chronic. The immune system is involved in the defense against these infections, and cell-mediated immunity appears to be particularly important. The mechanisms involved in generating immunologic reactions in the skin are complex, with epidermal Langerhans cells, other dendritic cells, lymphocytes, microvascular endothelial cells, and the keratinocytes themselves all participating in one way or another. A variety of defects in the immunologic response to the superficial mycoses have been described. In some cases the defect may be preexistent, whereas in others the infection itself may interfere with protective cell-mediated immune responses against the organisms. A number of different mechanisms may underlie these immunologic defects and lead to the development of chronic superficial fungal infection in individual patients. Although the immunologic defects appear to be involved in the chronicity of certain types of cutaneous fungal infections, treatment of these defects remains experimental at the present time. PMID:7553568

Laser assisted immunotherapy (LIT) for chemotherapy-resistant neoplasms: recent case reports

NASA Astrophysics Data System (ADS)

Nordquist, Robert E.; Bahavar, Cody; Zhou, Feifan; Hode, Tomas; Chen, Wei R.; Li, Xiaosong; Naylor, Mark F.

2014-02-01

T-cell stimulators such as anti-CTLA-4 antibodies enhance immunologic responses to chemotherapy-resistant solid tumors, such as melanoma, advanced breast cancer, ovarian cancer and pancreatic cancer. The efficacy of these new immunotherapy agents can in theory be enhanced substantially by therapies that stimulate new immunologic (T-cell) responses against the tumor. Laser immunotherapy (LIT) with imiquimod and InCVAX are techniques that produce useful responses in patients with advanced melanoma, the prototypical chemotherapy resistant solid tumor. The mechanism of action of these therapies is thought to be immunological, including the development of new T-cell responses. We have therefore been combining LIT using imiquimod and InCVAX treatment with the new T-cell stimulators (ipilimumab) in cases of stage IV melanoma. While still anecdotal, the use of novel combinations of immunologic therapies should provide much improved responses for chemotherapy-resistant solid tumors (such as melanoma) than was previously possible. Newer T-cell stimulating drugs such as the anti-PD-1 antibodies and anti-PD-L1 antibodies will make this general approach to treating chemoresistant advanced tumors even more effective in the future.

Enhancing the Breadth of Efficacy of Therapeutic Vaccines for Breast Cancer

DTIC Science & Technology

2014-10-01

4b. Generate specific tumor antigen lysates from recombinant baculovirus- infected insect cells. *Currently expressing antigens in C1R cells since... Immunology Conference, Breckenridge CO (invited by Jim Hagman). Sept 20, 2014, Analysis of the T cell repertoire in breast cancer using emulsion...by Jonathan Bramson).   13 Nov 11, 2014 (anticipated), Elimination of the bottlenecks in T cell receptor antigen discovery, Immunology Forum

21 CFR 866.5530 - Immunoglobulin G (Fc fragment specific) immunological test system.

Code of Federal Regulations, 2011 CFR

2011-04-01

... HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES IMMUNOLOGY AND MICROBIOLOGY DEVICES Immunological... immunoglobulin G (resulting from breakdown of immunoglobulin G antibodies) in urine, serum, and other body fluids. Measurement of immunoglobulin G Fc fragments aids in the diagnosis of plasma cell antibody-forming...

21 CFR 866.5530 - Immunoglobulin G (Fc fragment specific) immunological test system.

Code of Federal Regulations, 2013 CFR

2013-04-01

... HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES IMMUNOLOGY AND MICROBIOLOGY DEVICES Immunological... immunoglobulin G (resulting from breakdown of immunoglobulin G antibodies) in urine, serum, and other body fluids. Measurement of immunoglobulin G Fc fragments aids in the diagnosis of plasma cell antibody-forming...

21 CFR 866.5530 - Immunoglobulin G (Fc fragment specific) immunological test system.

Code of Federal Regulations, 2014 CFR

2014-04-01

... HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES IMMUNOLOGY AND MICROBIOLOGY DEVICES Immunological... immunoglobulin G (resulting from breakdown of immunoglobulin G antibodies) in urine, serum, and other body fluids. Measurement of immunoglobulin G Fc fragments aids in the diagnosis of plasma cell antibody-forming...

21 CFR 866.5530 - Immunoglobulin G (Fc fragment specific) immunological test system.

Code of Federal Regulations, 2012 CFR

2012-04-01

... HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES IMMUNOLOGY AND MICROBIOLOGY DEVICES Immunological... immunoglobulin G (resulting from breakdown of immunoglobulin G antibodies) in urine, serum, and other body fluids. Measurement of immunoglobulin G Fc fragments aids in the diagnosis of plasma cell antibody-forming...

Role of Osmolytes in Regulating Immune System.

PubMed

Kumar, Tarun; Yadav, Manisha; Singh, Laishram Rajendrakumar

2016-01-01

The immune system has evolved to protect the host organism from diverse range of pathogenic microbes that are themselves constantly evolving. It is a complex network of cells, humoral factors, chemokines and cytokines. Dysregulation of immune system results in various kinds of immunological disorders. There are several external agents which govern the regulation of immune system. Recent studies have indicated the role of osmolytes in regulation of various immunological processes such as Ag-Ab interaction, Ig assembly, Ag presentation etc. In this present review, we have systematically discussed the role of osmolytes involved in regulation of several key immunological processes. Osmolytes are involved in the regulation of several key immunological processes such as immunoglobulin assembly and folding, immune cells proliferation, regulation of immune cells function, Ag-Ab interaction, antigen presentation, inflammatory response and protection against photo-immunosuppression. Hence, osmolytes and their transporters might be used as potential drug and drug targets respectively. This review is therefore designed to help clinicians in development of osmolyte based therapeutic strategies in the treatment of various immunological disorders. Appropriate future perspectives have also been included.

The Immunologic Revolution: Photoimmunology

PubMed Central

Ullrich, Stephen E.; Byrne, Scott N.

2011-01-01

UV radiation targets the skin and is a primary cause of skin cancer (both melanoma and non-melanoma skin cancer). Exposure to UV also suppresses the immune response, and UV-induced immune suppression is a major risk factor for skin cancer induction. The efforts of Dermatologists and Cancer Biologists to understand how UV exposure suppresses the immune response and contributes to skin cancer induction led to the development of the sub-discipline we call photoimmunology. Advances in photoimmunology have generally paralleled advances in immunology. However, there are a number of examples where investigations into the mechanisms underlying UV-induced immune suppression reshaped our understanding of basic immunological concepts. Unconventional immune regulatory roles for Langerhans cells, mast cells, and NKT cells as well as the immune suppressive function of lipid mediators of inflammation and alarmins, are just some examples of how advances in immunodermatology have altered our understanding of basic immunology. In this anniversary issue celebrating 75 years of Cutaneous Science, we will provide examples of how concepts that grew out of efforts by Immunologists and Dermatologists to understand immune regulation by UV radiation impacted on immunology in general. PMID:22170491

Kinetics and clonality of immunological memory in humans.

PubMed

Beverley, Peter C L

2004-10-01

T-cell immunological memory consists largely of clones of proliferating lymphocytes maintained by antigenic stimulation and the survival and proliferative effects of cytokines. The duration of survival of memory clones in humans is determine by the Hayflick limit on the number of cell divisions, the rate of cycling of memory cells and factors that control erosion of telomeres, including mechanisms that control telomerase.

Immunological aspects in chronic lymphocytic leukemia (CLL) development.

PubMed

García-Muñoz, Ricardo; Galiacho, Verónica Roldan; Llorente, Luis

2012-07-01

Chronic lymphocytic leukemia (CLL) is unique among B cell malignancies in that the malignant clones can be featured either somatically mutated or unmutated IGVH genes. CLL cells that express unmutated immunoglobulin variable domains likely underwent final development prior to their entry into the germinal center, whereas those that express mutated variable domains likely transited through the germinal center and then underwent final development. Regardless, the cellular origin of CLL remains unknown. The aim of this review is to summarize immunological aspects involved in this process and to provide insights about the complex biology and pathogenesis of this disease. We propose a mechanistic hypothesis to explain the origin of B-CLL clones into our current picture of normal B cell development. In particular, we suggest that unmutated CLL arises from normal B cells with self-reactivity for apoptotic bodies that have undergone receptor editing, CD5 expression, and anergic processes in the bone marrow. Similarly, mutated CLL would arise from cells that, while acquiring self-reactivity for autoantigens-including apoptotic bodies-in germinal centers, are also still subject to tolerization mechanisms, including receptor editing and anergy. We believe that CLL is a proliferation of B lymphocytes selected during clonal expansion through multiple encounters with (auto)antigens, despite the fact that they differ in their state of activation and maturation. Autoantigens and microbial pathogens activate BCR signaling and promote tolerogenic mechanisms such as receptor editing/revision, anergy, CD5+ expression, and somatic hypermutation in CLL B cells. The result of these tolerogenic mechanisms is the survival of CLL B cell clones with similar surface markers and homogeneous gene expression signatures. We suggest that both immunophenotypic surface markers and homogenous gene expression might represent the evidence of several attempts to re-educate self-reactive B cells.

A Pronounced Inflammatory Activity Characterizes the Early Fracture Healing Phase in Immunologically Restricted Patients

PubMed Central

Hoff, Paula; Gaber, Timo; Strehl, Cindy; Jakstadt, Manuela; Hoff, Holger; Schmidt-Bleek, Katharina; Lang, Annemarie; Röhner, Eric; Huscher, Dörte; Matziolis, Georg; Burmester, Gerd-Rüdiger; Schmidmaier, Gerhard; Perka, Carsten; Duda, Georg N.; Buttgereit, Frank

2017-01-01

Immunologically restricted patients such as those with autoimmune diseases or malignancies often suffer from delayed or insufficient fracture healing. In human fracture hematomas and the surrounding bone marrow obtained from immunologically restricted patients, we analyzed the initial inflammatory phase on cellular and humoral level via flow cytometry and multiplex suspension array. Compared with controls, we demonstrated higher numbers of immune cells like monocytes/macrophages, natural killer T (NKT) cells, and activated T helper cells within the fracture hematomas and/or the surrounding bone marrow. Also, several pro-inflammatory cytokines such as Interleukin (IL)-6 and Tumor necrosis factor α (TNFα), chemokines (e.g., Eotaxin and RANTES), pro-angiogenic factors (e.g., IL-8 and Macrophage migration inhibitory factor: MIF), and regulatory cytokines (e.g., IL-10) were found at higher levels within the fracture hematomas and/or the surrounding bone marrow of immunologically restricted patients when compared to controls. We conclude here that the inflammatory activity on cellular and humoral levels at fracture sites of immunologically restricted patients considerably exceeds that of control patients. The initial inflammatory phase profoundly differs between these patient groups and is probably one of the reasons for prolonged or insufficient fracture healing often occurring within immunologically restricted patients. PMID:28282868

Clinical and Immunological Features of Common Variable Immunodeficiency in China

PubMed Central

Lin, Lian-Jun; Wang, Yu-Chuan; Liu, Xin-Min

2015-01-01

Background: Common variable immunodeficiency (CVID) is one of the most common symptomatic primary immunodeficiency syndromes. The purpose of this article was to broaden our knowledge about CVID for better diagnosis and treatment. Methods: Clinical and immunological features of 40 Chinese patients with CVID were analyzed retrospectively. Results: The median age at onset was 11-year-old (range 4–51 years). The median age at diagnosis was 14.5-year-old (range 5–66 years). The average time of delay in diagnosis was 5.3 years (range 1–41 years). The most common main complaint was fever due to infections (35 cases, 87.5%). Pneumonia (28 cases, 70%) was the most common type of infections. Bronchiectasis was present in 6 patients (15%). Autoimmune disease was detected in 6 cases of CVID, and malignancy in 2 cases. The median total serum levels of IgG, IgA, and IgM at diagnosis were 1.07 g/L, 0.07 g/L, and 0.28 g/L, respectively. The percentages of CD3−/CD10+ B-cells were 1%–3.14%. Conclusions: Infection is the most frequent presentation of CVID. Patients with unexplainable infections should receive further examination including serum immunoglobulin (Ig) and lymphocyte subset analysis. Regular and sufficient substitution with Ig is recommended. PMID:25635425

HIV Molecular Immunology 2015

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yusim, Karina; Korber, Bette Tina; Brander, Christian

The scope and purpose of the HIV molecular immunology database: HIV Molecular Immunology is a companion volume to HIV Sequence Compendium. This publication, the 2015 edition, is the PDF version of the web-based HIV Immunology Database (http://www.hiv.lanl.gov/ content/immunology/). The web interface for this relational database has many search options, as well as interactive tools to help immunologists design reagents and interpret their results. In the HIV Immunology Database, HIV-specific B-cell and T-cell responses are summarized and annotated. Immunological responses are divided into three parts, CTL, T helper, and antibody. Within these parts, defined epitopes are organized by protein and bindingmore » sites within each protein, moving from left to right through the coding regions spanning the HIV genome. We include human responses to natural HIV infections, as well as vaccine studies in a range of animal models and human trials. Responses that are not specifically defined, such as responses to whole proteins or monoclonal antibody responses to discontinuous epitopes, are summarized at the end of each protein section. Studies describing general HIV responses to the virus, but not to any specific protein, are included at the end of each part. The annotation includes information such as cross-reactivity, escape mutations, antibody sequence, TCR usage, functional domains that overlap with an epitope, immune response associations with rates of progression and therapy, and how specific epitopes were experimentally defined. Basic information such as HLA specificities for T-cell epitopes, isotypes of monoclonal antibodies, and epitope sequences are included whenever possible. All studies that we can find that incorporate the use of a specific monoclonal antibody are included in the entry for that antibody. A single T-cell epitope can have multiple entries, generally one entry per study. Finally, maps of all defined linear epitopes relative to the HXB2 reference proteins are provided. Alignments of CTL, helper T-cell, and antibody epitopes are available through the search interface on our web site at http:// www.hiv.lanl.gov/content/immunology.« less

Unique Features of Fish Immune Repertoires: Particularities of Adaptive Immunity Within the Largest Group of Vertebrates

PubMed Central

Sunyer, Oriol J.

2016-01-01

Fishes (i.e., teleost fishes) are the largest group of vertebrates. Although their immune system is based on the fundamental receptors, pathways, and cell types found in all groups of vertebrates, fishes show a diversity of particular features that challenge some classical concepts of immunology. In this chapter, we discuss the particularities of fish immune repertoires from a comparative perspective. We examine how allelic exclusion can be achieved when multiple Ig loci are present, how isotypic diversity and functional specificity impact clonal complexity, how loss of the MHC class II molecules affects the cooperation between T and B cells, and how deep sequencing technologies bring new insights about somatic hypermutation in the absence of germinal centers. The unique coexistence of two distinct B-cell lineages respectively specialized in systemic and mucosal responses is also discussed. Finally, we try to show that the diverse adaptations of immune repertoires in teleosts can help in understanding how somatic adaptive mechanisms of immunity evolved in parallel in different lineages across vertebrates. PMID:26537384

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas.

PubMed

Campbell, Joshua D; Yau, Christina; Bowlby, Reanne; Liu, Yuexin; Brennan, Kevin; Fan, Huihui; Taylor, Alison M; Wang, Chen; Walter, Vonn; Akbani, Rehan; Byers, Lauren Averett; Creighton, Chad J; Coarfa, Cristian; Shih, Juliann; Cherniack, Andrew D; Gevaert, Olivier; Prunello, Marcos; Shen, Hui; Anur, Pavana; Chen, Jianhong; Cheng, Hui; Hayes, D Neil; Bullman, Susan; Pedamallu, Chandra Sekhar; Ojesina, Akinyemi I; Sadeghi, Sara; Mungall, Karen L; Robertson, A Gordon; Benz, Christopher; Schultz, Andre; Kanchi, Rupa S; Gay, Carl M; Hegde, Apurva; Diao, Lixia; Wang, Jing; Ma, Wencai; Sumazin, Pavel; Chiu, Hua-Sheng; Chen, Ting-Wen; Gunaratne, Preethi; Donehower, Larry; Rader, Janet S; Zuna, Rosemary; Al-Ahmadie, Hikmat; Lazar, Alexander J; Flores, Elsa R; Tsai, Kenneth Y; Zhou, Jane H; Rustgi, Anil K; Drill, Esther; Shen, Ronglei; Wong, Christopher K; Stuart, Joshua M; Laird, Peter W; Hoadley, Katherine A; Weinstein, John N; Peto, Myron; Pickering, Curtis R; Chen, Zhong; Van Waes, Carter

2018-04-03

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smoking and/or human papillomavirus (HPV). SCCs harbor 3q, 5p, and other recurrent chromosomal copy-number alterations (CNAs), DNA mutations, and/or aberrant methylation of genes and microRNAs, which are correlated with the expression of multi-gene programs linked to squamous cell stemness, epithelial-to-mesenchymal differentiation, growth, genomic integrity, oxidative damage, death, and inflammation. Low-CNA SCCs tended to be HPV(+) and display hypermethylation with repression of TET1 demethylase and FANCF, previously linked to predisposition to SCC, or harbor mutations affecting CASP8, RAS-MAPK pathways, chromatin modifiers, and immunoregulatory molecules. We uncovered hypomethylation of the alternative promoter that drives expression of the ΔNp63 oncogene and embedded miR944. Co-expression of immune checkpoint, T-regulatory, and Myeloid suppressor cells signatures may explain reduced efficacy of immune therapy. These findings support possibilities for molecular classification and therapeutic approaches. Published by Elsevier Inc.

The effect of incident tuberculosis on immunological response of HIV patients on highly active anti-retroviral therapy at the university of Gondar hospital, northwest Ethiopia: a retrospective follow-up study.

PubMed

Assefa, Abate; Gelaw, Baye; Getnet, Gebeyaw; Yitayew, Gashaw

2014-08-27

Human immunodeficiency virus (HIV) infection is usually complicated by high rates of tuberculosis (TB) co-infection. Impaired immune response has been reported during HIV/TB co-infection and may have significant effect on anti-retroviral therapy (ART). TB/HIV co - infection is a major public health problem in Ethiopia. Therefore, the aim of the study was to assess the effect of TB incidence on immunological response of HIV patients during ART. A retrospective follow-up study was conducted among adult HIV patients who started ART at the University of Gondar Hospital. Changes in CD4+ T - lymphocyte count and incident TB episodes occurring during 42 months of follow up on ART were assessed. Life table was used to estimate the cumulative immunologic failure. Kaplan-Meier curve was used to compare survival curves between the different categories. Cox-proportional hazard model was employed to examine predictors of immunological failure. Among 400 HIV patients, 89(22.2%) were found to have immunological failure with a rate of 8.5 per 100 person-years (PY) of follow-up. Incident TB developed in 26(6.5%) of patients, with an incidence rate of 2.2 cases per 100 PY. The immunological failure rate was high (20.1/100PY) at the first year of treatment. At multivariate analysis, Cox regression analysis showed that baseline CD4+ T - cell count <100 cells/mm3 (adjusted hazard ratio (AHR) 1.8; 95%CI: 1.10 - 2.92, p = 0.023) and being male sex (AHR 1.6; 95%CI: 1.01 - 2.68, p = 0.046) were found to be significant predictors of immunological failure. There was borderline significant association with incident TB (AHR 2.2; 95%CI: 0.94 - 5.09, p = 0.06). The risk of immunological failure was significantly higher (38.5%) among those with incident TB compared with TB - free (21.1%) (Log rank p = 0.036). High incidence of immunological failure occurred within the first year of initiating ART. The proportions of patients with impaired immune restoration were higher among patients with incident TB. Lower baseline CD4+ T - cells count of <100 cells/mm3 and being male sex were significant predictors of immunological failure. The result highlighted the beneficial effects of earlier initiation of ART on CD4+ T - cell count recovery.

Basic and clinical immunology

NASA Technical Reports Server (NTRS)

Chinen, Javier; Shearer, William T.

2003-01-01

Progress in immunology continues to grow exponentially every year. New applications of this knowledge are being developed for a broad range of clinical conditions. Conversely, the study of primary and secondary immunodeficiencies is helping to elucidate the intricate mechanisms of the immune system. We have selected a few of the most significant contributions to the fields of basic and clinical immunology published between October 2001 and October 2002. Our choice of topics in basic immunology included the description of T-bet as a determinant factor for T(H)1 differentiation, the role of the activation-induced cytosine deaminase gene in B-cell development, the characterization of CD4(+)CD25(+) regulatory T cells, and the use of dynamic imaging to study MHC class II transport and T-cell and dendritic cell membrane interactions. Articles related to clinical immunology that were selected for review include the description of immunodeficiency caused by caspase 8 deficiency; a case series report on X-linked agammaglobulinemia; the mechanism of action, efficacy, and complications of intravenous immunoglobulin; mechanisms of autoimmunity diseases; and advances in HIV pathogenesis and vaccine development. We also reviewed two articles that explore the possible alterations of the immune system caused by spaceflights, a new field with increasing importance as human space expeditions become a reality in the 21st century.

Advances in cancer immunology and cancer immunotherapy.

PubMed

Voena, Claudia; Chiarle, Roberto

2016-02-01

After decades of setbacks, cancer immunology is living its Golden Age. Recent advances in cancer immunology have provided new therapeutic approaches to treat cancer. The objective clinical response observed in patients treated with antibodies that block the immune checkpoints, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell-death protein 1 (PD-1)/programmed cell-death 1 ligand 1 (PD-L1) pathways, has led to their FDA approval for the treatment of melanoma in 2011 and in 2014, respectively. The anti-PD-1 antibody nivolumab has received the FDA-approval in March 2015 for squamous lung cancer treatment. In addition, antibodies targeting PD-1 or PD-L1 have demonstrated their efficacy and safety in additional tumors, including non-small cell lung carcinoma (NSCLC), renal cell carcinoma (RCC), bladder cancer, and Hodgkin's lymphoma. Almost at the same time, the field of adoptive cell transfer has exploded. The chimeric antigen receptor (CAR) T technology has provided strong evidence of efficacy in the treatment of B cell malignancies, and different T cell based treatments are currently under investigation for different types of tumors. In this review we will discuss the latest advances in cancer immunology and immunotherapy as well as new treatments now under development in the clinic and potential strategies that have shown promising results in preclinical models.

Consortium biology in immunology: the perspective from the Immunological Genome Project.

PubMed

Benoist, Christophe; Lanier, Lewis; Merad, Miriam; Mathis, Diane

2012-10-01

Although the field has a long collaborative tradition, immunology has made less use than genetics of 'consortium biology', wherein groups of investigators together tackle large integrated questions or problems. However, immunology is naturally suited to large-scale integrative and systems-level approaches, owing to the multicellular and adaptive nature of the cells it encompasses. Here, we discuss the value and drawbacks of this organization of research, in the context of the long-running 'big science' debate, and consider the opportunities that may exist for the immunology community. We position this analysis in light of our own experience, both positive and negative, as participants of the Immunological Genome Project.

Novel T lymphocyte proliferation assessment using whole mouse cryo-imaging

NASA Astrophysics Data System (ADS)

Wuttisarnwattana, Patiwet; Raza, Syed A.; Eid, Saada; Cooke, Kenneth R.; Wilson, David L.

2014-03-01

New imaging technologies enable one to assess T-cell proliferation, an important feature of the immunological response. However, none of the traditional imaging modalities allow one to examine quantiatively T-cell function with microscopic resolution and single cell sensitivity over an entire mouse. To address this need, we established T-cells proliferation assays using 3D microscopic cryo-imaging. Assays include: (1) biodistribution of T-cells, (2) secondary lymphoid organ (SLO) volume measurement, (3) carboxyfluorescein succinimidyl ester (CFSE) dilution per cell as cells divide. To demonstrate the application, a graft-versus-host-disease (GVHD) model was used. 3D visualization show that T-cells specifically homed to the SLOs (spleen and lymph nodes) as well as GVHD target organs (such as GI-tract, liver, skin and thymus).The spleen was chosen as representative of the SLOs. For spleen size analysis, volumes of red and white pulp were measured. Spleen volumes of the allogeneic mice (with GVHD) were significantly larger than those of the syngeneic mice (without GVHD) at 72 to 120 hours post-transplant. For CFSE dilution approach, we employed color-coded volume rendering and probability density function (PDF) of single cell intensity to assess T-cell proliferation in the spleen. As compared to syngeneic T-cells, the allogeneic T-cells quickly aggregated in the spleen as indicated by increasing of CFSE signal over the first 48 hours. Then they rapidly proliferated as evidenced by reduced CFSE intensity (at 48-96 hours). Results suggest that assays can be used to study GVHD treatments using T-cell proliferation and biodistibution as assays. In summary, this is the first time that we are able to track and visualize T-cells in whole mouse with single cell sensitivity. We believe that our technique can be an alternative choice to traditional in vitro immunological proliferation assays by providing assessment of proliferation in an in vivo model.

Widespread immunological functions of mast cells: fact or fiction?

PubMed

Rodewald, Hans-Reimer; Feyerabend, Thorsten B

2012-07-27

Immunological functions of mast cells are currently considered to be much broader than the original role of mast cells in IgE-driven allergic disease. The spectrum of proposed mast cell functions includes areas as diverse as the regulation of innate and adaptive immune responses, protective immunity against viral, microbial, and parasitic pathogens, autoimmunity, tolerance to graft rejection, promotion of or protection from cancer, wound healing, angiogenesis, cardiovascular diseases, diabetes, obesity, and others. The vast majority of in vivo mast cell data have been based on mast cell-deficient Kit mutant mice. However, work in new mouse mutants with unperturbed Kit function, which have a surprisingly normal immune system, has failed to corroborate some key immunological aspects, formerly attributed to mast cells. Here, we consider the implications of these recent developments for the state of the field as well as for future work, aiming at deciphering the physiological functions of mast cells. Copyright © 2012 Elsevier Inc. All rights reserved.

Mechanisms for Cell-to-Cell Transmission of HIV-1

PubMed Central

Bracq, Lucie; Xie, Maorong; Benichou, Serge; Bouchet, Jérôme

2018-01-01

While HIV-1 infection of target cells with cell-free viral particles has been largely documented, intercellular transmission through direct cell-to-cell contact may be a predominant mode of propagation in host. To spread, HIV-1 infects cells of the immune system and takes advantage of their specific particularities and functions. Subversion of intercellular communication allows to improve HIV-1 replication through a multiplicity of intercellular structures and membrane protrusions, like tunneling nanotubes, filopodia, or lamellipodia-like structures involved in the formation of the virological synapse. Other features of immune cells, like the immunological synapse or the phagocytosis of infected cells are hijacked by HIV-1 and used as gateways to infect target cells. Finally, HIV-1 reuses its fusogenic capacity to provoke fusion between infected donor cells and target cells, and to form infected syncytia with high capacity of viral production and improved capacities of motility or survival. All these modes of cell-to-cell transfer are now considered as viral mechanisms to escape immune system and antiretroviral therapies, and could be involved in the establishment of persistent virus reservoirs in different host tissues. PMID:29515578

Molecular regulation of effector and memory T cell differentiation

PubMed Central

Chang, John T; Wherry, E John; Goldrath, Ananda W

2015-01-01

Immunological memory is a cardinal feature of adaptive immunity and an important goal of vaccination strategies. Here we highlight advances in the understanding of the diverse T lymphocyte subsets that provide acute and long-term protection from infection. These include new insights into the transcription factors, and the upstream ‘pioneering’ factors that regulate their accessibility to key sites of gene regulation, as well as metabolic regulators that contribute to the differentiation of effector and memory subsets; ontogeny and defining characteristics of tissue-resident memory lymphocytes; and origins of the remarkable heterogeneity exhibited by activated T cells. Collectively, these findings underscore progress in delineating the underlying pathways that control diversification in T cell responses but also reveal gaps in the knowledge, as well as the challenges that arise in the application of this knowledge to rationally elicit desired T cell responses through vaccination and immunotherapy. PMID:25396352

Allergic- and immunologic-mediated diseases of the eye and adnexae.

PubMed

Bistner, S

1994-07-01

Significant allergic- and immunologic-mediated diseases of the eye are reviewed. Included are diseases of the lacrimal gland namely keratoconjunctivitis sicca, immune-mediated diseases of the conjunctiva, atopic blepharoconjunctivitis, and marginal blepharitis, uveitis including lens-induced uveitis, episcleritis, orbital cellulitis, and optic neuritis. Significant diagnostic features, an approach to diagnostic workup, and treatment are presented.

Final Technical Report to proposal DE-FG02-95ER20187

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dangl, Jeff

Our long term aim over our many years of generous DOE-BES funding was to understand mechanisms by which the pathogen virulence factors (called ‘type III effectors’) AvrRpm1 and AvrB activate the plant NLR immune receptor RPM1. In general effectors are delivered from the infecting bacteria into host cells by the type III pilus, where they manipulate host machinery to help pathogens overcome host defense. Delivery of effectors to increase virulence is a general feature of all classes of plant pathogens, from fungi to insects to oomcyetes and bacteria. Hence, understanding the overall diversity of effectors, their myriad delivery systems andmore » their effectors on host cell biology, is of central importance in plant immunology.« less

Postdoctoral Fellow | Center for Cancer Research

Cancer.gov

Highly motivated postdoctoral fellows sought to work on tumor immunology with a strong background in biology preferentially cellular immunology. The tumor immunology group in the laboratory is exploring mechanisms of improving vaccines and immunotherapy for cancer, especially by discovering new principles to enhance and steer T cell immune responses. The group is focusing on

Therapeutic cloning in individual parkinsonian mice

PubMed Central

Tabar, Viviane; Tomishima, Mark; Panagiotakos, Georgia; Wakayama, Sayaka; Menon, Jayanthi; Chan, Bill; Mizutani, Eiji; Al-Shamy, George; Ohta, Hiroshi; Wakayama, Teruhiko; Studer, Lorenz

2009-01-01

Cell transplantation with embryonic stem (ES) cell progeny requires immunological compatibility with host tissue. ‘Therapeutic cloning’ is a strategy to overcome this limitation by generating nuclear transfer (nt)ES cells that are genetically matched to an individual. Here we establish the feasibility of treating individual mice via therapeutic cloning. Derivation of 187 ntES cell lines from 24 parkinsonian mice, dopaminergic differentiation, and transplantation into individually matched host mice showed therapeutic efficacy and lack of immunological response. PMID:18376409

Adipose tissue as an immunological organ

PubMed Central

Grant, Ryan W.; Dixit, Vishwa Deep

2014-01-01

Objective This review will focus on the immunological aspects of adipose tissue and its potential role in development of chronic inflammation that instigates obesity-associated co-morbidities. Design and Methods The review utilized PubMed searches of current literature to examine adipose tissue leukocytosis. Results The adipose tissue of obese subjects becomes inflamed and contributes to the development of insulin resistance, type 2 diabetes and metabolic syndrome. Numerous immune cells including B cells, T cells, macrophages and neutrophils have been identified in adipose tissue, and obesity influences both the quantity and the nature of immune cell subtypes which emerges as an active immunological organ capable of modifying whole body metabolism through paracrine and endocrine mechanisms. Conclusion Adipose tissue is a large immunologically active organ during obesity that displays hallmarks of both and innate and adaptive immune response. Despite the presence of hematopoietic lineage cells in adipose tissue, it is presently unclear whether the adipose compartment has a direct role in immune-surveillance or host defense. Understanding the interactions between leukocytes and adipocytes may reveal the clinically relevant pathways that control adipose tissue inflammation and is likely to reveal mechanism by which obesity contributes to increased susceptibility to both metabolic and certain infectious disease. PMID:25612251

Immunological characterization of pulmonary intravascular macrophages

NASA Technical Reports Server (NTRS)

Chitko-McKown, C. G.; Reddy, D. N.; Chapes, S. K.; McKown, R. D.; Blecha, F.; Spooner, B. S. (Principal Investigator)

1992-01-01

Pulmonary intravascular macrophages (PIMs) are lung macrophages found apposed to the endothelium of pulmonary capillaries. In many species, they are responsible for the clearance of blood-borne particulates and pathogens; however, little else is known about their roles as immunologic effector cells. We compared PIMs with pulmonary alveolar macrophages (PAMs) to determine the relative immunological activities of these two cell populations. Our results suggested that both populations possess similar phagocytic and bactericidal activities. In assays measuring cytotoxicity, PIMs were more cytotoxic than PAMs against virally infected target cells; however, differences between these macrophage populations were not as marked when noninfected targets were used. LPS-stimulated PIMs produced more T-cell proliferative cytokines than PAMs, and both populations of nonstimulated macrophages produced similar amounts of the cytokines. In contrast, PAMs produced more TNF alpha and NO2- than PIMs when both populations were stimulated with LPS; however, nonstimulated PAMs and PIMs produced similar amounts of TNF alpha and NO2. These data suggest that bovine PIMs are immunologically active. Differences between the degrees of activity of PIMs and PAMs indicate that these macrophage populations may have different roles in lung surveillance.

Epstein-Barr virus-driven B Cell Proliferation with CD4+ T Cell Expansion: A Lymphomatoid Granulomatosis-like Disease Related to Hyperinterleukin-10 Secretion of Remarkably Favourable Outcome with Rituximab.

PubMed

Cervera, P; Guihot, A; Gorochov, G; Lassoued, K; Coppo, P

2015-12-01

Granulomatous lymphomatosis is an Epstein-Barr virus (EBV)-driven B cell proliferation associated with an exuberant CD4(+) T cell reaction with usually histopathological pictures of angiocentrism. So far, the characteristics of CD4(+) T cells in granulomatous lymphomatosis and the mechanism leading to their expansion remain poorly explored. We report a 56-year-old female with a past history of cold agglutinin disease, which was successfully treated with 4 weekly infusions of rituximab. She presented one year later with features of granulomatous lymphomatosis that resulted in severe lung and bone marrow infiltration. We provide evidence that CD4(+) T cell expansion was oligoclonal, involved anergic cells and did not result from an EBV-driven stimulation. Rather, it resulted possibly from a high production of interleukin-10 by immunoblastic EBV-positive B cells. The outcome was remarkably favourable with rituximab and steroids. Our results suggest that an EBV-driven B cell proliferation should be investigated in patients presenting with a CD4(+) T cells alveolitis or other systemic manifestations resulting from a CD4(+) T cell expansion. These features should prompt to introduce an immunosuppressive therapy including steroids and rituximab. Our results deserve further investigations to confirm our pathophysiological hypotheses in CD4(+) T cell expansions associated with EBV-driven B cell proliferations and to assess whether granulomatous lymphomatosis could result from comparable mechanisms. © 2015 The Foundation for the Scandinavian Journal of Immunology.

Identification of a subset of human natural killer cells expressing high levels of programmed death 1: A phenotypic and functional characterization.

PubMed

Pesce, Silvia; Greppi, Marco; Tabellini, Giovanna; Rampinelli, Fabio; Parolini, Silvia; Olive, Daniel; Moretta, Lorenzo; Moretta, Alessandro; Marcenaro, Emanuela

2017-01-01

Programmed death 1 (PD-1) is an immunologic checkpoint that limits immune responses by delivering potent inhibitory signals to T cells on interaction with specific ligands expressed on tumor/virus-infected cells, thus contributing to immune escape mechanisms. Therapeutic PD-1 blockade has been shown to mediate tumor eradication with impressive clinical results. Little is known about the expression/function of PD-1 on human natural killer (NK) cells. We sought to clarify whether human NK cells can express PD-1 and analyze their phenotypic/functional features. We performed multiparametric cytofluorimetric analysis of PD-1 + NK cells and their functional characterization using degranulation, cytokine production, and proliferation assays. We provide unequivocal evidence that PD-1 is highly expressed (PD-1 bright ) on an NK cell subset detectable in the peripheral blood of approximately one fourth of healthy subjects. These donors are always serologically positive for human cytomegalovirus. PD-1 is expressed by CD56 dim but not CD56 bright NK cells and is confined to fully mature NK cells characterized by the NKG2A - KIR + CD57 + phenotype. Proportions of PD-1 bright NK cells were higher in the ascites of a cohort of patients with ovarian carcinoma, suggesting their possible induction/expansion in tumor environments. Functional analysis revealed a reduced proliferative capability in response to cytokines, low degranulation, and impaired cytokine production on interaction with tumor targets. We have identified and characterized a novel subpopulation of human NK cells expressing high levels of PD-1. These cells have the phenotypic characteristics of fully mature NK cells and are increased in patients with ovarian carcinoma. They display low proliferative responses and impaired antitumor activity that can be partially restored by antibody-mediated disruption of PD-1/programmed death ligand interaction. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Immunological Tolerance to Muscle Autoantigens Involves Peripheral Deletion of Autoreactive CD8+ T Cells

PubMed Central

Franck, Emilie; Bonneau, Carole; Jean, Laetitia; Henry, Jean-Paul; Lacoume, Yann; Salvetti, Anna; Boyer, Olivier; Adriouch, Sahil

2012-01-01

Muscle potentially represents the most abundant source of autoantigens of the body and can be targeted by a variety of severe autoimmune diseases. Yet, the mechanisms of immunological tolerance toward muscle autoantigens remain mostly unknown. We investigated this issue in transgenic SM-Ova mice that express an ovalbumin (Ova) neo-autoantigen specifically in skeletal muscle. We previously reported that antigen specific CD4+ T cell are immunologically ignorant to endogenous Ova in this model but can be stimulated upon immunization. In contrast, Ova-specific CD8+ T cells were suspected to be either unresponsive to Ova challenge or functionally defective. We now extend our investigations on the mechanisms governing CD8+ tolerance in SM-Ova mice. We show herein that Ova-specific CD8+ T cells are not detected upon challenge with strongly immunogenic Ova vaccines even after depletion of regulatory T cells. Ova-specific CD8+ T cells from OT-I mice adoptively transferred to SM-Ova mice started to proliferate in vivo, acquired CD69 and PD-1 but subsequently down-regulated Bcl-2 and disappeared from the periphery, suggesting a mechanism of peripheral deletion. Peripheral deletion of endogenous Ova-specific cells was formally demonstrated in chimeric SM-Ova mice engrafted with bone marrow cells containing T cell precursors from OT-I TCR-transgenic mice. Thus, the present findings demonstrate that immunological tolerance to muscle autoantigens involves peripheral deletion of autoreactive CD8+ T cells. PMID:22570714

Immunological Approaches to Biomass Characterization and Utilization

PubMed Central

Pattathil, Sivakumar; Avci, Utku; Zhang, Tiantian; Cardenas, Claudia L.; Hahn, Michael G.

2015-01-01

Plant biomass is the major renewable feedstock resource for sustainable generation of alternative transportation fuels to replace fossil carbon-derived fuels. Lignocellulosic cell walls are the principal component of plant biomass. Hence, a detailed understanding of plant cell wall structure and biosynthesis is an important aspect of bioenergy research. Cell walls are dynamic in their composition and structure, varying considerably among different organs, cells, and developmental stages of plants. Hence, tools are needed that are highly efficient and broadly applicable at various levels of plant biomass-based bioenergy research. The use of plant cell wall glycan-directed probes has seen increasing use over the past decade as an excellent approach for the detailed characterization of cell walls. Large collections of such probes directed against most major cell wall glycans are currently available worldwide. The largest and most diverse set of such probes consists of cell wall glycan-directed monoclonal antibodies (McAbs). These McAbs can be used as immunological probes to comprehensively monitor the overall presence, extractability, and distribution patterns among cell types of most major cell wall glycan epitopes using two mutually complementary immunological approaches, glycome profiling (an in vitro platform) and immunolocalization (an in situ platform). Significant progress has been made recently in the overall understanding of plant biomass structure, composition, and modifications with the application of these immunological approaches. This review focuses on such advances made in plant biomass analyses across diverse areas of bioenergy research. PMID:26579515

PD-1 blocks lytic granule polarization with concomitant impairment of integrin outside-in signaling in the natural killer cell immunological synapse.

PubMed

Huang, Yu; Chen, Zhiying; Jang, Joon Hee; Baig, Mirza S; Bertolet, Grant; Schroeder, Casey; Huang, Shengjian; Hu, Qian; Zhao, Yong; Lewis, Dorothy E; Qin, Lidong; Zhu, Michael Xi; Liu, Dongfang

2018-04-18

The inhibitory receptor programmed cell death protein 1 (PD-1) is upregulated on a variety of immune cells, including natural killer (NK) cells, during chronic viral infection and tumorigenesis. Blockade of PD-1 or its ligands produces durable clinical responses with tolerable side effects in patients with a broad spectrum of cancers. However, the underlying molecular mechanisms of how PD-1 regulates NK cell function remain poorly characterized. We sought to determine the effect of PD-1 signaling on NK cells. PD-1 was overexpressed in CD16-KHYG-1 (a human NK cell line with both antibody-dependent cellular cytotoxicity through CD16 and natural cytotoxicity through NKG2D) cells and stimulated by exposing the cells to NK-sensitive target cells expressing programmed death ligand 1 (PD-L1). PD-1 engagement by PD-L1 specifically blocked NK cell-mediated cytotoxicity without interfering with the conjugation between NK cells and target cells. Further examination showed that PD-1 signaling blocked lytic granule polarization in NK cells, which was accompanied by failure of integrin-linked kinase, a key molecule in the integrin outside-in signaling pathway, to accumulate in the immunological synapse after NK-target cell conjugation. Our results suggest that NK cell cytotoxicity is inhibited by PD-1 engagement, which blocks lytic granule polarization to the NK cell immunological synapse with concomitant impairment of integrin outside-in signaling. This study provides novel mechanistic insights into how PD-1 inhibition disrupts NK cell function. Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Mass spectrometry-based proteomic exploration of the human immune system: focus on the inflammasome, global protein secretion, and T cells.

PubMed

Nyman, Tuula A; Lorey, Martina B; Cypryk, Wojciech; Matikainen, Sampsa

2017-05-01

The immune system is our defense system against microbial infections and tissue injury, and understanding how it works in detail is essential for developing drugs for different diseases. Mass spectrometry-based proteomics can provide in-depth information on the molecular mechanisms involved in immune responses. Areas covered: Summarized are the key immunology findings obtained with MS-based proteomics in the past five years, with a focus on inflammasome activation, global protein secretion, mucosal immunology, immunopeptidome and T cells. Special focus is on extracellular vesicle-mediated protein secretion and its role in immune responses. Expert commentary: Proteomics is an essential part of modern omics-scale immunology research. To date, MS-based proteomics has been used in immunology to study protein expression levels, their subcellular localization, secretion, post-translational modifications, and interactions in immune cells upon activation by different stimuli. These studies have made major contributions to understanding the molecular mechanisms involved in innate and adaptive immune responses. New developments in proteomics offer constantly novel possibilities for exploring the immune system. Examples of these techniques include mass cytometry and different MS-based imaging approaches which can be widely used in immunology.

Highlights of the advances in basic immunology in 2011.

PubMed

Liu, Juan; Liu, Shuxun; Cao, Xuetao

2012-05-01

In this review, we summarize the major fundamental advances in immunological research reported in 2011. The highlights focus on the improved understanding of key questions in basic immunology, including the initiation and activation of innate responses as well as mechanisms for the development and function of various T-cell subsets. The research includes the identification of novel cytosolic RNA and DNA sensors as well as the identification of the novel regulators of the Toll-like receptor (TLR) and retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) signaling pathway. Moreover, remarkable advances have been made in the developmental and functional properties of innate lymphoid cells (ILCs). Helper T cells and regulatory T (Treg) cells play indispensable roles in orchestrating adaptive immunity. There have been exciting discoveries regarding the regulatory mechanisms of the development of distinct T-cell subsets, particularly Th17 cells and Treg cells. The emerging roles of microRNAs (miRNAs) in T cell immunity are discussed, as is the recent identification of a novel T-cell subset referred to as follicular regulatory T (TFR) cells.

Highlights of the advances in basic immunology in 2011

PubMed Central

Liu, Juan; Liu, Shuxun; Cao, Xuetao

2012-01-01

In this review, we summarize the major fundamental advances in immunological research reported in 2011. The highlights focus on the improved understanding of key questions in basic immunology, including the initiation and activation of innate responses as well as mechanisms for the development and function of various T-cell subsets. The research includes the identification of novel cytosolic RNA and DNA sensors as well as the identification of the novel regulators of the Toll-like receptor (TLR) and retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) signaling pathway. Moreover, remarkable advances have been made in the developmental and functional properties of innate lymphoid cells (ILCs). Helper T cells and regulatory T (Treg) cells play indispensable roles in orchestrating adaptive immunity. There have been exciting discoveries regarding the regulatory mechanisms of the development of distinct T-cell subsets, particularly Th17 cells and Treg cells. The emerging roles of microRNAs (miRNAs) in T cell immunity are discussed, as is the recent identification of a novel T-cell subset referred to as follicular regulatory T (TFR) cells. PMID:22522654

Immunological considerations in in utero hematopoetic stem cell transplantation (IUHCT)

PubMed Central

Loewendorf, Andrea I.; Csete, Marie; Flake, Alan

2014-01-01

In utero hematopoietic stem cell transplantation (IUHCT) is an attractive approach and a potentially curative surgery for several congenital hematopoietic diseases. In practice, this application has succeeded only in the context of Severe Combined Immunodeficiency Disorders. Here, we review potential immunological hurdles for the long-term establishment of chimerism and discuss relevant models and findings from both postnatal hematopoietic stem cell transplantation and IUHCT. PMID:25610396

Diversity in immunological synapse structure

PubMed Central

Thauland, Timothy J; Parker, David C

2010-01-01

Immunological synapses (ISs) are formed at the T cell–antigen-presenting cell (APC) interface during antigen recognition, and play a central role in T-cell activation and in the delivery of effector functions. ISs were originally described as a peripheral ring of adhesion molecules surrounding a central accumulation of T-cell receptor (TCR)–peptide major histocompatibility complex (pMHC) interactions. Although the structure of these ‘classical’ ISs has been the subject of intense study, non-classical ISs have also been observed under a variety of conditions. Multifocal ISs, characterized by adhesion molecules dispersed among numerous small accumulations of TCR–pMHC, and motile ‘immunological kinapses’ have both been described. In this review, we discuss the conditions under which non-classical ISs are formed. Specifically, we explore the profound effect that the phenotypes of both T cells and APCs have on IS structure. We also comment on the role that IS structure may play in T-cell function. PMID:21039474

Association between discordant immunological response to highly active anti-retroviral therapy, regulatory T cell percentage, immune cell activation and very low-level viraemia in HIV-infected patients.

PubMed

Saison, J; Ferry, T; Demaret, J; Maucort Boulch, D; Venet, F; Perpoint, T; Ader, F; Icard, V; Chidiac, C; Monneret, G

2014-06-01

The mechanisms sustaining the absence of complete immune recovery in HIV-infected patients upon long-term effective highly active anti-retroviral therapy (HAART) remain elusive. Immune activation, regulatory T cells (T(regs)) or very low-level viraemia (VLLV) have been alternatively suspected, but rarely investigated simultaneously. We performed a cross-sectional study in HIV-infected aviraemic subjects (mean duration of HAART: 12 years) to concomitantly assess parameters associated independently with inadequate immunological response. Patients were classified as complete immunological responders (cIR, n = 48) and inadequate immunological responders (iIR, n = 39), depending on the CD4(+) T cell count (> or < 500/mm(3)). Clinical and virological data (including very low-level viraemia) were collected. In parallel, immunophenotyping of CD4(+) lymphocytes, including T(reg) subsets, and CD8(+) T cells was performed. Percentages of activated CD4(+) T cells, T(regs), effector T(regs) and terminal effector T(regs) were found to be significantly elevated in iIR. Neither the percentage of activated CD8(+) T cells nor VLLV were found to be associated with iIR. In the multivariate analysis, nadir of CD4(+) T cell count and percentage of T(regs) were the only two parameters associated independently with iIR [odds ratio (OR) = 2·339, P = 0·001, and OR = 0·803, P = 0·041]. We present here the largest study investigating simultaneously the immune response to long-term HAART, activation of CD4(+) and CD8(+) T cells, T(reg) percentages and very low-level viraemia. Causative interactions between T(regs) and CD4(+) T cells should now be explored prospectively in a large patients cohort. © 2014 British Society for Immunology.

Immune cells and prognosis in HPV-associated oropharyngeal squamous cell carcinomas: Review of the literature.

PubMed

Saber, Camelia Nami; Grønhøj Larsen, Christian; Dalianis, Tina; von Buchwald, Christian

2016-07-01

Currently, oropharyngeal squamous cell carcinomas (OPSCC) are treated based on the traditional TNM-classification, although this scheme might be inadequate for the subgroup of human papillomavirus (HPV)-associated OPSCCs. It remains debatable whether this subgroup of patients with favorable prognosis should be offered altered treatment. Besides the well-known biomarkers of HPV and p16, new promising immune cells and markers might nuance the prognosis and treatment for patients with HPV+ OPSCC. We systematically reviewed the literature on immunological features of HPV-associated OPSCCs, and report that a high number of cytotoxic T cells (CD8s) and a low number of CD98 positive cells is associated with better outcome, while an increased CD4/CD8 ratio and a high human leukocyte antigen 1 (HLA1) intensity is most likely associated with worse outcome. These findings might contribute to future OPSCC staging and treatment. Copyright © 2016 Elsevier Ltd. All rights reserved.

Increased IL-35 producing Tregs and CD19+IL-35+ cells are associated with disease progression in leprosy patients.

PubMed

Tarique, Mohd; Saini, Chaman; Naqvi, Raza Ali; Khanna, Neena; Rao, D N

2017-03-01

The clinical forms of leprosy consist of a spectrum that reflects the host's immune response to the M. leprae; it provides an ideal model to study the host pathogen interaction and immunological dysregulation in humans. IL-10 and TGF-β producing Tregs are high in leprosy patients and responsible for immune suppression and M. leprae specific T cells anergy. In leprosy, involvement of IL-35 producing Tregs and Bregs remain unstudied. To study the role of IL-35 producing Tregs and Bregs in the human leprosy. Peripheral blood mononuclear cells from leprosy patients were isolated and stimulated with M. leprae antigen (MLCwA) for 48h. Intracellular cytokine IL-35 was evaluated in CD4 + CD25 + Tregs, CD19 + cells by FACS. Expression of PD-1 on CD4 + CD25 + Tregs, CD19 + cells and its ligand (PD-L1) on B cells, CD11c cells were evaluated by flow cytometry (FACS). Serum IL-35 level was estimated by ELISA. The frequency of IL-35 producing Tregs and Bregs cells were found to be high in leprosy patients (p<0.0001) as compared to healthy controls. These cells produced suppressive cytokine IL-35 which showed positive correlation with bacteriological index (BI) and TGF-β producing Tregs, indicating its suppressive nature. We found higher expression of PD-1 on Tregs, B cell and its ligand (PD-L1) on antigen presenting cells in leprosy patients. This study point out a shift in our understanding of the immunological features that mediate and regulate the immune suppression and the disease progression in leprosy patients with a new paradigm (IL-35 producing Tregs and Bregs) that is beyond TGF-β and IL-10 producing Treg cells. Copyright © 2016 Elsevier Ltd. All rights reserved.

Innate lymphoid cells and their stromal microenvironments.

PubMed

Kellermayer, Zoltán; Vojkovics, Dóra; Balogh, Péter

2017-09-01

In addition to the interaction between antigen presenting cells, T and B lymphocytes, recent studies have revealed important roles for a diverse set of auxiliary cells that profoundly influence the induction and regulation of immune responses against pathogens. Of these the stromal cells composed of various non-hematopoietic constituents are crucial for the creation and maintenance of specialized semi-static three-dimensional lymphoid tissue microenvironment, whereas the more recently described innate lymphoid cells are generated by the diversification of committed lymphoid precursor cells independently from clonally rearranged antigen receptor genes. Recent findings have revealed important contributions by innate lymphoid cells in inflammation and protection against pathogens in a tissue-specific manner. Importantly, lymphoid stromal cells also influence the onset of immune responses in tissue-specific fashion, raising the possibility of tissue-specific stromal - innate lymphoid cell collaboration. In this review we summarize the main features and interactions between these two cells types, with particular emphasis on ILC type 3 cells and their microenvironmental partners. Copyright © 2017 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.

Years in Cologne.

PubMed

Rajewsky, Klaus

2013-01-01

This review describes the building and scientific activity of the Immunology Department at the Institute for Genetics in Cologne, cofounded by Max Delbrück in post-World War II Germany. The protagonist, a child of Russian emigrants, became interested in antibodies as a postdoc at the Pasteur Institute in Paris and a proponent of the antigen-bridge model of T-B cell collaboration during his early time in Cologne. He was challenged by the gap between cellular immunology and molecular genetics and profited from the advances of the latter as well as postwar economic growth in Germany. The Immunology Department became a place, and little universe in itself, where young scientists from all over the world came together to study cellular and molecular mechanisms of antibody formation. This included work on normal and malignant B cells in the human, particularly the origin of Hodgkin lymphoma, but the main focus was on B cell development and homeostasis, the germinal center reaction, and immunological memory, developing recombinase-assisted and conditional gene targeting in mice as a main technical tool.

Cosmos-1989 immunology studies

NASA Technical Reports Server (NTRS)

Sonnenfeld, Gerald

1991-01-01

Evidence from both human and rodent studies has indicated that alterations in immunological parameters occur after space flight. The number of flight experiments has been small, and the full breadth of immunological alterations occurring after space flight remains to be established. Among the major effects on immune responses after space flight that have been reported are: alterations in lymphocyte blastogenesis and natural killer cell activity, alterations in production of cytokines, changes in leukocyte sub-population distribution, and decreases in the ability in the ability of bone marrow cells to respond to colony stimulating factors. Changes have been reported in immunological parameters of both humans and rodents. The significance of these alterations in relation to resistance to infection remains to be established. The current study involved a determination of the effects of flight on Cosmos mission 2044 on leukocyte subset distribution and the sensitivity of bone marrow cells to colony stimulating factor-GM. A parallel study with antiorthostatic suspension was also carried out. The study involved repetition and expansion of studies carried out on Cosmos 1887.

Naive B cells generate regulatory T cells in the presence of a mature immunologic synapse.

PubMed

Reichardt, Peter; Dornbach, Bastian; Rong, Song; Beissert, Stefan; Gueler, Faikah; Loser, Karin; Gunzer, Matthias

2007-09-01

Naive B cells are ineffective antigen-presenting cells and are considered unable to activate naive T cells. However, antigen-specific contact of these cells leads to stable cell pairs that remain associated over hours in vivo. The physiologic role of such pairs has not been evaluated. We show here that antigen-specific conjugates between naive B cells and naive T cells display a mature immunologic synapse in the contact zone that is absent in T-cell-dendritic-cell (DC) pairs. B cells induce substantial proliferation but, contrary to DCs, no loss of L-selectin in T cells. Surprisingly, while DC-triggered T cells develop into normal effector cells, B-cell stimulation over 72 hours induces regulatory T cells inhibiting priming of fresh T cells in a contact-dependent manner in vitro. In vivo, the regulatory T cells home to lymph nodes where they potently suppress immune responses such as in cutaneous hypersensitivity and ectopic allogeneic heart transplant rejection. Our finding might help to explain old observations on tolerance induction by B cells, identify the mature immunologic synapse as a central functional module of this process, and suggest the use of naive B-cell-primed regulatory T cells, "bTregs," as a useful approach for therapeutic intervention in adverse adaptive immune responses.

Immunology of Bee Venom.

PubMed

Elieh Ali Komi, Daniel; Shafaghat, Farzaneh; Zwiener, Ricardo D

2018-06-01

Bee venom is a blend of biochemicals ranging from small peptides and enzymes to biogenic amines. It is capable of triggering severe immunologic reactions owing to its allergenic fraction. Venom components are presented to the T cells by antigen-presenting cells within the skin. These Th2 type T cells then release IL-4 and IL-13 which subsequently direct B cells to class switch to production of IgE. Generating venom-specific IgE and crosslinking FcεR1(s) on the surface of mast cells complete the sensitizing stage in allergic individuals who are most likely to experience severe and even fatal allergic reactions after being stung. Specific IgE for bee venom is a double-edged sword as it is a powerful mediator in triggering allergic events but is also applied successfully in diagnosis of the venom allergic patient. The healing capacity of bee venom has been rediscovered under laboratory-controlled conditions using animal models and cell cultures. The potential role of enzymatic fraction of bee venom including phospholipase A2 in the initiation and development of immune responses also has been studied in numerous research settings. Undoubtedly, having insights into immunologic interactions between bee venom components and innate/specific immune cells both locally and systematically will contribute to the development of immunologic strategies in specific and epitope-based immunotherapy especially in individuals with Hymenoptera venom allergy.

In vitro evaluation of immunological properties of extracellular polysaccharides produced by Lactobacillus delbrueckii strains

PubMed Central

KISHIMOTO, Mana; NOMOTO, Ryohei; OSAWA, Ro

2014-01-01

We investigated the variation in immunological properties of the extracellular polysaccharides (EPSs) produced by different Lactobacillus delbrueckii strains as well as that of their monosaccharide composition. The monosaccharide composition of each EPS produced by L. delbrueckii strains, as determined by thin layer chromatography (TLC), showed an appreciable variation in a strain-dependent manner, which could be broadly assigned to 4 TLC groups. Meanwhile, the immunological properties of the EPSs produced by 10 L. delbrueckii strains were evaluated in a semi-intestinal model using a Transwell co-culture system, which employed human intestinal epithelial Caco-2 cells on the apical side and murine macrophage RAW264.7 cells on the basolateral side. Each EPS was added to the apical side to allow direct contact with Caco-2 cells and incubated for 6 hr. After incubation, the amounts of TNF-α and several cytokines that had been released by either RAW264.7 or Caco-2 cells were then quantified by cytotoxic activity on L929 cells or the RT-PCR method. It was found that the EPS-stimulated RAW264.7 cells express different profiles of cytokine production via Caco-2 cells but that the profile difference could not be related to the above TLC grouping. The evidence suggests that the EPSs of L. delbrueckii strains are diverse not only in their biochemical structure but also in their immunological properties. PMID:25625033

In vitro evaluation of immunological properties of extracellular polysaccharides produced by Lactobacillus delbrueckii strains.

PubMed

Kishimoto, Mana; Nomoto, Ryohei; Osawa, Ro

2015-01-01

We investigated the variation in immunological properties of the extracellular polysaccharides (EPSs) produced by different Lactobacillus delbrueckii strains as well as that of their monosaccharide composition. The monosaccharide composition of each EPS produced by L. delbrueckii strains, as determined by thin layer chromatography (TLC), showed an appreciable variation in a strain-dependent manner, which could be broadly assigned to 4 TLC groups. Meanwhile, the immunological properties of the EPSs produced by 10 L. delbrueckii strains were evaluated in a semi-intestinal model using a Transwell co-culture system, which employed human intestinal epithelial Caco-2 cells on the apical side and murine macrophage RAW264.7 cells on the basolateral side. Each EPS was added to the apical side to allow direct contact with Caco-2 cells and incubated for 6 hr. After incubation, the amounts of TNF-α and several cytokines that had been released by either RAW264.7 or Caco-2 cells were then quantified by cytotoxic activity on L929 cells or the RT-PCR method. It was found that the EPS-stimulated RAW264.7 cells express different profiles of cytokine production via Caco-2 cells but that the profile difference could not be related to the above TLC grouping. The evidence suggests that the EPSs of L. delbrueckii strains are diverse not only in their biochemical structure but also in their immunological properties.

Delayed xenograft rejection.

PubMed

Hancock, W W

1997-01-01

The triumph of genetic engineering in overcoming hyperacute rejection (HAR) of a discordant organ xenograft is clear, but the promise of clinical application of xenotransplantation remains unfulfilled as further immunologic barriers are defined that lead to rejection of a vascularized xenograft within days of transplantation. This report describes the features of this second set of immunologic responses, collectively termed delayed xenograft rejection (DXR). DXR is a syndrome seen in xenograft recipients in which HAR has been avoided or suppressed by antibody depletion or blockade of complement activation. DXR may result, at least in part, from the persisting activation of those pathways first encountered during the HAR phase. Serial studies over several days after transplant show that, histologically, xenografts undergoing DXR demonstrate varying combinations of (1) progressive infiltration by activated macrophages and natural killer (NK) cells, (2) platelet aggregation and fibrin deposition throughout the microvasculature, and (3) endothelial activation. In various experimental models, DXR is T cell-independent and can occur in the absence of demonstrable xenoreactive antibodies. Hence DXR is probably best regarded as arising from the activation of innate host defense mechanisms coupled with failure of normal regulatory mechanisms due to manifold molecular incompatibilities. Although DXR-like features can be seen in concordant models, T cell involvement in the latter is probably requisite. Similarly, in a much muted form, aspects of a DXR-like process may contribute to numerous inflammatory processes, including allograft rejection. The importance of DXR in xenotransplantation is that its development appears resistant to all but the most dense and toxic forms of immunosuppression, which prolong xenograft survival at the expense of inducing host leukopenia, thrombocytopenia, and coagulopathies. It is likely that until the basis of DXR is more clearly understood there can be no further significant progress toward clinical xenotransplantation. However, as the mechanisms responsible for DXR are dissected and understood, still further genetic engineering of donor pigs, involving the introduction of additional or multiple genes to regulate macrophage and NK cell responses, local coagulation, and endothelial cell activation, may once again prove to be an attractive, practical, powerful therapeutic option.

STUDIES ON NON-HEMOLYTIC STREPTOCOCCI ISOLATED FROM THE RESPIRATORY TRACT OF MAN

PubMed Central

Horsfall, Frank L.

1951-01-01

The type specific immunological properties of certain non-hemolytic streptococci, including Str. salivarius type I and type II, present in the respiratory tract of human beings appear to be dependent upon the presence of capsular polysaccharides. The levans formed from sucrose by Str. salivarius (encapsulated S cells or non-encapsulated R variants), or by cell-free enzymes derived from these microorganisms, are indistinguishable immunologically and show no evidence of type specificity. Such levans appear to be immunologically distinct from and unrelated to the capsular polysaccharides of the microorganisms which produce them. PMID:14824398

Complex chimerism

PubMed Central

Ma, Kimberly K.; Petroff, Margaret G.; Coscia, Lisa A.; Armenti, Vincent T.; Adams Waldorf, Kristina M.

2013-01-01

Thousands of women with organ transplantation have undergone successful pregnancies, however little is known about how the profound immunologic changes associated with pregnancy might influence tolerance or rejection of the allograft. Pregnant women with a solid organ transplant are complex chimeras with multiple foreign cell populations from the donor organ, fetus, and mother of the pregnant woman. We consider the impact of complex chimerism and pregnancy-associated immunologic changes on tolerance of the allograft both during pregnancy and the postpartum period. Mechanisms of allograft tolerance are likely dynamic during pregnancy and affected by the influx of fetal microchimeric cells, HLA relationships (between the fetus, pregnant woman and/or donor), peripheral T cell tolerance to fetal cells, and fetal minor histocompatibility antigens. Further research is necessary to understand the complex immunology during pregnancy and the postpartum period of women with a solid organ transplant. PMID:23974274

Association of T and B Cells Infiltrating Orbital Tissues With Clinical Features of Graves Orbitopathy.

PubMed

Rotondo Dottore, Giovanna; Torregrossa, Liborio; Caturegli, Patrizio; Ionni, Ilaria; Sframeli, Angela; Sabini, Elena; Menconi, Francesca; Piaggi, Paolo; Sellari-Franceschini, Stefano; Nardi, Marco; Latrofa, Francesco; Vitti, Paolo; Marcocci, Claudio; Basolo, Fulvio; Marinò, Michele

2018-06-01

Graves orbitopathy (GO) responds to immunosuppressive treatments when clinically active but poorly when inactive. In other autoimmune diseases, response has been ascribed to a reduction in lymphocytes infiltrating the target organ. It is not known whether active vs inactive GO differs in this regard, which would help in understanding the link between GO immunologic features and clinical behavior. To investigate the association between orbital lymphocytic infiltrate and GO clinical features. A cohort study aimed at assessing the extent and immunohistochemical phenotype of orbital lymphocytes and associating it with the ophthalmologic features of GO, especially its clinical activity score (CAS), was conducted at a tertiary referral center. Twenty consecutive patients with GO who underwent orbital decompression were included. The study was conducted from January 1 to May 31, 2017. Orbital tissue histology and immunohistochemistry testing as well as ophthalmologic evaluation. Association between CAS and orbital lymphocytes, analyzed as total number of lymphocytes and main lymphoid subsets. The patient population included 8 men and 12 women, all of white race, with a mean (SD) age of 46 (13) years. With an established cutoff value of 300 lymphoid cells per tissue sample, lymphocytes above this value were found in orbital tissues of 9 of 20 patients (45%), often organized into distinct foci. The lymphocytes comprised a mixture of T (CD3-positive) and B (CD20-positive) cells, suggesting a mature, polyclonal autoimmune response. In a simple linear regression model, the total number of lymphocytes, as well as the number of CD3- and CD20-positive subsets, correlated with CAS (R = 0.63; 95% CI, 0.27-0.84; P = .003; R = 0.59; 95% CI, 0.20-0.82; P = .006; and R = 0.65; 95% CI, 0.30-0.85; P = .002, respectively). In a multiple linear regression model, lymphocytes maintained their effect on CAS when adjusted for 2 additional variables that were correlated with CAS-smoking and GO duration-highlighting even more the important role of orbital lymphocytes in affecting CAS (total number: R = 0.58; 95% CI, 0.18-0.82; P = .01; CD3-positive: R = 0.58; 95% CI, 0.17-0.82; P = .01; and CD20-positive: R = 0.59; 95% CI, 0.19-0.83; P = .01). This study shows a correlation between T and B lymphocytes infiltrating orbital tissues and the activity of GO, possibly enhancing our understanding of the association between GO immunologic features and clinical expression.

The role of EMMPRIN in T cell biology and immunological diseases.

PubMed

Hahn, Jennifer Nancy; Kaushik, Deepak Kumar; Yong, V Wee

2015-07-01

EMMPRIN (CD147), originally described as an inducer of the expression of MMPs, has gained attention in its involvement in various immunologic diseases, such that anti-EMMPRIN antibodies are considered as potential therapeutic medications. Given that MMPs are involved in the pathogenesis of various disease states, it is relevant that targeting an upstream inducer would make for an effective therapeutic strategy. Additionally, EMMPRIN is now appreciated to have multiple roles apart from MMP induction, including in cellular functions, such as migration, adhesion, invasion, energy metabolism, as well as T cell activation and proliferation. Here, we review what is known about EMMPRIN in numerous immunologic/inflammatory disease conditions with a particular focus on its complex roles in T cell biology. © Society for Leukocyte Biology.

[Value of immunologic phenotyping of acute leukemias in children].

PubMed

Vannier, J P; Bene, M C

1989-10-01

Immunologic typing has demonstrated considerable heterogeneity among the acute leukemias. The most significant recent advance has been development of monoclonal antibody techniques. Some markers identified using these techniques seem to be specific for a given stage of maturation of one lymphoid or myeloid cell line. Most acute lymphoblastic leukemias (ALLs) are malignant proliferations whose differentiation appears to have become 'stuck' at one stage of maturation. Results of immunologic typing correlate well with the other clinical and biological data. For prognostic purposes, several patterns can be identified. Among B line ALLs, four varieties have been differentiated, i.e., CD10 negative ALLs, common ALLs, pre-B ALLs, and B ALLs. T ALLs include a broad spectrum of heterogeneous proliferations whose immunologic classification is made difficult by the large number of phenotypes encountered. Among acute myeloblastic leukemias (AMLs), some highly undifferentiated forms have been recognized, by means of immunologic typing, as originating in one of the myeloid cell lines. However, the nosologic and prognostic significance of these studies is less obvious than in ALLs.

Each cell counts: Hematopoiesis and immunity research in the era of single cell genomics.

PubMed

Jaitin, Diego Adhemar; Keren-Shaul, Hadas; Elefant, Naama; Amit, Ido

2015-02-01

Hematopoiesis and immunity are mediated through complex interactions between multiple cell types and states. This complexity is currently addressed following a reductionist approach of characterizing cell types by a small number of cell surface molecular features and gross functions. While the introduction of global transcriptional profiling technologies enabled a more comprehensive view, heterogeneity within sampled populations remained unaddressed, obscuring the true picture of hematopoiesis and immune system function. A critical mass of technological advances in molecular biology and genomics has enabled genome-wide measurements of single cells - the fundamental unit of immunity. These new advances are expected to boost detection of less frequent cell types and fuzzy intermediate cell states, greatly expanding the resolution of current available classifications. This new era of single-cell genomics in immunology research holds great promise for further understanding of the mechanisms and circuits regulating hematopoiesis and immunity in both health and disease. In the near future, the accuracy of single-cell genomics will ultimately enable precise diagnostics and treatment of multiple hematopoietic and immune related diseases. Copyright © 2015 Elsevier Ltd. All rights reserved.

Patients with RA in remission on TNF blockers: when and in whom can TNF blocker therapy be stopped?

PubMed

Saleem, Benazir; Keen, Helen; Goeb, Vincent; Parmar, Rekha; Nizam, Sharmin; Hensor, Elizabeth M A; Churchman, Sarah M; Quinn, Mark; Wakefield, Richard; Conaghan, Philip G; Ponchel, Frederique; Emery, Paul

2010-09-01

Combination therapy with methotrexate (MTX) and tumour necrosis factor (TNF) blockade has increased remission rates in patients with rheumatoid arthritis. However, there are no guidelines regarding cessation of therapy. There is a need for markers predictive of sustained remission following cessation of TNF blocker therapy. Patients in remission (DAS28 <2.6) treated with a TNF blocker and MTX as initial or delayed therapy were recruited. Joints were assessed for grey scale synovitis and power Doppler (PD) activity. Immunological assessment involved advanced six-colour flow cytometry. Of the 47 patients recruited, 27 had received initial treatment and 20 delayed treatment with TNF blocking drugs. Two years after stopping TNF blocker therapy, the main predictor of successful cessation was timing of treatment; 59% of patients in the initial treatment group sustained remission compared with 15% in the delayed treatment group (p=0.003). Within the initial treatment group, secondary analysis showed that the only clinical predictor of successful cessation of treatment was shorter symptom duration before receiving treatment (median 5.5 months vs 9 months; p=0.008). No other clinical features were associated with successful cessation of therapy. Thirty-five per cent of patients had low PD activity but levels were not informative. Several immunological parameters were significantly associated with sustained remission including abnormal differentiation subset of T cells and regulatory T cells. Similar non-significant trends were observed in the delayed treatment group. In patients in remission with low levels of imaging synovitis receiving combination treatment with a TNF blocker and MTX, immunological parameters and short duration of untreated symptoms were associated with successful cessation of TNF blocker therapy.

Postdoctoral Fellow | Center for Cancer Research

Cancer.gov

Dr. Hinrichs’ laboratory in the NCI Experimental Transplantation and Immunology Branch in Bethesda, Maryland, is recruiting postdoctoral fellows in tumor immunology, and T-cell receptor (TCR) and chimeric antigen receptor (CAR) genetic engineering.

Immunologic Regulation in Pregnancy: From Mechanism to Therapeutic Strategy for Immunomodulation

PubMed Central

Chen, Shyi-Jou; Liu, Yung-Liang; Sytwu, Huey-Kang

2012-01-01

The immunologic interaction between the fetus and the mother is a paradoxical communication that is regulated by fetal antigen presentation and/or by recognition of and reaction to these antigens by the maternal immune system. There have been significant advances in understanding of abnormalities in the maternal-fetal immunologic relationship in the placental bed that can lead to pregnancy disorders. Moreover, immunologic recognition of pregnancy is vital for the maintenance of gestation, and inadequate recognition of fetal antigens may cause abortion. In this paper, we illustrate the complex immunologic aspects of human reproduction in terms of the role of human leukocyte antigen (HLA), immune cells, cytokines and chemokines, and the balance of immunity in pregnancy. In addition, we review the immunologic processes of human reproduction and the current immunologic therapeutic strategies for pathological disorders of pregnancy. PMID:22110530

AZT Impairs Immunological Recovery on First-line ART: Collaborative analysis of cohort studies in Southern Africa

PubMed Central

WANDELER, Gilles; GSPONER, Thomas; MULENGA, Lloyd; GARONE, Daniela; WOOD, Robin; MASKEW, Mhairi; PROZESKY, Hans; HOFFMANN, Christopher; EHMER, Jochen; DICKINSON, Diana; DAVIES, Mary-Ann; EGGER, Matthias; KEISER, Olivia

2013-01-01

Objectives Zidovudine (AZT) is recommended for first-line antiretroviral therapy (ART) in resource limited settings. AZT may, however, lead to anemia and impaired immunological response. We compared CD4 counts over 5 years between patients starting ART with and without AZT in Southern Africa. Design Cohort study Methods Patients aged ≥16 years who started first-line ART in South Africa, Botswana, Zambia or Lesotho were included. We used linear mixed-effect models to compare CD4 cell count trajectories between patients on AZT-containing regimens and patients on other regimens, censoring follow-up at first treatment change. Impaired immunological recovery, defined as a CD4 count below 100 cells/μl at 1 year, was assessed in logistic regression. Analyses were adjusted for baseline CD4 count and haemoglobin level, age, gender, type of regimen, viral load monitoring and calendar year. Results 72,597 patients starting ART, including 19,758 (27.2%) on AZT, were analysed. Patients on AZT had higher CD4 cell counts (150 vs.128 cells/μl) and haemoglobin level (12.0 vs. 11.0 g/dl) at baseline, and were less likely to be female than those on other regimens. Adjusted differences in CD4 counts between regimens containing and not containing AZT were −16 cells/μl (95% CI −18 to −14) at 1 year and −56 cells/μl (95% CI −59 to −52) at 5 years. Impaired immunological recovery was more likely with AZT compared to other regimens (odds ratio 1.40, 95% CI 1.22–1.61). Conclusions In Southern Africa AZT is associated with inferior immunological recovery compared to other backbones. Replacing AZT with another NRTI could avoid unnecessary switches to second-line ART. PMID:23660577

A baseline metabolomic signature is associated with immunological CD4+ T-cell recovery after 36 months of antiretroviral therapy in HIV-infected patients.

PubMed

Rodríguez-Gallego, Esther; Gómez, Josep; Pacheco, Yolanda M; Peraire, Joaquim; Viladés, Consuelo; Beltrán-Debón, Raúl; Mallol, Roger; López-Dupla, Miguel; Veloso, Sergi; Alba, Verónica; Blanco, Julià; Cañellas, Nicolau; Rull, Anna; Leal, Manuel; Correig, Xavier; Domingo, Pere; Vidal, Francesc

2018-03-13

Poor immunological recovery in treated HIV-infected patients is associated with greater morbidity and mortality. To date, predictive biomarkers of this incomplete immune reconstitution have not been established. We aimed to identify a baseline metabolomic signature associated with a poor immunological recovery after antiretroviral therapy (ART) to envisage the underlying mechanistic pathways that influence the treatment response. This was a multicentre, prospective cohort study in ART-naive and a pre-ART low nadir (<200 cells/μl) HIV-infected patients (n = 64). We obtained clinical data and metabolomic profiles for each individual, in which low molecular weight metabolites, lipids and lipoproteins (including particle concentrations and sizes) were measured by NMR spectroscopy. Immunological recovery was defined as reaching CD4 T-cell count at least 250 cells/μl after 36 months of virologically successful ART. We used univariate comparisons, Random Forest test and receiver-operating characteristic curves to identify and evaluate the predictive factors of immunological recovery after treatment. HIV-infected patients with a baseline metabolic pattern characterized by high levels of large high density lipoprotein (HDL) particles, HDL cholesterol and larger sizes of low density lipoprotein particles had a better immunological recovery after treatment. Conversely, patients with high ratios of non-HDL lipoprotein particles did not experience this full recovery. Medium very-low-density lipoprotein particles and glucose increased the classification power of the multivariate model despite not showing any significant differences between the two groups. In HIV-infected patients, a baseline healthier metabolomic profile is related to a better response to ART where the lipoprotein profile, mainly large HDL particles, may play a key role.

HIV Molecular Immunology 2014

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yusim, Karina; Korber, Bette Tina Marie; Barouch, Dan

HIV Molecular Immunology is a companion volume to HIV Sequence Compendium. This publication, the 2014 edition, is the PDF version of the web-based HIV Immunology Database (http://www.hiv.lanl.gov/content/immunology/). The web interface for this relational database has many search options, as well as interactive tools to help immunologists design reagents and interpret their results. In the HIV Immunology Database, HIV-specific B-cell and T-cell responses are summarized and annotated. Immunological responses are divided into three parts, CTL, T helper, and antibody. Within these parts, defined epitopes are organized by protein and binding sites within each protein, moving from left to right through themore » coding regions spanning the HIV genome. We include human responses to natural HIV infections, as well as vaccine studies in a range of animal models and human trials. Responses that are not specifically defined, such as responses to whole proteins or monoclonal antibody responses to discontinuous epitopes, are summarized at the end of each protein section. Studies describing general HIV responses to the virus, but not to any specific protein, are included at the end of each part. The annotation includes information such as crossreactivity, escape mutations, antibody sequence, TCR usage, functional domains that overlap with an epitope, immune response associations with rates of progression and therapy, and how specific epitopes were experimentally defined. Basic information such as HLA specificities for T-cell epitopes, isotypes of monoclonal antibodies, and epitope sequences are included whenever possible. All studies that we can find that incorporate the use of a specific monoclonal antibody are included in the entry for that antibody. A single T-cell epitope can have multiple entries, generally one entry per study. Finally, maps of all defined linear epitopes relative to the HXB2 reference proteins are provided.« less

Cosmos 2229 immunology study (Experiment K-8-07)

NASA Technical Reports Server (NTRS)

Sonnenfeld, Gerald

1993-01-01

The purpose of the current study was to further validate use of the rhesus monkey as a model for humans in future space flight testing. The areas of immunological importance examined in the Cosmos 2229 flight were represented by two sets of studies. The first set of studies determined the effect of space flight on the ability of bone marrow cells to respond to granulocyte/monocyte colony stimulating factor (GM-CSF). GM-CSF is an important regulator in the differentiation of bone marrow cells of both monocyte/macrophage and granulocyte lineages and any change in the ability of these cells to respond to GM-CSF can result in altered immune function. A second set of studies determined space flight effects on the expression of cell surface markers on both spleen and bone marrow cells. Immune cell markers included in this study were those for T-cell, B-cell, natural killer cell, and interleukin-2 populations. Variations from a normal cell population percentage, as represented by these markers, can be correlated with alterations in immunological function. Cells were stained with fluorescein-labelled antibodies directed against the appropriate antigens, and then analyzed using a flow cytometer.

Immunology for rheumatology residents: working toward a Canadian national curriculum consensus.

PubMed

Chow, Shirley L; Herman-Kideckel, Sari; Mahendira, Dharini; McDonald-Blumer, Heather

2015-01-01

Immunologic mechanisms play an integral role in understanding the pathogenesis and management of rheumatic conditions. Currently, there is limited access to formal instruction in immunology for rheumatology trainees across Canada. The aims of this study were (1) to describe current immunology curricula among adult rheumatology training programs across Canada and (2) to compare the perceived learning needs of rheumatology trainees from the perspective of program directors and trainees to help develop a focused nationwide immunology curriculum. Rheumatology trainees and program directors from adult rheumatology programs across Canada completed an online questionnaire and were asked to rank a comprehensive list of immunology topics. A modified Delphi approach was implemented to obtain consensus on immunology topics. Only 42% of program directors and 31% of trainees felt the current method of teaching immunology was effective. Results illustrate concordance between program directors and trainees for the highest-ranked immunology topics including innate immunity, adaptive immunity, and cells and tissues of the immune system. However, there was discordance among other topics, such as diagnostic laboratory immunology and therapeutics. There is a need to improve immunology teaching in rheumatology training programs. Results show high concordance between the basic immunology topics. This study provides the groundwork for development of future immunology curricula.

Expression of autophagy related genes mTOR, Becline-1, LC3 and p62 in the peripheral blood mononuclear cells of systemic lupus erythematosus.

PubMed

Wu, Zhen-Zhen; Zhang, Jun-Jun; Gao, Cong-Cong; Zhao, Man; Liu, Sheng-Yun; Gao, Guan-Min; Zheng, Zhao-Hui

2017-01-01

To determine the expression of mTOR, Becline-1, LC3 and p62 in the peripheral blood mononuclear cells (PBMCs) of systemic lupus erythematosus (SLE) and assess their relationship with disease activity and immunologic features. The expression of mTOR, Becline-1, LC3 and p62 was detected by RT-PCR in 81 SLE subjects and 86 age- and sex-matched healthy controls. Data regarding demographics and clinical parameters were collected. Disease activity of SLE was evaluated according to the SLE Disease Activity Index (SLEDAI) score. Independent sample t-test was used to analyze the expression of mTOR, Becline-1, LC3, and p62 in the two groups. Pearson's or Spearman's correlation was performed to analyze their relationship with disease activity and immunologic features. The mean levels of Becline-1, LC3 and p62 mRNA were significantly higher in SLE patients than the controls (9.96×10 -4 vs 7.38×10 -4 for Becline-1 with P <0.001; 4.04×10 -5 vs 2.62×10 -5 for LC3 with P <0.001; 9.51×10 -4 vs 7.59×10 -4 for p62 with P =0.008). However, the levels of mTOR mRNA in SLE patients were not significantly different from that in controls. Correlation analysis showed that Becline-1, LC3 and p62 mRNA levels correlated positively with SLEDAI, IgG and ds-DNA, negatively with C3. Our results suggested that autophagosomes formation were activated and their degradation were blocked in SLE. Moreover, the maintenance of autophagy balance can improve disease activity and immune disorders in SLE patients.

An experimental model of allergic asthma in cats sensitized to house dust mite or bermuda grass allergen.

PubMed

Norris Reinero, Carol R; Decile, Kendra C; Berghaus, Roy D; Williams, Kurt J; Leutenegger, Christian M; Walby, William F; Schelegle, Edward S; Hyde, Dallas M; Gershwin, Laurel J

2004-10-01

Animal models are used to mimic human asthma, however, not all models replicate the major characteristics of the human disease. Spontaneous development of asthma with hallmark features similar to humans has been documented to occur with relative frequency in only one animal species, the cat. We hypothesized that we could develop an experimental model of feline asthma using clinically relevant aeroallergens identified from cases of naturally developing feline asthma, and characterize immunologic, physiologic, and pathologic changes over 1 year. House dust mite (HDMA) and Bermuda grass (BGA) allergen were selected by screening 10 privately owned pet cats with spontaneous asthma using a serum allergen-specific IgE ELISA. Parenteral sensitization and aerosol challenges were used to replicate the naturally developing disease in research cats. The asthmatic phenotype was characterized using intradermal skin testing, serum allergen-specific IgE ELISA, serum and bronchoalveolar lavage fluid (BALF) IgG and IgA ELISAs, airway hyperresponsiveness testing, BALF cytology, cytokine profiles using TaqMan PCR, and histopathologic evaluation. Sensitization with HDMA or BGA in cats led to allergen-specific IgE production, allergen-specific serum and BALF IgG and IgA production, airway hyperreactivity, airway eosinophilia, an acute T helper 2 cytokine profile in peripheral blood mononuclear cells and BALF cells, and histologic evidence of airway remodeling. Using clinically relevant aeroallergens to sensitize and challenge the cat provides an additional animal model to study the immunopathophysiologic mechanisms of allergic asthma. Chronic exposure to allergen in the cat leads to a variety of immunologic, physiologic, and pathologic changes that mimic the features seen in human asthma.

Targeting Deacetylases to Improve Outcomes after Allogeneic Bone Marrow Transplantation

PubMed Central

Reddy, Pavan

2013-01-01

Graft-versus-host disease (GVHD) is the major complication of allogeneic bone marrow transplantation (BMT). GVHD is a complex immunologically mediated biological process. Recent data have shown that histone deacetylase inhibitors (HDACis) have potent anti-inflammatory effects. We have been studying the role of acetylation through inhibition of histone deacetylases (HDACs) in modulating immunity, specifically, GVHD. HDAC inhibition regulates GVHD, at least in part, through suppression of the function of host antigen presenting cells such as dendritic cells (DCs). HDACis reduce DC responses by enhancing the expression of indoleamine 2,3 dioxygenase (IDO) in a STAT-3–dependent manner. They also alter the function of other immune cells such as T regulatory cells and NK cells, which also play important roles in the biology of GVHD. Based on these observations, a clinical trial has been launched to evaluate its impact on clinical GVHD. The clinical features, biology of GVHD, the experimental studies with HDACis, and preliminary observations from humans are discussed. PMID:23874019

75 FR 11896 - National Institute of Allergy and Infectious Diseases; Notice of Closed Meetings

Federal Register 2010, 2011, 2012, 2013, 2014

2010-03-12

...: National Institute of Allergy and Infectious Diseases Special Emphasis Panel; B cell Immunology Partnership..., Allergy, Immunology, and Transplantation Research; 93.856, Microbiology and Infectious Diseases Research...

[The experimental evaluation with flow cytofluorimetry technique of the level of cellular immunologic memory in persons vaccinated against plague and anthrax].

PubMed

Bogacheva, N V; Kriuchkov, A V; Darmov, I V; Vorob'ev, K A; Pechenkin, D V; Elagin, G D; Kolesnikiov, D P

2013-11-01

The article deals with experimental evaluation with flow cytofluorimetry technique of the level of cellular immunologic memory in persons vaccinated with plague and anthrax live dry vaccines. It is established that the introduction of plague and anthrax live dry vaccines into organism of vaccinated persons ignites immunologic rearrangement manifested by reliable increase of level of blood concentration of Th1-lymphocytes (immunologic memory cells) against the background of vaccination. The higher correlation coefficient is detected between leucocytes lysis coefficient and stimulation coefficient according blood concentration level of T-lymphocytes predominantly at the expense of Th1-lymphocytes. The values of stimulation coefficient were calculated for corresponding blood cells of vaccinated persons. This data testifies the effectiveness of application of vaccination against plague and anthrax.

Membrane-bound Dickkopf-1 in Foxp3+ regulatory T cells suppresses T-cell-mediated autoimmune colitis.

PubMed

Chae, Wook-Jin; Park, Jong-Hyun; Henegariu, Octavian; Yilmaz, Saliha; Hao, Liming; Bothwell, Alfred L M

2017-10-01

Induction of tolerance is a key mechanism to maintain or to restore immunological homeostasis. Here we show that Foxp3 + regulatory T (Treg) cells use Dickkopf-1 (DKK-1) to regulate T-cell-mediated tolerance in the T-cell-mediated autoimmune colitis model. Treg cells from DKK-1 hypomorphic doubleridge mice failed to control CD4 + T-cell proliferation, resulting in CD4 T-cell-mediated autoimmune colitis. Thymus-derived Treg cells showed a robust expression of DKK-1 but not in naive or effector CD4 T cells. DKK-1 expression in Foxp3 + Treg cells was further increased upon T-cell receptor stimulation in vitro and in vivo. Interestingly, Foxp3 + Treg cells expressed DKK-1 in the cell membrane and the functional inhibition of DKK-1 using DKK-1 monoclonal antibody abrogated the suppressor function of Foxp3 + Treg cells. DKK-1 expression was dependent on de novo protein synthesis and regulated by the mitogen-activated protein kinase pathway but not by the canonical Wnt pathway. Taken together, our results highlight membrane-bound DKK-1 as a novel Treg-derived mediator to maintain immunological tolerance in T-cell-mediated autoimmune colitis. © 2017 The Authors. Immunology Published by John Wiley & Sons Ltd.

Cellular Sites of Immunologic Unresponsiveness*

PubMed Central

Chiller, Jacques M.; Habicht, Gail S.; Weigle, William O.

1970-01-01

The reconstitution of the immune response of lethally irradiated mice to human γ-globulin is dependent on the synergistic action of bone marrow with thymus cells. Immunologic unresponsiveness appears to involve a functional defect at each of these cellular levels, inasmuch as neither bone marrow nor thymus cells from unresponsive donors are capable of demonstrating synergism in combination with their normal counterpart. PMID:4192271

Advances in basic and clinical immunology in 2016.

PubMed

Chinen, Javier; Badran, Yousef R; Geha, Raif S; Chou, Janet S; Fried, Ari J

2017-10-01

Advances in basic immunology in 2016 included studies that further characterized the role of different proteins in the differentiation of effector T and B cells, including cytokines and proteins involved in the actin cytoskeleton. Regulation of granule formation and secretion in cytotoxic cells was also further described by examining patients with familial hemophagocytic lymphohistiocytosis. The role of prenylation in patients with mevalonate kinase deficiency leading to inflammation has been established. We reviewed advances in clinical immunology, as well as new approaches of whole-genome sequencing and genes newly reported to be associated with immunodeficiency, such as linker of activation of T cells (LAT); B-cell CLL/lymphoma 11B (BCL11B); RGD, leucine-rich repeat, tropomodulin domain, and proline-rich domain-containing protein (RLTPR); moesin; and Janus kinase 1 (JAK1). Trials of hematopoietic stem cell transplantation and gene therapy for primary immunodeficiency have had relative success; the use of autologous virus-specific cytotoxic T cells has proved effective as well. New medications are being explored, such as pioglitazone, which is under study for its role in enhancing the oxidative burst in patients with chronic granulomatous disease. Development of vaccines for HIV infection continues to provide insight into the immune response against a virus with an extraordinary mutation rate. Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

IMMUNOLOGIC MEMORY CELLS OF BONE MARROW ORIGIN

PubMed Central

Miller, Harold C.; Cudkowicz, Gustavo

1972-01-01

Individual immunocompetent precursor cells of (C57BL/10 x C3H)F1 mouse marrow generate, on transplantation, three to five times more antibody-forming cells localized in recipient spleens during secondary than during primary immune responses. The increased burst size is immunologically specific since antigens of horse and chicken erythrocytes and of Salmonella typhimurium do not cause this effect in marrow cells responsive to sheep red blood cells. Both sensitized and nonsensitized precursors require the helper function of thymus-derived cells and antigen for the final steps of differentiation and maturation. The burst size of primed precursor cells is the same after cooperative interactions with virgin or educated helper cells of thymic origin. The greater potential of these marrow precursors may be attributable to self-replication and migration before differentiation into antibody-forming descendants. In fact, the progeny cells of primed precursor units are distributed among a multiplicity of foci, whereas those of nonimmune precursors are clustered into one focus. The described properties of specifically primed marrow precursors are those underlying immunologic memory. It remains to be established whether memory cells are induced or selected by antigens and whether the thymus plays a role in this process. PMID:4553850

Isolation and preservation of peripheral blood mononuclear cells for analysis of islet antigen-reactive T cell responses: position statement of the T-Cell Workshop Committee of the Immunology of Diabetes Society.

PubMed

Mallone, R; Mannering, S I; Brooks-Worrell, B M; Durinovic-Belló, I; Cilio, C M; Wong, F S; Schloot, N C

2011-01-01

Autoimmune T cell responses directed against insulin-producing β cells are central to the pathogenesis of type 1 diabetes (T1D). Detection of such responses is therefore critical to provide novel biomarkers for T1D 'immune staging' and to understand the mechanisms underlying the disease. While different T cell assays are being developed for these purposes, it is important to optimize and standardize methods for processing human blood samples for these assays. To this end, we review data relevant to critical parameters in peripheral blood mononuclear cell (PBMC) isolation, (cryo)preservation, distribution and usage for detecting antigen-specific T cell responses. Based on these data, we propose recommendations on processing blood samples for T cell assays and identify gaps in knowledge that need to be addressed. These recommendations may be relevant not only for the analysis of T cell responses in autoimmune disease, but also in cancer and infectious disease, particularly in the context of clinical trials. © 2010 The Authors. Clinical and Experimental Immunology © 2010 British Society for Immunology.

Whole Exome Sequencing identifies a splicing mutation in NSUN2 as a cause of a Dubowitz-like syndrome

PubMed Central

Martinez, Fernando; Lee, Jeong Ho; Lee, Ji Eun; Blanco, Sandra; Nickerson, Elizabeth; Gabriel, Stacey; Frye, Michaela; Al-Gazali, Lihadh; Gleeson, Joseph G.

2016-01-01

Dubowitz Syndrome is an autosomal recessive disorder characterized by the constellation of mild microcephaly, growth and mental retardation, eczema and peculiar facies, but causes are still unknown. We studied a multiplex consanguineous family with many features of Dubowitz syndrome using whole exome sequencing and identified a splice mutation in NSUN2, encoding a conserved RNA methyltransferase. NSUN2 has been implicated in Myc-induced cell proliferation and mitotic spindle stability, which might help explain the varied clinical presentations that can include chromosomal instability and immunological defects. Patient cells displayed loss of NSUN2-specific methylation at two residues of the aspartate tRNA. Our findings establish NSUN2 as the first causal gene with relationship to the Dubowitz syndrome spectrum phenotype. PMID:22577224

The complex pathophysiology of acquired aplastic anaemia.

PubMed

Zeng, Y; Katsanis, E

2015-06-01

Immune-mediated destruction of haematopoietic stem/progenitor cells (HSPCs) plays a central role in the pathophysiology of acquired aplastic anaemia (aAA). Dysregulated CD8(+) cytotoxic T cells, CD4(+) T cells including T helper type 1 (Th1), Th2, regulatory T cells and Th17 cells, natural killer (NK) cells and NK T cells, along with the abnormal production of cytokines including interferon (IFN)-γ, tumour necrosis factor (TNF)-α and transforming growth factor (TGF)-β, induce apoptosis of HSPCs, constituting a consistent and defining feature of severe aAA. Alterations in the polymorphisms of TGF-β, IFN-γ and TNF-α genes, as well as certain human leucocyte antigen (HLA) alleles, may account for the propensity to immune-mediated killing of HSPCs and/or ineffective haematopoiesis. Although the inciting autoantigens remain elusive, autoantibodies are often detected in the serum. In addition, recent studies provide genetic and molecular evidence that intrinsic and/or secondary deficits in HSPCs and bone marrow mesenchymal stem cells may underlie the development of bone marrow failure. © 2015 British Society for Immunology.

Merkel cell carcinoma: Do you know your guidelines?

PubMed

Miles, Brett A; Goldenberg, David

2016-05-01

Merkel cell carcinoma (MCC) is a cutaneous neuroendocrine malignancy that exhibits clinically aggressive features and is associated with a poor prognosis. The incidence of MCC seems to be increasing for reasons unknown, and is estimated to be 0.32/100,000 in the United States. This article will review the current literature and National Comprehensive Cancer Network practice guidelines in the treatment of MCC. Resection of MCC with negative margins remains the mainstay of therapy. Positive nodal disease should be treated with neck dissection and adjuvant radiotherapy. High-risk patients should undergo adjuvant radiotherapy, which improves oncologic outcomes. The role of chemotherapy is less clear and is currently reserved for advanced-stage MCC and palliative therapy. The pathogenesis of MCC has recently been impacted with the discovery of the Merkel cell polyomavirus (MCPyV). Research to establish targeted and immunologic therapeutic options are ongoing. © 2015 Wiley Periodicals, Inc.

Clinical-grade production of human mesenchymal stromal cells: occurrence of aneuploidy without transformation.

PubMed

Tarte, Karin; Gaillard, Julien; Lataillade, Jean-Jacques; Fouillard, Loic; Becker, Martine; Mossafa, Hossein; Tchirkov, Andrei; Rouard, Hélène; Henry, Catherine; Splingard, Marie; Dulong, Joelle; Monnier, Delphine; Gourmelon, Patrick; Gorin, Norbert-Claude; Sensebé, Luc

2010-02-25

Clinical-grade human mesenchymal stromal cells (MSCs) have been expanded in vitro for tissue engineering or immunoregulatory purposes without standardized culture conditions or release criteria. Although human MSCs show poor susceptibility for oncogenic transformation, 2 recent studies described their capacity to accumulate chromosomal instability and to give rise to carcinoma in immunocompromised mice after long-term culture. We thus investigated the immunologic and genetic features of MSCs expanded with fetal calf serum and fibroblast growth factor or with platelet lysate in 4 cell-therapy facilities during 2 multicenter clinical trials. Cultured MSCs showed a moderate expression of human leukocyte antigen-DR without alteration of their low immunogenicity or their immunomodulatory capacity. Moreover, some transient and donor-dependent recurring aneuploidy was detected in vitro, independently of the culture process. However, MSCs with or without chromosomal alterations showed progressive growth arrest and entered senescence without evidence of transformation either in vitro or in vivo.

AntiJen: a quantitative immunology database integrating functional, thermodynamic, kinetic, biophysical, and cellular data

PubMed Central

Toseland, Christopher P; Clayton, Debra J; McSparron, Helen; Hemsley, Shelley L; Blythe, Martin J; Paine, Kelly; Doytchinova, Irini A; Guan, Pingping; Hattotuwagama, Channa K; Flower, Darren R

2005-01-01

AntiJen is a database system focused on the integration of kinetic, thermodynamic, functional, and cellular data within the context of immunology and vaccinology. Compared to its progenitor JenPep, the interface has been completely rewritten and redesigned and now offers a wider variety of search methods, including a nucleotide and a peptide BLAST search. In terms of data archived, AntiJen has a richer and more complete breadth, depth, and scope, and this has seen the database increase to over 31,000 entries. AntiJen provides the most complete and up-to-date dataset of its kind. While AntiJen v2.0 retains a focus on both T cell and B cell epitopes, its greatest novelty is the archiving of continuous quantitative data on a variety of immunological molecular interactions. This includes thermodynamic and kinetic measures of peptide binding to TAP and the Major Histocompatibility Complex (MHC), peptide-MHC complexes binding to T cell receptors, antibodies binding to protein antigens and general immunological protein-protein interactions. The database also contains quantitative specificity data from position-specific peptide libraries and biophysical data, in the form of diffusion co-efficients and cell surface copy numbers, on MHCs and other immunological molecules. The uses of AntiJen include the design of vaccines and diagnostics, such as tetramers, and other laboratory reagents, as well as helping parameterize the bioinformatic or mathematical in silico modeling of the immune system. The database is accessible from the URL: . PMID:16305757

Nutritional and Immunological Correlates of Memory and Neurocognitive Development Among HIV-Infected Children Living in Kayunga, Uganda.

PubMed

Ruiseñor-Escudero, Horacio; Familiar-Lopez, Itziar; Sikorskii, Alla; Jambulingam, Nikita; Nakasujja, Noelline; Opoka, Robert; Bass, Judith; Boivin, Michael

2016-04-15

To identify the nutritional and immunological correlates of memory and neurocognitive development as measured by the Mullen Scales of Early Learning (MSEL) and by the Color Object Association Test (COAT) among children in Uganda. This analysis uses baseline data collected between 2008 and 2010 from 119 HIV-infected children aged 1-6 years, participating in a randomized controlled trial of an interventional parenting program in Kayunga, Uganda. Peripheral blood draws were performed to determine immunological biomarkers. Unadjusted and adjusted linear regression models were used to relate MSEL and COAT scores to sociodemographic characteristics, weight-for-age Z scores (WAZs), antiretroviral therapy status, and immunological biomarkers. In the final analysis, 111 children were included. Lower levels of CD4 CD38 T cells (P = 0.04) were associated to higher immediate and total recall scores (P = 0.04). Higher levels of CD8 HLA-DR T cells were associated with higher total recall score (P = 0.04) of the COAT. Higher CD4 CD38 HLA-DR T cells levels were associated with higher gross motor scores of the MSEL (P = 0.02). WAZ was positively correlated to visual reception, fine motor, expressive language, and composite score of the MSEL. Overall, WAZ was a stronger predictor of neurocognitive outcomes assessed by the MSEL. CD4 CD38 T cells were more specifically associated with memory-related outcomes. Future research should include immunological markers and standardized neurocognitive tests to further understand this relationship.

A correlative and quantitative imaging approach enabling characterization of primary cell-cell communication: Case of human CD4+ T cell-macrophage immunological synapses.

PubMed

Kasprowicz, Richard; Rand, Emma; O'Toole, Peter J; Signoret, Nathalie

2018-05-22

Cell-to-cell communication engages signaling and spatiotemporal reorganization events driven by highly context-dependent and dynamic intercellular interactions, which are difficult to capture within heterogeneous primary cell cultures. Here, we present a straightforward correlative imaging approach utilizing commonly available instrumentation to sample large numbers of cell-cell interaction events, allowing qualitative and quantitative characterization of rare functioning cell-conjugates based on calcium signals. We applied this approach to examine a previously uncharacterized immunological synapse, investigating autologous human blood CD4 + T cells and monocyte-derived macrophages (MDMs) forming functional conjugates in vitro. Populations of signaling conjugates were visualized, tracked and analyzed by combining live imaging, calcium recording and multivariate statistical analysis. Correlative immunofluorescence was added to quantify endogenous molecular recruitments at the cell-cell junction. By analyzing a large number of rare conjugates, we were able to define calcium signatures associated with different states of CD4 + T cell-MDM interactions. Quantitative image analysis of immunostained conjugates detected the propensity of endogenous T cell surface markers and intracellular organelles to polarize towards cell-cell junctions with high and sustained calcium signaling profiles, hence defining immunological synapses. Overall, we developed a broadly applicable approach enabling detailed single cell- and population-based investigations of rare cell-cell communication events with primary cells.

Innate lymphoid cells and parasites: Ancient foes with shared history.

PubMed

Neill, D R; Fallon, P G

2018-02-01

This special issue of Parasite Immunology charts the rapid advances made in our understanding of the myriad interactions between innate lymphoid cells and parasites and how these interactions have shaped our evolutionary history. Here, we provide an overview of the issue and highlight key findings from studies in mice and man. © 2017 The Authors. Parasite Immunology Published by John Wiley & Sons Ltd.

An in vitro investigation of immunomodulatory properties of Lactobacillus plantarum and L. delbrueckii cells and their extracellular polysaccharides

PubMed Central

KISHIMOTO, Mana; NOMOTO, Ryohei; MIZUNO, Masashi; OSAWA, Ro

2017-01-01

Many probiotic lactobacilli and their extracellular polysaccharides (EPS) have beneficial immunological properties. However, it is unclear how they elicit the host immune response. We thus investigated the immunological properties of UV-killed Lactobacillus delbrueckii TU-1 and L. plantarum KM-9 cells as well as their extracellular polysaccharides (EPSs). High-performance liquid chromatography and ion exchange chromatography analyses showed that their EPSs differ in sugar composition and sugar fractionation. The immunological properties were evaluated in a semi-intestinal model using a Transwell co-culture system that employed human intestinal epithelial (Caco-2) cells on the apical side and murine macrophage (RAW264.7) cells on the basolateral side. The UV-killed cells and EPSs were added to the apical side to allow direct contact with Caco-2 cells and incubated for 6 hr. After incubation, the amounts of tumor necrosis factor-α and several cytokines released by RAW264.7 or Caco-2 cells were quantified by cytotoxic activity on L929 cells (murine fibrosarcoma cell line) and quantitative reverse-transcriptase PCR. We found that the UV-killed cells and their EPSs had immunological effects on RAW264.7 cells via Caco-2 cells. The RAW264.7 cells showed different cytokine production profiles when treated with UV-killed cells and EPSs. The UV-killed cells and EPSs promoted a Th1-type cellular response. Furthermore, we found that the UV-killed cells sent positive signals through Toll-like receptor (TLR) 2. Meanwhile, neither EPS sent a positive signal through TLR4 and TLR2. This evidence suggests that both UV-killed cells of the lactobacillus strains and their EPSs trigger a Th1-type immune response in a human host, with the former triggering the response via the TLRs expressed on its epithelium and the latter employing a mechanism yet to be determined, possibly involving a novel receptor that is designed to recognize specific patterns of repeating sugar in the EPSs. PMID:28748131

An in vitro investigation of immunomodulatory properties of Lactobacillus plantarum and L. delbrueckii cells and their extracellular polysaccharides.

PubMed

Kishimoto, Mana; Nomoto, Ryohei; Mizuno, Masashi; Osawa, Ro

2017-01-01

Many probiotic lactobacilli and their extracellular polysaccharides (EPS) have beneficial immunological properties. However, it is unclear how they elicit the host immune response. We thus investigated the immunological properties of UV-killed Lactobacillus delbrueckii TU-1 and L. plantarum KM-9 cells as well as their extracellular polysaccharides (EPSs). High-performance liquid chromatography and ion exchange chromatography analyses showed that their EPSs differ in sugar composition and sugar fractionation. The immunological properties were evaluated in a semi-intestinal model using a Transwell co-culture system that employed human intestinal epithelial (Caco-2) cells on the apical side and murine macrophage (RAW264.7) cells on the basolateral side. The UV-killed cells and EPSs were added to the apical side to allow direct contact with Caco-2 cells and incubated for 6 hr. After incubation, the amounts of tumor necrosis factor-α and several cytokines released by RAW264.7 or Caco-2 cells were quantified by cytotoxic activity on L929 cells (murine fibrosarcoma cell line) and quantitative reverse-transcriptase PCR. We found that the UV-killed cells and their EPSs had immunological effects on RAW264.7 cells via Caco-2 cells. The RAW264.7 cells showed different cytokine production profiles when treated with UV-killed cells and EPSs. The UV-killed cells and EPSs promoted a Th1-type cellular response. Furthermore, we found that the UV-killed cells sent positive signals through Toll-like receptor (TLR) 2. Meanwhile, neither EPS sent a positive signal through TLR4 and TLR2. This evidence suggests that both UV-killed cells of the lactobacillus strains and their EPSs trigger a Th1-type immune response in a human host, with the former triggering the response via the TLRs expressed on its epithelium and the latter employing a mechanism yet to be determined, possibly involving a novel receptor that is designed to recognize specific patterns of repeating sugar in the EPSs.

75 FR 48978 - National Institute of Allergy and Infectious Diseases; Notice of Closed Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2010-08-12

... Infectious Diseases Special Emphasis Panel; T-Cell Immunology. Date: September 16, 2010. Time: 12:30 p.m. to....gov . (Catalogue of Federal Domestic Assistance Program Nos. 93.855, Allergy, Immunology, and...

Breaking immunological tolerance through OX40 (CD134).

PubMed

Bansal-Pakala, P; Croft, M

2001-11-06

Immunological tolerance represents a mechanism by which cells of the host remain protected from the immune system. Breaking of immunological tolerance can result in a variety of autoimmune diseases such as rheumatoid arthritis, diabetes, and multiple sclerosis. The reasons for tolerance breaking down and autoimmune processes arising are largely unknown but of obvious interest for therapeutic intervention of these diseases. Although reversal of the tolerant state is generally unwanted, there are instances where this may be of benefit to the host. In particular, one way a cancerous cell escapes being targeted by the immune system is through tolerance mechanisms that in effect turn off the reactivity of T lymphocytes that can respond to tumor-associated peptides. Thus tolerance represents a major obstacle in developing effective immunotherapy against tumors. The molecules that are involved in regulating immunological tolerance are then of interest as they may be great targets for positively or negatively manipulating the tolerance process.

Importin Beta Plays an Essential Role in the Regulation of the LysRS-Ap4A Pathway in Immunologically Activated Mast Cells ▿

PubMed Central

Carmi-Levy, Irit; Motzik, Alex; Ofir-Birin, Yifat; Yagil, Zohar; Yang, Christopher Maolin; Kemeny, David Michael; Han, Jung Min; Kim, Sunghoon; Kay, Gillian; Nechushtan, Hovav; Suzuki, Ryo; Rivera, Juan; Razin, Ehud

2011-01-01

We recently reported that diadenosine tetraphosphate hydrolase (Ap4A hydrolase) plays a critical role in gene expression via regulation of intracellular Ap4A levels. This enzyme serves as a component of our newly described lysyl tRNA synthetase (LysRS)-Ap4A biochemical pathway that is triggered upon immunological challenge. Here we explored the mechanism of this enzyme's translocation into the nucleus and found its immunologically dependent association with importin beta. Silencing of importin beta prevented Ap4A hydrolase nuclear translocation and affected the local concentration of Ap4A, which led to an increase in microphthalmia transcription factor (MITF) transcriptional activity. Furthermore, immunological activation of mast cells resulted in dephosphorylation of Ap4A hydrolase, which changed the hydrolytic activity of the enzyme. PMID:21402779

Lupus erythematosus revisited.

PubMed

Kuhn, Annegret; Wenzel, Joerg; Bijl, Marc

2016-01-01

Lupus erythematosus (LE) is a multifactorial autoimmune disease with clinical manifestations of differing severity. The exact pathomechanisms and interactions resulting in the inflammatory and immunological processes of this heterogeneous disease remain elusive. Approaches in the understanding of the pathomechanisms revealed that the clinical expression of LE is predisposed by susceptibility genes and that various environmental factors are responsible for an abnormal immune response. Several studies demonstrated that ultraviolet (UV) light is one of the major factors in the pathogenesis of the disease. Standardized photoprovocation in patients with LE has been shown to be a safe and efficient model for evaluating the underlying pathomechanisms which lead to the production of autoantibodies and immune complexes. In particular, interferons were defined as important players in the early activation of the immune system and were observed to play a specific role in the immunological interface between the innate and the adaptive immune system. Abnormalities or disturbances in the different processes of cell death, such as apoptosis or necrosis, have also been recognized as crucial in the pathogenesis of LE. Although each process is different and characterized by unique features, the processes are interrelated and result in a complex disease.

Diagnosis, Treatment and Long-Term Follow Up of Patients with ADA Deficiency: a Single-Center Experience.

PubMed

Baffelli, Renata; Notarangelo, Lucia D; Imberti, Luisa; Hershfield, Michael S; Serana, Federico; Santisteban, Ines; Bolda, Federica; Porta, Fulvio; Lanfranchi, Arnalda

2015-10-01

We carried out a retrospective analysis of 27 patients with Adenosine Deaminase (ADA) deficiency diagnosed in a single center from 1997 to the 2013, for evaluating whether data regarding types of disease-inducing mutations, biochemical and immunological features as well as clinical outcomes of patients treated with enzyme replacement or transplantation, were comparable to those obtained in multicenter studies. The ADA deficiency diagnosis was performed with biochemical, immunological and molecular techniques. Ten patients treated with hematopoietic stem cell transplantation and three in treatment with enzyme replacement were followed up in our center. Twenty-four different mutations were identified and five were not previously reported. Identical mutations were found among patients from the same Romani ethnic group or from the same geographical region. A more rapid recovery was observed in enzyme replacement treated patients in comparison with those transplanted that, however, showed a continuous and long-lasting improvement both in terms of immune and metabolic recovery. The data obtained in our single center are comparable with those that have been reported in multicenter surveys.

Annular erythema in primary Sjogren's syndrome: description of 43 non-Asian cases.

PubMed

Brito-Zerón, P; Retamozo, S; Akasbi, M; Gandía, M; Perez-De-Lis, M; Soto-Cardenas, M-J; Diaz-Lagares, C; Kostov, B; Bove, A; Bosch, X; Perez-Alvarez, R; Siso, A; Ramos-Casals, M

2014-02-01

The objective of this paper is to evaluate the prevalence and characterize the main epidemiological, clinical and immunological features of annular erythema (AE) in non-Asian patients with primary Sjögren's syndrome (SS). We carried out a retrospective study searching for AE in 377 Spanish patients with primary SS fulfilling the 2002 American-European criteria. In addition, we searched PubMed (1994-2012) using the MeSH terms "annular erythema" and "primary Sjögren's syndrome" for additional cases. All cases with AE reported in patients with SS associated with systemic lupus erythematosus were excluded. In our Spanish cohort, we found 35 (9%) patients diagnosed with AE. All were white females, with a mean age of 47 years at diagnosis of AE. AE preceded diagnosis of SS in 27 (77%) patients. Cutaneous AE lesions involved principally the face and upper extremities. All patients reported photosensitivity, with cutaneous flares being reported during the warmest months in 93% of patients. Immunological markers consisted of anti-Ro/La antibodies in 31 (89%) patients. In the literature search, we identified eight additional non-Asian patients with primary SS diagnosed with AE. In comparison with 52 Asian patients, the 43 non-Asian patients with AE related to primary SS were more frequently women (100% vs 78%, p=0.008), and cutaneous lesions were less frequently reported in the face (55% vs 81%, p=0.045) and more frequently in the neck (40% vs 14%, p=0.041). Immunologically, non-Asian patients had a lower frequency of anti-Ro antibodies and a higher frequency of negative Ro/La antibodies, although the differences were not statistically significant. AE is not an exclusive cutaneous feature of Asian patients with primary SS. In addition to the characteristic cutaneous expression, AE has a very specific clinical and immunological profile: often presenting before the fulfillment of SS criteria, overwhelmingly associated with anti-Ro antibodies but weakly associated with other immunological markers and the main systemic SS-related features.

Loss of the Cyclin-Dependent Kinase Inhibitor 1 in the Context of Brachyury-Mediated Phenotypic Plasticity Drives Tumor Resistance to Immune Attack.

PubMed

Hamilton, Duane H; McCampbell, Kristen K; Palena, Claudia

2018-01-01

The acquisition of mesenchymal features by carcinoma cells is now recognized as a driver of metastasis and tumor resistance to a range of anticancer therapeutics, including chemotherapy, radiation, and certain small-molecule targeted therapies. With the recent successful implementation of immunotherapies for the treatment of various types of cancer, there is growing interest in understanding whether an immunological approach could be effective at eradicating carcinoma cells bearing mesenchymal features. Recent studies, however, demonstrated that carcinoma cells that have acquired mesenchymal features may also exhibit decreased susceptibility to lysis mediated by immune effector cells, including antigen-specific CD8 + T cells, innate natural killer (NK), and lymphokine-activated killer (LAK) cells. Here, we investigated the mechanism involved in the immune resistance of carcinoma cells that express very high levels of the transcription factor brachyury, a molecule previously shown to drive the acquisition of mesenchymal features by carcinoma cells. Our results demonstrate that very high levels of brachyury expression drive the loss of the cyclin-dependent kinase inhibitor 1 (p21CIP1, p21), an event that results in decreased tumor susceptibility to immune-mediated lysis. We show here that reconstitution of p21 expression markedly increases the lysis of brachyury-high tumor cells mediated by antigen-specific CD8 + T cells, NK, and LAK cells, TNF-related apoptosis-inducing ligand, and chemotherapy. Several reports have now demonstrated a role for p21 loss in cancer as an inducer of the epithelial-mesenchymal transition. The results from the present study situate p21 as a central player in many of the aspects of the phenomenon of brachyury-mediated mesenchymalization of carcinomas, including resistance to chemotherapy and immune-mediated cytotoxicity. We also demonstrate here that the defects in tumor cell death described in association with very high levels of brachyury could be alleviated via the use of a WEE1 inhibitor. Several vaccine platforms targeting brachyury have been developed and are undergoing clinical evaluation. These studies provide further rationale for the use of WEE1 inhibition in combination with brachyury-based immunotherapeutic approaches.

Loss of the Cyclin-Dependent Kinase Inhibitor 1 in the Context of Brachyury-Mediated Phenotypic Plasticity Drives Tumor Resistance to Immune Attack

PubMed Central

Hamilton, Duane H.; McCampbell, Kristen K.; Palena, Claudia

2018-01-01

The acquisition of mesenchymal features by carcinoma cells is now recognized as a driver of metastasis and tumor resistance to a range of anticancer therapeutics, including chemotherapy, radiation, and certain small-molecule targeted therapies. With the recent successful implementation of immunotherapies for the treatment of various types of cancer, there is growing interest in understanding whether an immunological approach could be effective at eradicating carcinoma cells bearing mesenchymal features. Recent studies, however, demonstrated that carcinoma cells that have acquired mesenchymal features may also exhibit decreased susceptibility to lysis mediated by immune effector cells, including antigen-specific CD8+ T cells, innate natural killer (NK), and lymphokine-activated killer (LAK) cells. Here, we investigated the mechanism involved in the immune resistance of carcinoma cells that express very high levels of the transcription factor brachyury, a molecule previously shown to drive the acquisition of mesenchymal features by carcinoma cells. Our results demonstrate that very high levels of brachyury expression drive the loss of the cyclin-dependent kinase inhibitor 1 (p21CIP1, p21), an event that results in decreased tumor susceptibility to immune-mediated lysis. We show here that reconstitution of p21 expression markedly increases the lysis of brachyury-high tumor cells mediated by antigen-specific CD8+ T cells, NK, and LAK cells, TNF-related apoptosis-inducing ligand, and chemotherapy. Several reports have now demonstrated a role for p21 loss in cancer as an inducer of the epithelial–mesenchymal transition. The results from the present study situate p21 as a central player in many of the aspects of the phenomenon of brachyury-mediated mesenchymalization of carcinomas, including resistance to chemotherapy and immune-mediated cytotoxicity. We also demonstrate here that the defects in tumor cell death described in association with very high levels of brachyury could be alleviated via the use of a WEE1 inhibitor. Several vaccine platforms targeting brachyury have been developed and are undergoing clinical evaluation. These studies provide further rationale for the use of WEE1 inhibition in combination with brachyury-based immunotherapeutic approaches. PMID:29774202

Association between discordant immunological response to highly active anti-retroviral therapy, regulatory T cell percentage, immune cell activation and very low-level viraemia in HIV-infected patients

PubMed Central

Saison, J; Ferry, T; Demaret, J; Maucort Boulch, D; Venet, F; Perpoint, T; Ader, F; Icard, V; Chidiac, C; Monneret, G

2014-01-01

The mechanisms sustaining the absence of complete immune recovery in HIV-infected patients upon long-term effective highly active anti-retroviral therapy (HAART) remain elusive. Immune activation, regulatory T cells (Tregs) or very low-level viraemia (VLLV) have been alternatively suspected, but rarely investigated simultaneously. We performed a cross-sectional study in HIV-infected aviraemic subjects (mean duration of HAART: 12 years) to concomitantly assess parameters associated independently with inadequate immunological response. Patients were classified as complete immunological responders (cIR, n = 48) and inadequate immunological responders (iIR, n = 39), depending on the CD4+ T cell count (> or < 500/mm3). Clinical and virological data (including very low-level viraemia) were collected. In parallel, immunophenotyping of CD4+ lymphocytes, including Treg subsets, and CD8+ T cells was performed. Percentages of activated CD4+ T cells, Tregs, effector Tregs and terminal effector Tregs were found to be significantly elevated in iIR. Neither the percentage of activated CD8+ T cells nor VLLV were found to be associated with iIR. In the multivariate analysis, nadir of CD4+ T cell count and percentage of Tregs were the only two parameters associated independently with iIR [odds ratio (OR) = 2·339, P = 0·001, and OR = 0·803, P = 0·041]. We present here the largest study investigating simultaneously the immune response to long-term HAART, activation of CD4+ and CD8+ T cells, Treg percentages and very low-level viraemia. Causative interactions between Tregs and CD4+ T cells should now be explored prospectively in a large patients cohort. PMID:24460818

Performance of immunological response in predicting virological failure.

PubMed

Ingole, Nayana; Mehta, Preeti; Pazare, Amar; Paranjpe, Supriya; Sarkate, Purva

2013-03-01

In HIV-infected individuals on antiretroviral therapy (ART), the decision on when to switch from first-line to second-line therapy is dictated by treatment failure, and this can be measured in three ways: clinically, immunologically, and virologically. While viral load (VL) decreases and CD4 cell increases typically occur together after starting ART, discordant responses may be seen. Hence the current study was designed to determine the immunological and virological response to ART and to evaluate the utility of immunological response to predict virological failure. All treatment-naive HIV-positive individuals aged >18 years who were eligible for ART were enrolled and assessed at baseline, 6 months, and 12 months clinically and by CD4 cell count and viral load estimations. The patients were categorized as showing concordant favorable (CF), immunological only (IO), virological only (VO), and concordant unfavorable responses (CU). The efficiency of immunological failure to predict virological failure was analyzed across various levels of virological failure (VL>50, >500, and >5,000 copies/ml). At 6 months, 87(79.81%), 7(5.5%), 13 (11.92%), and 2 (1.83%) patients and at 12 months 61(69.3%), 9(10.2%), 16 (18.2%), and 2 (2.3%) patients had CF, IO, VO, and CU responses, respectively. Immunological failure criteria had a very low sensitivity (11.1-40%) and positive predictive value (8.3-25%) to predict virological failure. Immunological criteria do not accurately predict virological failure resulting in significant misclassification of therapeutic responses. There is an urgent need for inclusion of viral load testing in the initiation and monitoring of ART.

Altered phenotype and functionality of varicella zoster virus-specific cellular immunity in individuals with active infection.

PubMed

Schub, David; Janssen, Eva; Leyking, Sarah; Sester, Urban; Assmann, Gunter; Hennes, Pia; Smola, Sigrun; Vogt, Thomas; Rohrer, Tilman; Sester, Martina; Schmidt, Tina

2015-02-15

Varicella zoster virus (VZV) establishes lifelong persistence and may reactivate in individuals with impaired immune function. To investigate immunologic correlates of protection and VZV reactivation, we characterized specific immunity in 207 nonsymptomatic immunocompetent and 132 immunocompromised individuals in comparison with patients with acute herpes zoster. VZV-specific CD4 T cells were quantified flow cytometrically after stimulation and characterized for expression of interferon-γ, interleukin 2, and tumor necrosis factor α and surface markers for differentiation (CD127) and anergy (cytotoxic T lymphocyte antigen 4 [CTLA-4] and programmed death [PD]-1). Immunoglobulin G and A levels were quantified using an enzyme-linked immunosorbent assay. In healthy individuals, VZV-specific antibody and T-cell levels were age dependent, with the highest median VZV-specific CD4 T-cell frequencies of 0.108% (interquartile range, 0.121%) during adolescence. VZV-specific T-cell profiles were multifunctional with predominant expression of all 3 cytokines, CD127 positivity, and low expression of CTLA-4 and PD-1. Nonsymptomatic immunocompromised patients had similar VZV-specific immunologic properties except for lower T-cell frequencies (P<.001) and restricted cytokine expression. In contrast, significantly elevated antibody- and VZV-specific CD4 T-cell levels were found in patients with zoster. Their specific T cells showed a shift in cytokine expression toward interferon γ single positivity, an increase in CTLA-4 and PD-1, and a decrease in CD127 expression (all P<.001). This phenotype normalized after resolution of symptoms. VZV-specific CD4-T cells in patients with zoster bear typical features of anergy. This phenotype is reversible and may serve as adjunct tool for monitoring VZV reactivations in high-risk patients. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

THE EFFICACY OF THREE MEDICINAL PLANTS: GARLIC, GINGER AND MIRAZID AND A CHEMICAL DRUG METRONIDAZOLE AGAINST CRYPTOSPORIDIUM PARVUM. I-IMMUNOLOGICAL RESPONSE.

PubMed

Abouel-Nour, Mohamed F; EL-Shewehy, Dina Magdy M; Hamada, Shadia F; Morsy, Tosson A

2015-12-01

Cryptosporidisis parvum is a zoonotic protozoan parasite infects intestinal epithelial cells causing a major health problem for man and animals. Experimentally the immunologic mediated elimination of C. parvum requires CD4+ T cells and IFN-gamma. But, the innate immune responses also have a significant protective role in both man and animals. the mucosal immune response to C. parvum in C57BL/6 neonatal and GKO mice shows a concomitant Thl and Th2 cytokine mRNA expression, with a crucial role for IFN-gamma in the resolution of the infection. NK cells and IFN-gamma have been shown to be important components in immunity in T and B cell-deficient mice, but IFN-gamma-dependent resistance is demonstrated in alymphocytic mice. Epithelial cells may play a vital role in immunity as once infected these cells have increased expression of inflammatory chemokines and cytokines and demonstrate anti-infection killing mechanisms. C. parvum immunological response was used to evaluate the efficacy of anti-cryptosporidisis agents of Garlic, Ginger, Mirazid and Metronidazole in experimentally infected mice.

Establishment of an Immortalized Skin Keratinocyte Cell Line Derived from the Animal Model Mastomys coucha.

PubMed

Hasche, Daniel; Stephan, Sonja; Savelyeva, Larissa; Westermann, Frank; Rösl, Frank; Vinzón, Sabrina E

2016-01-01

In the present report we describe the establishment of a spontaneous immortalized skin keratinocyte cell line derived from the skin of the multimammate rodent Mastomys coucha. These animals are used in preclinical studies for a variety of human diseases such as infections with nematodes, bacteria and papillomaviruses, especially regarding cutaneous manifestations such as non-melanoma skin cancer. Here we characterize the cells in terms of their origin and cytogenetic features. Searching for genomic signatures, a spontaneous mutation in the splicing donor sequence of Trp53 (G to A transition at the first position of intron 7) could be detected. This point mutation leads to alternative splicing and to a premature stop codon, resulting in a truncated and, in turn, undetectable form of p53, probably contributing to the process of immortalization. Mastomys coucha-derived skin keratinocytes can be used as an in vitro system to investigate molecular and immunological aspects of infectious agent interactions with their host cells.

The IFN Response in Bats Displays Distinctive IFN-Stimulated Gene Expression Kinetics with Atypical RNASEL Induction.

PubMed

De La Cruz-Rivera, Pamela C; Kanchwala, Mohammed; Liang, Hanquan; Kumar, Ashwani; Wang, Lin-Fa; Xing, Chao; Schoggins, John W

2018-01-01

Bats host a large number of zoonotic viruses, including several viruses that are highly pathogenic to other mammals. The mechanisms underlying this rich viral diversity are unknown, but they may be linked to unique immunological features that allow bats to act as asymptomatic viral reservoirs. Vertebrates respond to viral infection by inducing IFNs, which trigger antiviral defenses through IFN-stimulated gene (ISG) expression. Although the IFN system of several bats is characterized at the genomic level, less is known about bat IFN-mediated transcriptional responses. In this article, we show that IFN signaling in bat cells from the black flying fox ( Pteropus alecto ) consists of conserved and unique ISG expression profiles. In IFN-stimulated cells, bat ISGs comprise two unique temporal subclusters with similar early induction kinetics but distinct late-phase declines. In contrast, human ISGs lack this decline phase and remained elevated for longer periods. Notably, in unstimulated cells, bat ISGs were expressed more highly than their human counterparts. We also found that the antiviral effector 2-5A-dependent endoribonuclease, which is not an ISG in humans, is highly IFN inducible in black flying fox cells and contributes to cell-intrinsic control of viral infection. These studies reveal distinctive innate immune features that may underlie a unique virus-host relationship in bats. Copyright © 2017 by The American Association of Immunologists, Inc.

Synthetic immunology: modulating the human immune system.

PubMed

Geering, Barbara; Fussenegger, Martin

2015-02-01

Humans have manipulated the immune system to dampen or boost the immune response for thousands of years. As our understanding of fundamental immunology and biotechnological methodology accumulates, we can capitalize on this combined knowledge to engineer biological devices with the aim of rationally manipulating the immune response. We address therapeutic approaches based on the principles of synthetic immunology that either ameliorate disorders of the immune system by interfering with the immune response, or improve diverse pathogenic conditions by exploiting immune cell effector functions. We specifically highlight synthetic proteins investigated in preclinical and clinical trials, summarize studies that have used engineered immune cells, and finish with a discussion of possible future therapeutic concepts. Copyright © 2014 Elsevier Ltd. All rights reserved.

Immunologic Approaches for the Treatment of Multiple Myeloma

PubMed Central

Rasche, Leo; Weinhold, Niels; Morgan, Gareth J; van Rhee, Frits; Davies, Faith E

2017-01-01

The FDA approval of two monoclonal antibodies in 2015 has heralded a new era of targeted immunotherapies for multiple myeloma (MM). In this review we discuss the recent approaches using different immunological components to treat MM. In particular, we review current monoclonal antibody based therapies, engineered T- and NK cell products, ‘off-target’ immunomodulation, and strategies utilizing allogeneic cell transplantation in MM. We discuss how an immunologic approach offers promise for the treatment of this genetically heterogeneous disease, and how patients with acquired drug resistance may particularly benefit from these therapies. We also describe some of the limitations of the current strategies and speculate on the future of personalized immunotherapies for MM. PMID:28431262

Mast Cell Function

PubMed Central

da Silva, Elaine Zayas Marcelino; Jamur, Maria Célia

2014-01-01

Since first described by Paul Ehrlich in 1878, mast cells have been mostly viewed as effectors of allergy. It has been only in the past two decades that mast cells have gained recognition for their involvement in other physiological and pathological processes. Mast cells have a widespread distribution and are found predominantly at the interface between the host and the external environment. Mast cell maturation, phenotype and function are a direct consequence of the local microenvironment and have a marked influence on their ability to specifically recognize and respond to various stimuli through the release of an array of biologically active mediators. These features enable mast cells to act as both first responders in harmful situations as well as to respond to changes in their environment by communicating with a variety of other cells implicated in physiological and immunological responses. Therefore, the critical role of mast cells in both innate and adaptive immunity, including immune tolerance, has gained increased prominence. Conversely, mast cell dysfunction has pointed to these cells as the main offenders in several chronic allergic/inflammatory disorders, cancer and autoimmune diseases. This review summarizes the current knowledge of mast cell function in both normal and pathological conditions with regards to their regulation, phenotype and role. PMID:25062998

Advances in asthma, allergy and immunology series 2004: basic and clinical immunology.

PubMed

Chinen, Javier; Shearer, William T

2004-08-01

This review highlights some of the most significant advances in basic and clinical immunology that were published from August 2002 to December 2003, focusing on manuscripts that appeared in the Journal. Articles selected were those considered most relevant to Journal readers. With regard to basic immunology, this report includes articles describing FcepsilonRI expression in mucosal Langerhans cells and type II dendritic cells, mechanisms of TH1 and TH2 regulation, the role of Foxp3 in the development of CD4+CD25+ regulatory T cells, and the increasing importance of Toll receptors in immunity. Articles related to clinical immunology that were selected include the first report of lymphocyte subsets values from a large cohort of normal children; the description of new genetic defects in primary immunodeficiencies; a description of the complications of gene therapy for X-linked severe combined immunodeficiency; a report of 79 patients with hyper-IgM syndrome; a report of the mechanism of action and complications of intravenous immunoglobulin; a report of new approaches for immunotherapy; and an article on advances in HIV infection and management, including a report of defensins, small molecules with anti-HIV properties. Also summarized is an article that studied the immune system during a prolonged stay in the Antarctic, a model for human studies on the effect of environmental conditions similar to space expeditions.

Nutritional and immunological correlates of memory and neurocognitive development among HIV infected children living in Kayunga, Uganda

PubMed Central

Horacio, Ruiseñor-Escudero; Itziar, Familiar-Lopez; Alla, Sikorskii; Nikita, Jambulingam; Noelline, Nakasujja; Robert, Opoka; Judith, Bass; Michael, Boivin

2015-01-01

Objective To identify the nutritional and immunological correlates of memory and neurocognitive development as measured by the Mullen Scales of Early Learning (MSEL) and by the Color Object Association Test (COAT) among children in Uganda. Design This analysis uses baseline data collected between 2008 and 2010 from 119 HIV-infected children ages 1–6 years participating in a randomized controlled trial of an interventional parenting program in Kayunga, Uganda. Methods Peripheral blood draws were performed to determine immunological biomarkers. Unadjusted and adjusted linear regression models were used to relate MSEL and COAT scores to sociodemographic characteristics, weight-for-age Z-scores (WAZ), antiretroviral therapy (ART) status and immunological biomarkers. Results 111 children were included in the final analysis. Lower levels of CD4+ CD38+ T-cells (p=0.04) were associated to higher Immediate and Total Recall scores (p=0.04). Higher levels of CD8+ HLA-DR+ T-cells were associated with higher Total Recall score (p=0.04) of the COAT. Higher CD4+ CD38+ HLA-DR+ T-cells levels were associated with higher Gross Motor scores of the MSEL (p=0.02). WAZ was positively correlated to Visual Reception, Fine Motor, Expressive Language and composite score of the MSEL. Conclusions Overall, WAZ was a stronger predictor of neurocognitive outcomes assessed by the MSEL. CD4+ CD38+ T-cells were more specifically associated with memory-related outcomes. Future research should include immunological markers and standardized neurocognitive tests to further understand this relationship. PMID:26605506

Interrelationship of clinical, histomorphometric and immunohistochemical features of oral lesions in chronic paracoccidioidomycosis.

PubMed

de Abreu E Silva, Mariana À; Salum, Fernanda G; Figueiredo, Maria A; Lopes, Tiago G; da Silva, Vinicius D; Cherubini, Karen

2013-03-01

This study aimed to analyze the oral lesions of chronic paracoccidioidomycosis concerning their histomorphometric, immunohistochemical, and clinical features in a standardized sample. Fifty biopsy specimens of oral lesions of chronic paracoccidioidomycosis were submitted to hematoxylin and eosin (H&E), Grocott-Gomori and immunohistochemical staining. Data regarding disease duration and size and number of oral lesions, as well as erythrocytes, leukocytes, lymphocytes, hematocrit, hemoglobin, and erythrocyte sedimentation rate, were collected from medical charts. Granuloma density and number and diameter of buds and fungal cells, and IL-2, TNF-alpha and IFN-gamma expression, as well as clinical and hematological features, were quantified and correlated. Bud diameter was significantly greater in intermediate density granulomas compared to higher density granulomas. The other variables (number of buds, number and diameter of fungi, expression of IL-2, TNF-alpha and IFN-gamma, and clinical and hematological features) did not significantly change with the density of granulomas. There was a positive correlation between bud number and fungal cell number (r = 0.834), bud diameter and fungal cell diameter (r = 0.496), erythrocytes and number of fungi (r = 0.420), erythrocytes and bud number (r = 0.408), and leukocytes and bud number (r = 0.396). Negative correlation occurred between number and diameter of fungi (r = -0.419), bud diameter and granuloma density (r = -0.367), TNF-alpha expression and number of fungi (r = -0.372), and TNF-alpha expression and bud number (r = -0.300). The histological, immunological, and clinical features of oral lesions evaluated did not differ significantly between patients in our sample of chronic paracoccidioidomycosis. TNF-alpha levels were inversely correlated with intensity of infection. © 2012 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd.

Linking innate to adaptive immunity through dendritic cells.

PubMed

Steinman, Ralph M

2006-01-01

The function of dendritic cells (DCs) in linking innate to adaptive immunity is often summarized with two terms. DCs are sentinels, able to capture, process and present antigens and to migrate to lymphoid tissues to select rare, antigen-reactive T cell clones. DCs are also sensors, responding to a spectrum of environmental cues by extensive differentiation or maturation. The type of DC and the type of maturation induced by different stimuli influences the immunological outcome, such as the differentiation of Thl vs. Th2 T cells. Here we summarize the contributions of DCs to innate defences, particularly the production of immune enhancing cytokines and the activation of innate lymphocytes. Then we outline three innate features of DCs that influence peripheral tolerance and lead to adaptive immunity: a specialized endocytic system for antigen capture and processing, location and movements in vivo, and maturation in response to an array of stimuli. A new approach to the analysis of DC biology is to target antigens selectively to maturing DCs in vivo. This leads to stronger, more prolonged and broader (many immunogenic peptides) immunity by both T cells and B cells.

Decrease in Dengue virus-2 infection and reduction of cytokine/chemokine production by Uncaria guianensis in human hepatocyte cell line Huh-7.

PubMed

Mello, Cíntia da Silva; Valente, Ligia Maria Marino; Wolff, Thiago; Lima-Junior, Raimundo Sousa; Fialho, Luciana Gomes; Marinho, Cintia Ferreira; Azeredo, Elzinandes Leal; Oliveira-Pinto, Luzia Maria; Pereira, Rita de Cássia Alves; Siani, Antonio Carlos; Kubelka, Claire Fernandes

2017-06-01

Dengue fever may present hemorrhages and cavitary effusions as result of exacerbated immune responses. We investigated hydro-alcoholic extracts from leaves (UGL) and bark (UGB) of the medicinal species Uncaria guinanensis with respect to antiviral effects in Dengue virus (DENV) infection and in immunological parameters associated with in vivo physiopathological features. Chemical profiles from UGB or UGL were compared in thin layer chromatography and 1H nuclear magnetic resonance using flavonoid compounds and a pentacyclic oxindole alkaloid-enriched fraction as references. DENV-2-infected hepatocytes (Huh-7) were treated with extracts. Cell viability, DENV antigens and immunological factors were detected by enzyme-linked immunosorbent assay (ELISA) or flow cytometry. The UGL mainly differed from UGB by selectively containing the flavonoid kaempferitrin. UGB and UGL improved hepatocyte viability. Both extracts reduced intracellular viral antigen and inhibited the secretion of viral non-structural protein (NS1), which is indicative of viral replication. Reduction in secretion of macrophage migration inhibitory factor was achieved by UGB, of interleukin-6 by UGL, and of interleukin-8 by both UGB and UGL. MAIN. The U. guianensis extracts presented, antiviral and immunomodulatory effects for DENV and possibly a hepatocyte-protective activity. Further studies may be performed to consider these products as potential candidates for the development of an herbal product for the future treatment of dengue.

Immunologically active biomaterials for cancer therapy.

PubMed

Ali, Omar A; Mooney, David J

2011-01-01

Our understanding of immunological regulation has progressed tremendously alongside the development of materials science, and at their intersection emerges the possibility to employ immunologically active biomaterials for cancer immunotherapy. Strong and sustained anticancer, immune responses are required to clear large tumor burdens in patients, but current approaches for immunotherapy are formulated as products for delivery in bolus, which may be indiscriminate and/or shortlived. Multifunctional biomaterial particles are now being developed to target and sustain antigen and adjuvant delivery to dendritic cells in vivo, and these have the potential to direct and prolong antigen-specific T cell responses. Three-dimensional immune cell niches are also being developed to regulate the recruitment, activation and deployment of immune cells in situ to promote potent antitumor responses. Recent studies demonstrate that materials with immune targeting and stimulatory capabilities can enhance the magnitude and duration of immune responses to cancer antigens, and preclinical results utilizing material-based immunotherapy in tumor models show a strong therapeutic benefit, justifying translation to and future testing in the clinic.

Engineering approaches to immunotherapy.

PubMed

Swartz, Melody A; Hirosue, Sachiko; Hubbell, Jeffrey A

2012-08-22

As the science of immunology grows increasingly mechanistic, motivation for developing quantitative, design-based engineering approaches has also evolved, both for therapeutic interventions and for elucidating immunological pathways in human disease. This has seeded the nascent field of "immunoengineering," which seeks to apply engineering analyses and design approaches to problems in translational immunology. For example, cell engineers are creating ways to tailor and use immune cells as living therapeutics; protein engineers are devising new methods of rapid antibody discovery; biomaterials scientists are guiding vaccine delivery and immune-cell activation with novel constructs; and systems immunologists are deciphering the evolution and maintenance of T and B cell receptor repertoires, which could help guide vaccine design. The field is multidisciplinary and collaborative, with engineers and immunologists working together to better understand and treat disease. We discuss the scientific progress in this young, yet rapidly evolving research area, which has yielded numerous start-up companies that are betting on impact in clinical and commercial translation in the near future.

Hematology and immunology studies - The second manned Skylab mission

NASA Technical Reports Server (NTRS)

Kimzey, S. L.; Johnson, P. C.; Ritzman, S. E.; Mengel, C. E.

1976-01-01

The hematologic and immunologic functions of the Skylab 3 astronauts were monitored during the preflight, inflight, and postflight phases of the mission. Plasma protein profiles showed high consistency in all phases. A transient suppression of lymphocyte responsiveness was observed postflight. A reduction in the circulating blood volume due to drops in both the plasma volume and red cell mass was found. The loss of red cell mass is most likely a suppressed erythrypoiesis. The functional integrity of the circulating red cells did not appear to be compromised in the course of flight.

Hematology and immunology studies

NASA Technical Reports Server (NTRS)

Kimzey, S. L.

1977-01-01

A coordinated series of experiments were conducted to evaluate immunologic and hemotologic system responses of Skylab crewmen to prolonged space flights. A reduced PHA responsiveness was observed on recovery, together with a reduced number of T-cells, with both values returning to normal 3 to 5 days postflight. Subnormal red cell count, hemoglobin concentration, and hematocrit values also returned gradually to preflight limits. Most pronounced changes were found in the shape of red blood cells during extended space missions with a rapid reversal of these changes upon reentry into a normal gravitational environment.

CD4 T-Cell Memory Generation and Maintenance

PubMed Central

Gasper, David J.; Tejera, Melba Marie; Suresh, M.

2014-01-01

Immunologic memory is the adaptive immune system's powerful ability to remember a previous antigen encounter and react with accelerated vigor upon antigen re-exposure. It provides durable protection against reinfection with pathogens and is the foundation for vaccine-induced immunity. Unlike the relatively restricted immunologic purview of memory B cells and CD8 T cells, the field of CD4 T-cell memory must account for multiple distinct lineages with diverse effector functions, the issue of lineage commitment and plasticity, and the variable distribution of memory cells within each lineage. Here, we discuss the evidence for lineage-specific CD4 T-cell memory and summarize the known factors contributing to memory-cell generation, plasticity, and long-term maintenance. PMID:24940912

Effect of age on immunological response in the first year of antiretroviral therapy in HIV-1-infected adults in West Africa.

PubMed

Balestre, Eric; Eholié, Serge P; Lokossue, Amani; Sow, Papa Salif; Charurat, Man; Minga, Albert; Drabo, Joseph; Dabis, François; Ekouevi, Didier K; Thiébaut, Rodolphe

2012-05-15

To assess the effect of aging on the immunological response to antiretroviral therapy (ART) in the West African context. The change in CD4 T-cell count was analysed according to age at the time of ART initiation among HIV-infected patients enrolled in the International epidemiological Database to Evaluate AIDS (IeDEA) Collaboration in the West African region. CD4 gain over 12 months of ART was estimated using linear mixed models. Models were adjusted for baseline CD4 cell count, sex, baseline clinical stage, calendar period and ART regimen. The total number of patients included was 24,107, contributing for 50,893 measures of CD4 cell count in the first year of ART. The baseline median CD4 cell count was 144 cells/μl [interquartile range (IQR) 61-235]; median CD4 cell count reached 310 cells/μl (IQR 204-443) after 1 year of ART. The median age at treatment initiation was 36.3 years (10th-90th percentiles = 26.5-50.1). In adjusted analysis, the mean CD4 gain was significantly higher in younger patients (P < 0.0001). At 12 months, patients below 30 years recovered an additional 22 cells/μl on average [95% confidence interval (CI) 2-43] compared to patients at least 50 years. Among HIV-infected adults in West Africa, the immunological response after 12 months of ART was significantly poorer in elderly patients. As the population of treated patients is likely to get older, the impact of this age effect on immunological response to ART may increase over time.

Advances in Mechanisms of Asthma, Allergy, and Immunology in 2008

PubMed Central

Boyce, Joshua A.; Broide, David; Matsumoto, Kenji; Bochner, Bruce S.

2009-01-01

This review summarizes selected articles appearing in 2008 in the Journal of Allergy and Clinical Immunology (JACI). Papers chosen include those improving our understanding of mechanisms of allergic diseases by focusing on human basophil, mast cell and eosinophil biology; IgE and its high affinity receptor on various cells; novel properties of omalizumab; airways remodeling; and genetics. Papers from other journals have been included to supplement the topics being presented. PMID:19281904

What vaccination studies tell us about immunological memory within the innate immune system of cultured shrimp and crayfish.

PubMed

Chang, Yu-Hsuan; Kumar, Ramya; Ng, Tze Hann; Wang, Han-Ching

2018-03-01

The possibility of immunological memory in invertebrates is a topic that has recently attracted a lot of attention. Today, even vertebrates are known to exhibit innate immune responses that show memory-like properties, and since these responses are triggered by cells that are involved in the innate immune system, it seems that immune specificity and immune memory do not necessarily require the presence of B cells and T cells after all. This kind of immune response has been called "immune priming" or "trained immunity". In this report, we review recent observations and our current understanding of immunological memory within the innate immune system in cultured shrimp and crayfish after vaccination with live vaccine, killed vaccine and subunit vaccines. We also discuss the possible mechanisms involved in this immune response. Copyright © 2017 Elsevier Ltd. All rights reserved.

An Investigation of Immunological Tolerance Based on Chimaera Analysis

PubMed Central

Michie, Donald; Woodruff, M. F. A.; Zeiss, Irmgard M.

1961-01-01

Newborn mice of strain A were injected intravenously at birth with 9–15 million spleen cells from adult CBA donors. The recipients exhibited splenomegaly and other signs of graft-versus-host reaction during the first 3 weeks of life. Adult survivors were uniformly tolerant of CBA skin. They showed no sign of a continuing graft-versus-host reaction. The spleens of the treated mice were tested for the presence of immunologically competent donor and host cells by Simonsen's discriminant spleen assay. From the age of 7 days onwards the spleens were found to contain a small percentage of donor cells which were immunologically active against antigens of a third strain. In spleens from adult survivors activity, attributable to the host component, against third-party antigens was undiminished as compared with that of untreated A-strain mice. But activity against the CBA donor strain was absent. PMID:14473459

Depletion of CD52-positive cells inhibits the development of central nervous system autoimmune disease, but deletes an immune-tolerance promoting CD8 T-cell population. Implications for secondary autoimmunity of alemtuzumab in multiple sclerosis.

PubMed

von Kutzleben, Stephanie; Pryce, Gareth; Giovannoni, Gavin; Baker, David

2017-04-01

The objective was to determine whether CD52 lymphocyte depletion can act to promote immunological tolerance induction by way of intravenous antigen administration such that it could be used to either improve efficiency of multiple sclerosis (MS) inhibition or inhibit secondary autoimmunities that may occur following alemtuzumab use in MS. Relapsing experimental autoimmune encephalomyelitis was induced in ABH mice and immune cell depletion was therapeutically applied using mouse CD52 or CD4 (in conjunction with CD8 or CD20) depleting monoclonal antibodies. Immunological unresponsiveness was then subsequently induced using intravenous central nervous system antigens and responses were assessed clinically. A dose-response of CD4 monoclonal antibody depletion indicated that the 60-70% functional CD4 T-cell depletion achieved in perceived failed trials in MS was perhaps too low to even stop disease in animals. However, more marked (~75-90%) physical depletion of CD4 T cells by CD4 and CD52 depleting antibodies inhibited relapsing disease. Surprisingly, in contrast to CD4 depletion, CD52 depletion blocked robust immunological unresponsiveness through a mechanism involving CD8 T cells. Although efficacy was related to the level of CD4 T-cell depletion, the observations that CD52 depletion of CD19 B cells was less marked in lymphoid organs than in the blood provides a rationale for the rapid B-cell hyper-repopulation that occurs following alemtuzumab administration in MS. That B cells repopulate in the relative absence of T-cell regulatory mechanisms that promote immune tolerance may account for the secondary B-cell autoimmunities, which occur following alemtuzumab treatment of MS. © 2016 The Authors. Immunology Published by John Wiley & Sons Ltd.

[Phase II clinical trial of autologous dendritic cell vaccine with immunologic adjuvant in cutaneous melanoma patients].

PubMed

Baldueva, I A; Novik, A V; Moiseenko, V M; Nekhaeva, T L; Danilova, A B; Danilov, A O; Protsenko, S A; Petrova, T Iu; Uleĭskaia, G I; Shchekina, L A; Semenova, A I; Mikhaĭlichenko, T D; Teletaeva, G M; Zhabina, A S; Volkov, N V; Komarov, Iu I

2012-01-01

This paper describes the clinical results and immunologic changes in cutaneous melanoma patients receiving active specific immunotherapy with autologous dendritic cell vaccine (DCV) in combination with cyclophosphamide used as immunologic adjuvant. Twenty eight patients with morphologically verified stage III-IV cutaneous melanoma receiving therapy in N. N. Petrov Research Institute of Oncology between 2008 and 2011 were included in the study. All patients signed an informed consent form. Nineteen patients (67,9%) received DCV in therapeutic setting, 9 (32,1%) received it in adjuvant setting. DCV therapy was well tolerated. No serious adverse events were registered. Frequent adverse events included Grade 1-2 unspecific symptoms (fever, fatigue, flu-like symptoms) observed in 22% patients after 3,5% of vaccinations. In therapeutic settings the use DCV lead to clinical effect (PR+SD) in 36,6% of patients. PR was observed in 5% of (95% CI 0-15%) patients, SD in 31,6% (95% CI 13-56%). Duration of the objective responses was 168-965+days. Addition of immunologic adjuvant (cyclophosphamide 300 mg/m2 IV 2 hours) 3 days before vaccination increased its efficacy. In this patients group (n=12) the therapy lead to clinical benefit in 42% (95% CI 17-69%) of cases, median time to progression was 91 (95% CI 55-126) days. This regimen was selected for adjuvant therapy. In the adjuvant therapy group (n=9) the median time to progression was 112 (95% CI 58-166) days. Immunologic monitoring showed correlation ofT- and B-cell immune response with DCV clinical efficacy (p<0,05), no correlation with delayed hypersensivity reaction was observed (p>0,1). DCV is well tolerated and shows immunological and clinical response in stage III-IV skin melanoma patients.

Contributions of basic immunology to human health.

PubMed

Albright, J F; Oppenheim, J J

1991-03-01

The sixth symposium in the series "Contemporary Topics in Immunology" was held in New Orleans on June 3, 1990, at the joint meeting of The American Association of Immunologists and the American Society of Biochemistry and Molecular Biology. The symposium was sponsored jointly by The American Association of Immunologists, the Clinical Immunology Society, and and the National Institute of Allergy and Infectious Diseases, and was titled "The Contributions of Basic Immunology to Human Health." Five speakers, whose research has clear relevance to the treatment and prevention of major human diseases, discussed topics of great current interest: hematopoietic stem cells, cell adhesion and lymphocyte homing; the complexities of autoimmunity and approaches to diverting or depressing autoaggressive immunity; structure and functions of the interferons and the construction of designer and chimeric interferons; the varied functions of transforming growth factors and molecular events that regulate the synthesis of TGF beta; and the roles of cytokines in the expression of human immunodeficiency virus and the prospects for controlling HIV infections by regulating selected cytokines. This symposium will be remembered for the exceptional clarity with which each speaker illustrated how fundamental knowledge in immunology fuels advances in the treatment and prevention of those human disorders that involve the immune system.

Genetic errors of the human CARD-BCL10-MALT1 (CBM) complex: molecular, immunological, and clinical heterogeneity

PubMed Central

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

2016-01-01

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 three CARD-BCL10-MALT1 (CBM) complexes activate NF-κB in both the innate and adaptive arms of immunity. Human inherited defects of the three components of the CBM complex, including the two adaptors CARD9 and CARD11 and the two core components BCL10 and MALT1, have recently been reported. Bi-allelic loss-of-function (LOF) mutant alleles underlie several different immunological and clinical phenotypes, which can be assigned to two 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, humans with these mutations have some features in common with the corresponding knockout mice, but other features are different between humans and mice. Moreover, germline and somatic gain-of-function (GOF) mutations of MALT1, BCL10 and CARD11 have also been found in other patients with lymphoproliferative disorders. This broad range of germline and somatic CBM lesions, including LOF and GOF mutations, highlights the contribution of each of the components of the CBM to human immunity. PMID:26277595

Primary Sjogren's syndrome with central nervous system involvement.

PubMed

Alhomoud, Iftetah A; Bohlega, Saeed A; Alkawi, Mohammed Z; Alsemari, Abdulaziz M; Omer, Saleh M; Alsenani, Fahmi M

2009-08-01

To describe the clinical, laboratory, and radiological features of Primary Sjogren's syndrome (PSS) with central nervous system (CNS) involvement. A retrospective case series of 12 female patients with PSS and CNS involvement at King Faisal Specialist Hospital and Research Center, Riyadh, Kingdom of Saudi Arabia from 1991-2009. The diagnosis of PSS is defined by the American-European Diagnostic Criteria. We analyzed the clinical, radiological, and immunological features. The mean age was 40 years (range 16-58 years); all patient were females and presented with active neurological symptoms. The neurological involvement preceded the classic sicca symptoms (33%). Eight patients (66%) presented with myelopathy, 9 patients (75%) had optic neuritis, and the rest had variable neurological signs. Immunological tests (anti-Sjogren's syndrome A and anti-Sjogren's syndrome B) were high in 7 patients (58%). Minor salivary gland biopsy revealed inflammatory cell infiltrate in 11 patients (92%). Brain MRI showed scattered white matter changes in 7 patients (58%). Spine MRI showed multiple foci of hyperintensity in T2-weighted image in 6 patients (50%), and long segment of hyperintensity at the cervical spinal cord in 2 patients (16%). Our findings demonstrate that CNS involvements in PSS have great clinical variability and could precede the classic sicca symptoms by years. Primary Sjogren's syndrome can mimic multiple sclerosis (primary progressive multiple sclerosis or relapsing remitting multiple sclerosis), therefore a screening test for PSS should be considered in suspected cases. A well-defined management protocol awaits studies with larger case numbers.

Atypical memory B cells in human chronic infectious diseases: An interim report.

PubMed

Portugal, Silvia; Obeng-Adjei, Nyamekye; Moir, Susan; Crompton, Peter D; Pierce, Susan K

2017-11-01

Immunological memory is a remarkable phenomenon in which survival of an initial infection by a pathogen leads to life-long protection from disease upon subsequent exposure to that same pathogen. For many infectious diseases, long-lived protective humoral immunity is induced after only a single infection in a process that depends on the generation of memory B cells (MBCs) and long-lived plasma cells. However, over the past decade it has become increasingly evident that many chronic human infectious diseases to which immunity is not readily established, including HIV-AIDS, malaria and TB, are associated with fundamental alterations in the composition and functionality of MBC compartments. A common feature of these diseases appears to be a large expansion of what have been termed exhausted B cells, tissue-like memory B cells or atypical memory B cells (aMBCs) that, for simplicity's sake, we refer to here as aMBCs. It has been suggested that chronic immune activation and inflammation drive the expansion of aMBCs and that in some way aMBCs contribute to deficiencies in the acquisition of immunity in chronic infectious diseases. Although aMBCs are heterogeneous both within individuals and between diseases, they have several features in common including low expression of the cell surface markers that define classical MBCs in humans including CD21 and CD27 and high expression of genes not usually expressed by classical MBCs including T-bet, CD11c and a variety of inhibitory receptors, notably members of the FcRL family. Another distinguishing feature is their greatly diminished ability to be stimulated through their B cell receptors to proliferate, secrete cytokines or produce antibodies. In this review, we describe our current understanding of the phenotypic markers of aMBCs, their specificity in relation to the disease-causing pathogen, their functionality, the drivers of their expansion in chronic infections and their life span. We briefly summarize the features of aMBCs in healthy individuals and in autoimmune disease. We also comment on the possible relationship of human aMBCs and T-bet + , CD11c + age/autoimmune-associated B cells, also a topic of this review volume. Published by Elsevier Inc.

Population-expression models of immune response

NASA Astrophysics Data System (ADS)

Stromberg, Sean P.; Antia, Rustom; Nemenman, Ilya

2013-06-01

The immune response to a pathogen has two basic features. The first is the expansion of a few pathogen-specific cells to form a population large enough to control the pathogen. The second is the process of differentiation of cells from an initial naive phenotype to an effector phenotype which controls the pathogen, and subsequently to a memory phenotype that is maintained and responsible for long-term protection. The expansion and the differentiation have been considered largely independently. Changes in cell populations are typically described using ecologically based ordinary differential equation models. In contrast, differentiation of single cells is studied within systems biology and is frequently modeled by considering changes in gene and protein expression in individual cells. Recent advances in experimental systems biology make available for the first time data to allow the coupling of population and high dimensional expression data of immune cells during infections. Here we describe and develop population-expression models which integrate these two processes into systems biology on the multicellular level. When translated into mathematical equations, these models result in non-conservative, non-local advection-diffusion equations. We describe situations where the population-expression approach can make correct inference from data while previous modeling approaches based on common simplifying assumptions would fail. We also explore how model reduction techniques can be used to build population-expression models, minimizing the complexity of the model while keeping the essential features of the system. While we consider problems in immunology in this paper, we expect population-expression models to be more broadly applicable.

Cutaneous immunology: basics and new concepts.

PubMed

Yazdi, Amir S; Röcken, Martin; Ghoreschi, Kamran

2016-01-01

As one of the largest organs, the skin forms a mechanical and immunological barrier to the environment. The skin immune system harbors cells of the innate immune system and cells of the adaptive immune system. Signals of the innate immune system typically initiate skin immune responses, while cells and cytokines of the adaptive immune system perpetuate the inflammation. Skin immune responses ensure effective host defense against pathogens but can also cause inflammatory skin diseases. An extensive crosstalk between the different cell types of the immune system, tissue cells, and pathogens is responsible for the complexity of skin immune reactions. Here we summarize the major cellular and molecular components of the innate and adaptive skin immune system.

Association of Immunological Cell Profiles with Specific Clinical Phenotypes of Scleroderma Disease

PubMed Central

Calzada, David; Mayayo, Teodoro; González-Rodríguez, María Luisa; Rabasco, Antonio María; Lahoz, Carlos

2014-01-01

This study aimed to search the correlation among immunological profiles and clinical phenotypes of scleroderma in well-characterized groups of scleroderma patients, comparing forty-nine scleroderma patients stratified according to specific clinical phenotypes with forty-nine healthy controls. Five immunological cell subpopulations (B, CD4+ and CD8+ T-cells, NK, and monocytes) and their respective stages of apoptosis and activation were analyzed by flow cytometry, in samples of peripheral blood mononuclear cells (PBMCs). Analyses of results were stratified according to disease stage, time since the diagnosis, and visceral damage (pulmonary fibrosis, pulmonary hypertension, and cardiac affliction) and by time of treatment with corticosteroids. An increase in the percentages of monocytes and a decrease in the B cells were mainly related to the disease progression. A general apoptosis decrease was found in all phenotypes studied, except in localized scleroderma. An increase of B and NK cells activation was found in patients diagnosed more than 10 years ago. Specific cell populations like monocytes, NK, and B cells were associated with the type of affected organ. This study shows how, in a heterogeneous disease, proper patient's stratification according to clinical phenotypes allows finding specific cellular profiles. Our data may lead to improvements in the knowledge of prognosis factors and to aid in the analysis of future specific therapies. PMID:24818126

The lymphopenic mouse in immunology: from patron to pariah.

PubMed

Singh, Nevil J; Schwartz, Ronald H

2006-12-01

A recent surge of interest in the behavior of T and B cells in lymphopenic model systems has resurrected a certain cynicism about the validity of using such models to answer important immunological questions. Here we discuss this skepticism in a broader historical context.

Xenografted human amniotic membrane-derived mesenchymal stem cells are immunologically tolerated and transdifferentiated into cardiomyocytes.

PubMed

Tsuji, Hiroko; Miyoshi, Shunichiro; Ikegami, Yukinori; Hida, Naoko; Asada, Hironori; Togashi, Ikuko; Suzuki, Junshi; Satake, Masaki; Nakamizo, Hikaru; Tanaka, Mamoru; Mori, Taisuke; Segawa, Kaoru; Nishiyama, Nobuhiro; Inoue, Junko; Makino, Hatsune; Miyado, Kenji; Ogawa, Satoshi; Yoshimura, Yasunori; Umezawa, Akihiro

2010-05-28

Amniotic membrane is known to have the ability to transdifferentiate into multiple organs and is expected to stimulate a reduced immunologic reaction. Determine whether human amniotic membrane-derived mesenchymal cells (hAMCs) can be an ideal allograftable stem cell source for cardiac regenerative medicine. We established hAMCs. After cardiomyogenic induction in vitro, hAMCs beat spontaneously, and the calculated cardiomyogenic transdifferentiation efficiency was 33%. Transplantation of hAMCs 2 weeks after myocardial infarction improved impaired left ventricular fractional shortening measured by echocardiogram (34+/-2% [n=8] to 39+/-2% [n=11]; P<0.05) and decreased myocardial fibrosis area (18+/-1% [n=9] to 13+/-1% [n=10]; P<0.05), significantly. Furthermore hAMCs transplanted into the infarcted myocardium of Wistar rats were transdifferentiated into cardiomyocytes in situ and survived for more than 4 weeks after the transplantation without using any immunosuppressant. Immunologic tolerance was caused by the hAMC-derived HLA-G expression, lack of MHC expression of hAMCs, and activation of FOXP3-positive regulatory T cells. Administration of IL-10 or progesterone, which is known to play an important role in feto-maternal tolerance during pregnancy, markedly increased HLA-G expression in hAMCs in vitro and, surprisingly, also increased cardiomyogenic transdifferentiation efficiency in vitro and in vivo. Because hAMCs have a high ability to transdifferentiate into cardiomyocytes and to acquire immunologic tolerance in vivo, they can be a promising cellular source for allograftable stem cells for cardiac regenerative medicine.

In vivo immunologic selection of class I major histocompatibility complex gene deletion variants from the B16-BL6 melanoma.

PubMed

Talmadge, J E; Talmadge, C B; Zbar, B; McEwen, R; Meeker, A K; Tribble, H

1987-06-01

The mechanism by which tumor allografts escape host immunologic attack was investigated. B16-BL6 cells (the bladder 6 subline of the B16 melanoma) (H-2b) were transfected with a gene (Dd) encoding an allogeneic class I major histocompatibility complex antigen. Clones that expressed Dd antigen were injected into the footpads of nonimmune syngeneic mice, syngeneic immune mice, and nude mice. Under conditions of immunologic selection a clone that contained multiple copies of the transfected gene formed variants that lacked the transfected gene. Primary tumors and pulmonary metastases of immunized mice and pulmonary metastases of nonimmunized mice had lost the Dd gene and, in most cases, all of the associated plasmid. In contrast, in immunodeficient nude mice, primary tumors and pulmonary metastases retained the Dd gene and the associated plasmid. Deletion of genes encoding cell surface antigens may be one of the mechanisms by which allogeneic tumors escape immunologic attack.

Movement Limitation and Immune Responses of Rhesus Monkeys

NASA Technical Reports Server (NTRS)

Sonnenfeld, Gerald; Morton, Darla S.; Swiggett, Jeanene P.; Hakenewerth, Anne M.; Fowler, Nina A.

1993-01-01

The effects of restraint on immunological parameters was determined in an 18 day ARRT (adult rhesus restraint test). The monkeys were restrained for 18 days in the experimental station for the orbiting primate (ESOP), the chair of choice for Space Shuttle experiments. Several immunological parameters were determined using peripheral blood, bone marrow, and lymph node specimens from the monkeys. The parameters included: response of bone marrow cells to GM-CSF (granulocyte-macrophage colony stimulating factor), leukocyte subset distribution, and production of IFN-alpha (interferon-alpha) and IFN-gamma (interferon-gamma). The only parameter changed after 18 days of restraint was the percentage of CDB+ T cells. No other immunological parameters showed changes due to restraint. Handling and changes in housing prior to the restraint period did apparently result in some restraint-independent immunological changes. Handling must be kept to a minimum and the animals allowed time to recover prior to flight. All experiments must be carefully controlled. Restraint does not appear to be a major issue regarding the effects of space flight on immune responses.

Spaceflight and immune responses of rhesus monkeys

NASA Technical Reports Server (NTRS)

Sonnenfeld, Gerald; Morton, Darla S.; Swiggett, Jeanene P.; Hakenewerth, Anne M.; Fowler, Nina A.

1995-01-01

The effects of restraint on immunological parameters was determined in an 18 day ARRT (adult rhesus restraint test). The monkeys were restrained for 18 days in the experimental station for the orbiting primate (ESOP), the chair of choice for Space Shuttle experiments. Several immunological parameters were determined using peripheral blood, bone marrow, and lymph node specimens from the monkeys. The parameters included: response of bone marrow cells to GM-CSF (granulocyte-macrophage colony stimulating factor), leukocyte subset distribution, and production of IFN-a (interferon-alpha) and IFN-gamma (interferon-gamma). The only parameter changed after 18 days of restraint was the percentage of CD8+ T cells. No other immunological parameters showed changes due to restraint. Handling and changes in housing prior to the restraint period did apparently result in some restraint-independent immunological changes. Handling must be kept to a minimum and the animals allowed time to recover prior to flight. All experiments must be carefully controlled. Restraint does not appear to be a major issue regarding the effects of space flight on immune responses.

Ocular diseases: immunological and molecular mechanisms

PubMed Central

Song, Jing; Huang, Yi-Fei; Zhang, Wen-Jing; Chen, Xiao-Fei; Guo, Yu-Mian

2016-01-01

Many factors, such as environmental, microbial and endogenous stress, antigen localization, can trigger the immunological events that affect the ending of the diverse spectrum of ocular disorders. Significant advances in understanding of immunological and molecular mechanisms have been researched to improve the diagnosis and therapy for patients with ocular inflammatory diseases. Some kinds of ocular diseases are inadequately responsive to current medications; therefore, immunotherapy may be a potential choice as an alternative or adjunctive treatment, even in the prophylactic setting. This article first provides an overview of the immunological and molecular mechanisms concerning several typical and common ocular diseases; second, the functions of immunological roles in some of systemic autoimmunity will be discussed; third, we will provide a summary of the mechanisms that dictate immune cell trafficking to ocular local microenvironment in response to inflammation. PMID:27275439

Ocular diseases: immunological and molecular mechanisms.

PubMed

Song, Jing; Huang, Yi-Fei; Zhang, Wen-Jing; Chen, Xiao-Fei; Guo, Yu-Mian

2016-01-01

Many factors, such as environmental, microbial and endogenous stress, antigen localization, can trigger the immunological events that affect the ending of the diverse spectrum of ocular disorders. Significant advances in understanding of immunological and molecular mechanisms have been researched to improve the diagnosis and therapy for patients with ocular inflammatory diseases. Some kinds of ocular diseases are inadequately responsive to current medications; therefore, immunotherapy may be a potential choice as an alternative or adjunctive treatment, even in the prophylactic setting. This article first provides an overview of the immunological and molecular mechanisms concerning several typical and common ocular diseases; second, the functions of immunological roles in some of systemic autoimmunity will be discussed; third, we will provide a summary of the mechanisms that dictate immune cell trafficking to ocular local microenvironment in response to inflammation.

Ratio of Circulating IFNγ (+) "Th17 Cells" in Memory Th Cells Is Inversely Correlated with the Titer of Anti-CCP Antibodies in Early-Onset Rheumatoid Arthritis Patients Based on Flow Cytometry Methods of the Human Immunology Project.

PubMed

Kotake, Shigeru; Nanke, Yuki; Yago, Toru; Kawamoto, Manabu; Kobashigawa, Tsuyoshi; Yamanaka, Hisashi

2016-01-01

Rheumatoid arthritis (RA) is a systemic autoimmune disease with chronic joint inflammation characterized by activated T cells. IL-17 and Th17 cells play important roles in the pathogenesis of RA. Recently, plasticity in helper T cells has been demonstrated; Th17 cells can convert to Th1 cells. However, it remains to be elucidated whether this conversion occurs in the early phase of RA. Here, we validated the methods of the Human Immunology Project using only the cell-surface marker through measuring the actual expression of IL-17 and IFNγ. We also evaluated the expression of CD161 in human Th17 cells. We then tried to identify Th17 cells, IL-17(+)Th17 cells, and IFNγ (+)Th17 cells in the peripheral blood of early-onset RA patients using the standardized method of the Human Immunology Project. Our findings validated the method and the expression of CD161. The ratio of IFNγ (+)Th17 cells in memory T cells was inversely correlated to the titers of anti-CCP antibodies in the early-onset RA patients. These findings suggest that Th17 cells play important roles in the early phase of RA and that anti-IL-17 antibodies should be administered to patients with early phase RA, especially those with high titers of CCP antibodies.

Chimeric antigen receptors: driving immunology towards synthetic biology

PubMed Central

Sadelain, Michel

2017-01-01

The advent of second generation CARs and the CD19 paradigm have ushered a new therapeutic modality in oncology. In contrast to earlier forms of adoptive cell therapy, which were based on the isolation and expansion of naturally occurring T cells, CAR therapy is based on the design and manufacture of engineered T cells with optimized properties. A new armamentarium, comprising not only CARs but also chimeric costimulatory receptors, chimeric cytokine receptors, inhibitory receptors and synthetic Notch receptors, expressed in naïve, central memory or stem cell-like memory T cells, is being developed for clinical use in a wide range of cancers. Immunological principles are thus finding a new purpose thanks to advances in genetic engineering, synthetic biology and cell manufacturing sciences. PMID:27372731

Meta-Analysis of the Changes of Peripheral Blood T Cell Subsets in Patients with Brucellosis

PubMed Central

Zheng, Rongjiong; Xie, Songsong; Niyazi, Shaniya; Lu, Xiaobo; Zhou, Yan

2018-01-01

Brucellosis is one of the most prevalent zoonotic diseases in the world, but its pathogenesis is not very clear. At present, it is thought that it may be related to the immunity of T cells. The conclusions of related studies are inconsistent, and its clinical significance is not explicit. We searched published articles in electronic databases up to December 2017 identified as relating to the clinical features of human brucellosis in China. Only eight studies had sufficient quality for data extraction. Meta-analysis showed a significantly decreased proportion of CD4+ T cells in human brucellosis patients compared to healthy subject individuals. The frequency of CD8+ T cells was significantly higher in human brucellosis patients than that in the healthy control group. The pooled analysis presented a significant decrease of the CD4+/CD8+ ratio in human brucellosis patients compared to healthy subjects. There is immunologic dysfunction of T lymphocyte in patients with human brucellosis, the CD4+ and CD8+ T cells might be the important factors affecting the progress of brucellosis. PMID:29888294

Maintenance of CCL5 mRNA stores by post-effector and memory CD8 T cells is dependent on transcription and is coupled to increased mRNA stability.

PubMed

Marçais, Antoine; Tomkowiak, Martine; Walzer, Thierry; Coupet, Charles-Antoine; Ravel-Chapuis, Aymeric; Marvel, Jacqueline

2006-10-01

Immunological memory is associated with the display of improved effector functions by cells of the adaptive immune system. The storage of untranslated mRNA coding for the CCL5 chemokine by CD8 memory cells is a new process supporting the immediate display of an effector function. Here, we show that, after induction during the primary response, high CCL5 mRNA levels are specifically preserved in CD8 T cells. We have investigated the mechanisms involved in the long-term maintenance of CCL5 mRNA levels by memory CD8 T cells. We demonstrate that the CCL5 mRNA half-life is increased in memory CD8 T cells and that these cells constitutively transcribe ccl5 gene. By inhibiting ccl5 transcription using IL-4, we demonstrate the essential role of transcription in the maintenance of CCL5 mRNA stores. Finally, we show that these stores are spontaneously reconstituted when the inhibitory signal is removed, indicating that the transcription of ccl5 is a default feature of memory CD8 T cells imprinted in their genetic program.

The up side of decidual natural killer cells: new developments in immunology of pregnancy.

PubMed

Jabrane-Ferrat, Nabila; Siewiera, Johan

2014-04-01

Early phases of human pregnancy are associated with the accumulation of a unique subset of natural killer (NK) cells in the maternal decidua. Decidual NK (dNK) cells that are devoid of cytotoxicity play a pivotal role in successful pregnancy. By secreting large amounts of cytokines/chemokines and angiogenic factors, dNK cells participate in all steps of placentation including trophoblast invasion into the maternal endometrium and vascular remodelling. In this review, we summarize some of dNK cell features and discuss more recent exciting data that challenge the conventional view of these cells. Our new data demonstrate that dNK cells undergo fine tuning or even subvert their classical inhibitory machinery and turn into a real defence force in order to prevent the spread of viruses to fetal tissue. Today it is not clear how these phenotypic and functional adaptations impact cellular cross-talk at the fetal-maternal interface and tissue homeostasis. Ultimately, precise understanding of the molecular mechanisms that govern dNK cell plasticity during congenital human cytomegalovirus infection should lead to the design of more robust strategies to reverse immune escape during viral infection and cancer. © 2013 John Wiley & Sons Ltd.

Toll-like receptor expression and function differ between splenic marginal zone B cell lymphoma and splenic diffuse red pulp B cell lymphoma

PubMed Central

Verney, Aurélie; Traverse-Glehen, Alexandra; Callet-Bauchu, Evelyne; Jallades, Laurent; Magaud, Jean-Pierre; Salles, Gilles; Genestier, Laurent; Baseggio, Lucile

2018-01-01

In splenic marginal zone lymphoma (SMZL), specific and functional Toll-like Receptor (TLR) patterns have been recently described, suggesting their involvement in tumoral proliferation. Splenic diffuse red pulp lymphoma with villous lymphocytes (SDRPL) is close to but distinct from SMZL, justifying here the comparison of TLR patterns and functionality in both entities. Distinct TLR profiles were observed in both lymphoma subtypes. SDRPL B cells showed higher expression of TLR7 and to a lesser degree TLR9, in comparison to SMZL B cells. In both entities, TLR7 and TLR9 pathways appeared functional, as shown by IL-6 production upon TLR7 and TLR9 agonists stimulations. Interestingly, circulating SDRPL, but not SMZL B cells, constitutively expressed CD86. In addition, stimulation with both TLR7 and TLR9 agonists significantly increased CD80 expression in circulating SDRPL but not SMZL B cells. Finally, TLR7 and TLR9 stimulations had no impact on proliferation and apoptosis of SMZL or SDRPL B cells. In conclusion, SMZL and SDRPL may derive from different splenic memory B cells with specific immunological features that can be used as diagnosis markers in the peripheral blood.

Environmental factors and human health: fibrous and particulate substance-induced immunological disorders and construction of a health-promoting living environment.

PubMed

Otsuki, Takemi; Matsuzaki, Hidenori; Lee, Suni; Kumagai-Takei, Naoko; Yamamoto, Shoko; Hatayama, Tamayo; Yoshitome, Kei; Nishimura, Yasumitsu

2016-03-01

Among the various scientific fields covered in the area of hygiene such as environmental medicine, epidemiology, public health and preventive medicine, we are investigating the immunological effects of fibrous and particulate substances in the environment and work surroundings, such as asbestos fibers and silica particles. In addition to these studies, we have attempted to construct health-promoting living conditions. Thus, in this review we will summarize our investigations regarding the (1) immunological effects of asbestos fibers, (2) immunological effects of silica particles, and (3) construction of a health-promoting living environment. This review article summarizes the 2014 Japanese Society for Hygiene (JSH) Award Lecture of the 85th Annual Meeting of the JSH entitled "Environmental health effects: immunological effects of fibrous and particulate matter and establishment of health-promoting environments" presented by the first author of this manuscript, Prof. Otsuki, Department of Hygiene, Kawasaki Medical School, Kurashiki, Japan, the recipient of the 2014 JSH award. The results of our experiments can be summarized as follows: (1) asbestos fibers reduce anti-tumor immunity, (2) silica particles chronically activate responder and regulatory T cells causing an unbalance of these two populations of T helper cells, which may contribute to the development of autoimmune disorders frequently complicating silicosis, and (3) living conditions to enhance natural killer cell activity were developed, which may promote the prevention of cancers and diminish symptoms of virus infections.

Leukocytes in expressed breast milk of asthmatic mothers.

PubMed

Dixon, D-L; Forsyth, K D

Infants are born immunologically immature. However, breastfeeding mothers retain an immunological link to their infants. While it is generally accepted that infants are at an immunological advantage when compared with formula-fed infants, the benefit of long-term exclusive breastfeeding by atopic mothers remains controversial. Inconsistency in the conferral of benefit may be due to differences in the immunological constituents passed to the recipient infant. The aim of this investigation was to examine the profile of human milk cells and cytokines from asthmatic compared to non-asthmatic mothers. Twenty-five exclusively breastfeeding mothers with a clinical diagnosis of asthma were postpartum age matched in a double-control 2:1 design with 50 non-asthmatic controls. Each mother provided a single milk sample which was assayed for cell differential by flow cytometry, for ex vivo cytokine production in culture and for aqueous phase cytokines. Milks from asthmatic mothers differed from non-asthmatics in that they contained a higher proportion of polymorphonuclear (PMN) cells and lower proportion of lymphocytes, predominantly CD3 + /CD4 + T helper cells, reflected by a decrease in the chemokine CCL5 in the milk aqueous phase. More PMN and lymphocytes from asthmatic mothers expressed the adhesion molecule CD11b and lymphocytes the IgE receptor CD23, than those from non-asthmatic mothers. Changes to human milk leucocyte prevalence, activation state and cytokines due to maternal asthma may result in changes to immunological priming in the infant. Consequently, the protective effect of long-term breastfeeding may be altered in these mother-infant pairs. Copyright © 2016 SEICAP. Published by Elsevier España, S.L.U. All rights reserved.

Dysregulation in microRNA Expression Is Associated with Alterations in Immune Functions in Combat Veterans with Post-Traumatic Stress Disorder

PubMed Central

Zhou, Juhua; Nagarkatti, Prakash; Zhong, Yin; Ginsberg, Jay P.; Singh, Narendra P.; Zhang, Jiajia; Nagarkatti, Mitzi

2014-01-01

While the immunological dysfunction in combat Veterans with post-traumatic stress disorder (PTSD) has been well documented, the precise mechanisms remain unclear. The current study evaluated the role of microRNA (miR) in immunological dysfunction associated with PTSD. The presence of peripheral blood mononuclear cells (PBMC) and various lymphocyte subsets in blood collected from PTSD patients were analyzed. Our studies demonstrated that the numbers of both PBMC and various lymphocyte subsets increased significantly in PTSD patients. When T cells were further analyzed, the percentage of Th1 cells and Th17 cells increased, regulatory T cells(Tregs) decreased, while Th2 cells remained unaltered in PTSD patients. These data correlated with increased plasma levels of IFN-γ and IL-17 while IL-4 showed no significant change. The increase in PBMC counts, Th1 and Th17 cells seen in PTSD patients correlated with the clinical scores. High-throughput analysis of PBMCs for 1163 miRs showed that the expression of a significant number of miRs was altered in PTSD patients. Pathway analysis of dysregulated miRs seen in PTSD patients revealed relationship between selected miRNAs and genes that showed direct/indirect role in immunological signaling pathways consistent with the immunological changes seen in these patients. Of interest was the down-regulation of miR-125a in PTSD, which specifically targeted IFN-γ production. Together, the current study demonstrates for the first time that PTSD was associated with significant alterations in miRNAs, which may promote pro-inflammatory cytokine profile. Such epigenetic events may provide useful tools to identify potential biomarkers for diagnosis, and facilitate therapy of PTSD. PMID:24759737

Dysregulation in microRNA expression is associated with alterations in immune functions in combat veterans with post-traumatic stress disorder.

PubMed

Zhou, Juhua; Nagarkatti, Prakash; Zhong, Yin; Ginsberg, Jay P; Singh, Narendra P; Zhang, Jiajia; Nagarkatti, Mitzi

2014-01-01

While the immunological dysfunction in combat Veterans with post-traumatic stress disorder (PTSD) has been well documented, the precise mechanisms remain unclear. The current study evaluated the role of microRNA (miR) in immunological dysfunction associated with PTSD. The presence of peripheral blood mononuclear cells (PBMC) and various lymphocyte subsets in blood collected from PTSD patients were analyzed. Our studies demonstrated that the numbers of both PBMC and various lymphocyte subsets increased significantly in PTSD patients. When T cells were further analyzed, the percentage of Th1 cells and Th17 cells increased, regulatory T cells(Tregs) decreased, while Th2 cells remained unaltered in PTSD patients. These data correlated with increased plasma levels of IFN-γ and IL-17 while IL-4 showed no significant change. The increase in PBMC counts, Th1 and Th17 cells seen in PTSD patients correlated with the clinical scores. High-throughput analysis of PBMCs for 1163 miRs showed that the expression of a significant number of miRs was altered in PTSD patients. Pathway analysis of dysregulated miRs seen in PTSD patients revealed relationship between selected miRNAs and genes that showed direct/indirect role in immunological signaling pathways consistent with the immunological changes seen in these patients. Of interest was the down-regulation of miR-125a in PTSD, which specifically targeted IFN-γ production. Together, the current study demonstrates for the first time that PTSD was associated with significant alterations in miRNAs, which may promote pro-inflammatory cytokine profile. Such epigenetic events may provide useful tools to identify potential biomarkers for diagnosis, and facilitate therapy of PTSD.

Computational and Experimental Validation of B and T-Cell Epitopes of the In Vivo Immune Response to a Novel Malarial Antigen

DTIC Science & Technology

2013-08-16

approach in the context of a novel, immunologically relevant antigen. The limited accuracy of the tested algorithms to predict the in vivo immune responses...overlapping peptides spanning the entire sequence are individually tested for antibody interacting residues. Conformational B cell epitopes, in contrast...a blind assessment of this approach in the context of a novel, immunologically relevant antigen. The limited accuracy of the tested algorithms to

Tumor Necrosis Factor Is a Therapeutic Target for Immunological Unbalance and Cardiac Abnormalities in Chronic Experimental Chagas' Heart Disease

PubMed Central

Pereira, Isabela Resende; Vilar-Pereira, Glaucia; Silva, Andrea Alice; Moreira, Otacilio Cruz; Britto, Constança; Sarmento, Ellen Diana Marinho

2014-01-01

Background. Chagas disease (CD) is characterized by parasite persistence and immunological unbalance favoring systemic inflammatory profile. Chronic chagasic cardiomyopathy, the main manifestation of CD, occurs in a TNF-enriched milieu and frequently progresses to heart failure. Aim of the Study. To challenge the hypothesis that TNF plays a key role in Trypanosoma cruzi-induced immune deregulation and cardiac abnormalities, we tested the effect of the anti-TNF antibody Infliximab in chronically T. cruzi-infected C57BL/6 mice, a model with immunological, electrical, and histopathological abnormalities resembling Chagas' heart disease. Results. Infliximab therapy did not reactivate parasite but reshaped the immune response as reduced TNF mRNA expression in the cardiac tissue and plasma TNF and IFNγ levels; diminished the frequency of IL-17A+ but increased IL-10+ CD4+ T-cells; reduced TNF+ but augmented IL-10+ Ly6C+ and F4/80+ cells. Further, anti-TNF therapy decreased cytotoxic activity but preserved IFNγ-producing VNHRFTLV-specific CD8+ T-cells in spleen and reduced the number of perforin+ cells infiltrating the myocardium. Importantly, Infliximab reduced the frequency of mice afflicted by arrhythmias and second degree atrioventricular blocks and decreased fibronectin deposition in the cardiac tissue. Conclusions. Our data support that TNF is a crucial player in the pathogenesis of Chagas' heart disease fueling immunological unbalance which contributes to cardiac abnormalities. PMID:25140115

Ratio of Circulating IFNγ + “Th17 Cells” in Memory Th Cells Is Inversely Correlated with the Titer of Anti-CCP Antibodies in Early-Onset Rheumatoid Arthritis Patients Based on Flow Cytometry Methods of the Human Immunology Project

PubMed Central

Kotake, Shigeru; Nanke, Yuki; Yago, Toru; Kawamoto, Manabu; Kobashigawa, Tsuyoshi; Yamanaka, Hisashi

2016-01-01

Rheumatoid arthritis (RA) is a systemic autoimmune disease with chronic joint inflammation characterized by activated T cells. IL-17 and Th17 cells play important roles in the pathogenesis of RA. Recently, plasticity in helper T cells has been demonstrated; Th17 cells can convert to Th1 cells. However, it remains to be elucidated whether this conversion occurs in the early phase of RA. Here, we validated the methods of the Human Immunology Project using only the cell-surface marker through measuring the actual expression of IL-17 and IFNγ. We also evaluated the expression of CD161 in human Th17 cells. We then tried to identify Th17 cells, IL-17+Th17 cells, and IFNγ +Th17 cells in the peripheral blood of early-onset RA patients using the standardized method of the Human Immunology Project. Our findings validated the method and the expression of CD161. The ratio of IFNγ +Th17 cells in memory T cells was inversely correlated to the titers of anti-CCP antibodies in the early-onset RA patients. These findings suggest that Th17 cells play important roles in the early phase of RA and that anti-IL-17 antibodies should be administered to patients with early phase RA, especially those with high titers of CCP antibodies. PMID:27294146

Interaction of microbial agents with the immune system during infectious disease.

PubMed

Frøland, S S

1984-01-01

Research during the last years has revealed a considerable complexity of the immune system. It is clear that immunological reactions depend on extensive and only partly clarified interactions between a number of different cell types (e.g. B lymphocytes, plasma cells, T cell subpopulations, cytotoxic K and NK cells, monocytic cells, neutrophilic and eosinophilic granulocytes) and their molecular products (e.g. immunoglobulins, lymphokines and interleukins). These components further interact with the complement system, as well as with immunologically nonspecific components like acute phase proteins (e.g. C-reactive protein) and with other pathophysiological phenomena occurring during infections, e.g. the fever response. The application of these observations from basic and experimental immunology to the investigation of antimicrobial immune reactions is still only in its beginning, but has already resulted in new concepts of clinical value for the understanding of infectious diseases. The present paper briefly describes certain aspects of the immune response to infections with various microbial agents, with particular emphasis on reactions of clinical importance. In addition to B and T cell reactions, possible antimicrobial functions of K cells and NK cells are discussed, and the possible importance in infectious disease of various T cell subpopulations, particularly T suppressor cells, is discussed. Lastly, various escape mechanisms are mentioned whereby certain microbial agents may evade elimination by the immune response of the host.

Pathogenetic and Clinical Aspects of Anti-Neutrophil Cytoplasmic Autoantibody-Associated Vasculitides

PubMed Central

Lamprecht, Peter; Kerstein, Anja; Klapa, Sebastian; Schinke, Susanne; Karsten, Christian M.; Yu, Xinhua; Ehlers, Marc; Epplen, Jörg T.; Holl-Ulrich, Konstanze; Wiech, Thorsten; Kalies, Kathrin; Lange, Tanja; Laudien, Martin; Laskay, Tamas; Gemoll, Timo; Schumacher, Udo; Ullrich, Sebastian; Busch, Hauke; Ibrahim, Saleh; Fischer, Nicole; Hasselbacher, Katrin; Pries, Ralph; Petersen, Frank; Weppner, Gesche; Manz, Rudolf; Humrich, Jens Y.; Nieberding, Relana; Riemekasten, Gabriela; Müller, Antje

2018-01-01

Anti-neutrophil cytoplasmic autoantibodies (ANCA) targeting proteinase 3 (PR3) and myeloperoxidase expressed by innate immune cells (neutrophils and monocytes) are salient diagnostic and pathogenic features of small vessel vasculitis, comprising granulomatosis with polyangiitis (GPA), microscopic polyangiitis, and eosinophilic GPA. Genetic studies suggest that ANCA-associated vasculitides (AAV) constitute separate diseases, which share common immunological and pathological features, but are otherwise heterogeneous. The successful therapeutic use of anti-CD20 antibodies emphasizes the prominent role of ANCA and possibly other autoantibodies in the pathogenesis of AAV. However, to elucidate causal effects in AAV, a better understanding of the complex interplay leading to the emergence of B lymphocytes that produce pathogenic ANCA remains a challenge. Different scenarios seem possible; e.g., the break of tolerance induced by a shift from non-pathogenic toward pathogenic autoantigen epitopes in inflamed tissue. This review gives a brief overview on current knowledge about genetic and epigenetic factors, barrier dysfunction and chronic non-resolving inflammation, necro-inflammatory auto-amplification of cellular death and inflammation, altered autoantigen presentation, alternative complement pathway activation, alterations within peripheral and inflamed tissue-residing T- and B-cell populations, ectopic lymphoid tissue neoformation, the characterization of PR3-specific T-cells, properties of ANCA, links between autoimmune disease and infection-triggered pathology, and animal models in AAV. PMID:29686675

Characterization of lymphoid cells in the blood of healthy adults: sequential immunological, cytochemical and cytokinetic studies

DOE Office of Scientific and Technical Information (OSTI.GOV)

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 tomore » that of E-sIg+ cells. The overall labeling index of the lymphoid cells examined was less than or equal to 0.2%.« less

IT-25DEVELOPMENTALLY REGULATED ANTIGENS FOR IMMUNOLOGIC TARGETING OF MEDULLOBLASTOMA SUBTYPES

PubMed Central

Pham, Christina; Flores, Catherine; Pei, Yanxin; Wechsler-Reya, Robert; Mitchell, Duane

2014-01-01

INTRODUCTION: Medulloblastoma (MB) remains incurable in one third of patients despite aggressive multi-modality standard therapies. Immunotherapy presents a promising alternative by specifically targeting cancer cells. To date, there have been no successful immunologic applications targeting MB. Emerging evidence from integrated genomic studies has suggested MB variants arise from deregulation of pathways affecting proliferation of progenitor cell populations within the developing cerebellum. Using total embryonic RNA as a source of tumor rejection antigens is attractive because it can be delivered as a single vaccine, target both known and unknown fetal proteins, and can be refined to preferentially treat distinct MB subtypes. METHODS: We have created two transplantable, syngeneic animal MB models recapitulating human SHH and Group 3 variants to investigate the immunologic targeting of different MB subtypes. We generated T cells specific to the developing mouse cerebellum (P5) and tested their reactivity to target cells pulsed with total RNA from two MB subtypes and the normal brain. Immune responses were evaluated by measuring cytokine secretion following re-stimulation of activated T cells with both normal and tumor cell targets. In vivo antitumor efficacy was also tested in survival studies of intracranial tumor-bearing animals. RESULTS: We generated T cells specific to the developing cerebellum in vitro, confirming the immunogenicity of developmentally regulated antigens. Additionally, we have shown that developmental antigen-specific T cells produce high levels of Th1-type cytokines in response to tumor cells of two immunologically distinct subtypes of MB. Interestingly, developmental antigen specific T cells do not show cross reactivity with the normal brain or subsequent stages of the developing brain after P5. Targeting developmental antigens also conferred a significant survival benefit in a treatment model of Group 3 tumor bearing animals. CONCLUSIONS: Developmental antigens can safely target multiple MB subtypes with equal effectiveness compared to previously established total tumor strategies.

Predicting Sensitivity of Breast Tumors to Src-Targeted Therapies through Assessment of Cas/Src/BCAR3 Activity

DTIC Science & Technology

2016-10-01

Amy H. Bouton, Ph.D. Associate Dean of Graduate and Medical ScienXst Programs Professor of Microbiology , Immunology, and Cancer Biology Box...We found that all of the BCAR3 in invasive breast cancer cells is present in a complex with Cas and 1Department of Microbiology , Immunology and Cancer...Harrisonburg, VA, USA. Correspondence: Dr AH Bouton, Department of Microbiology , Immunology and Cancer Biology, University of Virginia School of Medicine, Box

Immunology: Exhausted T cells perk up

NASA Astrophysics Data System (ADS)

Williams, Matthew A.; Bevan, Michael J.

2006-02-01

During persistent infections, the immune cells responsible for killing infected cells and maintaining inflammation gradually stop functioning, allowing the pathogen to thrive. But can this process be reversed?

Seventeen-Year Journey Working With a Master.

PubMed

Zhu, Jinfang

2018-01-01

It had been a great honor for me to work with the late Dr. William E. Paul for 17 years in the Laboratory of Immunology (LI) from 1998 until his passing in 2015. He was such a master in the immunology field. Under his outstanding guidance, my research has been focusing on transcriptional regulation of T helper (Th) cell differentiation, especially, on the role of a master transcription factor GATA3 during Th2 cell differentiation. Just as enormous scientific contributions of Dr. Paul (we all call him Bill) to the immunology community are far beyond his serving as the Chief of the LI, GATA3 also plays important roles in different lymphocytes at various developmental stages besides its critical functions in Th2 cells. In this special review dedicated to the memory of Bill, I will summarize the research that I have carried out in Bill's lab working on GATA3 in the context of related studies by other groups in the field of T cell differentiation and innate lymphoid cell (ILC) development. These include the essential role of GATA3 in regulating Th2/ILC2 differentiation/development and their functions, the critical role of GATA3 during the development of T cells and innate lymphoid cells, and dynamic and quantitative expression of GATA3 in controlling lymphocyte homeostasis and functions.

The research on the influences of hyperthermal perfusion chemotherapy combined with immunologic therapy on the immunologic function and levels of circulating tumor cells of the advanced colorectal cancer patients with liver metastasis.

PubMed

Sun, J-J; Fan, G-L; Wang, X-G; Xu, K

2017-07-01

To investigated the influence of hyperthermal perfusion chemotherapy combined with immunologic therapy on the immunologic function and levels of circulating tumor cells of the advanced colorectal cancer patients with liver metastasis. We enrolled 98 advanced colorectal cancer patients with liver metastasis that were admitted to this hospital for treatment and were randomly divided into two groups, the observation group (n = 49) and the control group (n = 49). We administered systemic vein chemotherapy for patients in the control group, and hyperthermal perfusion chemotherapy for the patients in the observation group in order to compare the subgroup levels of T lymphocytes, NK cells and immunoglobulin (IgG, IgA, and IgM) in the immune system of patients in both groups. We also assayed the circulating tumor cells (CTC) in the peripheral blood of patients in both groups using the cell search method, and compared the efficacy using response evaluation criteria in solid tumors and the survival rates of patients in both groups using the Kaplan-Meier method. After two treatment courses, the levels of CD3+, CD4+ and CD4+/CD8+ of the patients in the observation group were significantly higher than those of the control group, but the levels of CD8+ of patients in the observation group was lower than that in the control group (p< 0.05). The levels of immunoglobulins (IgG, IgA, and IgM) in the observation group were higher than the control group (p < 0.05). The levels of NK cell cells were significantly lower than the control group (p < 0.05). The objective response rate, as well as the disease control rate of the observation group, were remarkably higher than those of the control group (p < 0.05). Compared to the control group, the observation group enjoyed a prolonged survival time, higher survival rate and significantly lower positive rate of CTC (p < 0.05). Better efficacy and tolerance, fewer toxic and side effects, improvement in the immunologic functions of patients for the indirect anti-tumor effect, a significant decrease in CTC of patients, and a higher long-term survival rate have been achieved in the treatment with hyperthermal perfusion chemotherapy combined with immunologic therapy for the advanced colorectal cancer patients with liver metastasis. Thus, it can serve as the preferable drug for the treatment of advanced colorectal cancer with liver metastasis.

Primary Immunodeficiency Diseases: An Update on the Classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency

PubMed Central

Al-Herz, Waleed; Bousfiha, Aziz; Casanova, Jean-Laurent; Chapel, Helen; Conley, Mary Ellen; Cunningham-Rundles, Charlotte; Etzioni, Amos; Fischer, Alain; Franco, Jose Luis; Geha, Raif S.; Hammarström, Lennart; Nonoyama, Shigeaki; Notarangelo, Luigi Daniele; Ochs, Hans Dieter; Puck, Jennifer M.; Roifman, Chaim M.; Seger, Reinhard; Tang, Mimi L. K.

2011-01-01

We report the updated classification of primary immunodeficiency diseases, compiled by the ad hoc Expert Committee of the International Union of Immunological Societies. As compared to the previous edition, more than 15 novel disease entities have been added in the updated version. For each disorders, the key clinical and laboratory features are provided. This updated classification is meant to help in the diagnostic approach to patients with these diseases. PMID:22566844

Expression of killer inhibitory receptors on cytotoxic cells from HIV-1-infected individuals

PubMed Central

Galiani, M D; Aguado, E; Tarazona, R; Romero, P; Molina, I; Santamaria, M; Solana, R; PeñA, J

1999-01-01

Dysfunction of cytotoxic activity of T and natural killer (NK) lymphocytes is a main immunological feature in patients with AIDS, but its basis are not well understood. It has been recently described that T and NK cell-mediated cytotoxicity can be regulated by HLA killer inhibitory receptors (KIR). In this work, we have determined on cytotoxic T cells and NK cells from HIV-1-infected individuals the expression of the following KIR molecules: p58, p70, and ILT2 (immunoglobulin-like family KIR) as well as CD94 and NKG2A (C-lectin-type family KIR). With some exceptions, no significant changes were found on the expression of immunoglobulin-like KIR in either CD8+ or CD56+ cells. Interestingly, the percentages of CD8+ and CD56+ cells expressing CD94 were significantly increased in these individuals. We also show that, in vitro, IL-10 up-regulates CD94 expression on CD8+ and CD56+ cells obtained from normal individuals, suggesting that the augmented expression observed in HIV-infected individuals could be related to the high levels of IL-10 previously described in HIV-1-infected individuals. PMID:10193420

Telltale tumor infiltrating lymphocytes (TIL) in oral, head & neck cancer.

PubMed

Lei, Yu; Xie, Yuying; Tan, Yee Sun; Prince, Mark E; Moyer, Jeffrey S; Nör, Jacques; Wolf, Gregory T

2016-10-01

Evidence gleaned from recent studies on the role of tumor-infiltrating lymphocytes (TILs) suggests that cancer is not only a genetic disease but also an immunologic disease. Head and Neck Squamous Cell Carcinoma (HNSCC) has been a significant model to study cancer cell-immune cell interactions. First, immune cell infiltration is an important feature of these tumors. Second, HNSCC frequently develops resistance to immunogenic cytotoxicity, which provides a window to decipher how tumors engage the immune system to establish immune tolerance. Finally, chemoradiation therapy, as a central modality for HNSCC treatment, has been shown to elicit immune activation. The presence of effector immune cells in the tumor microenvironment is often associated with superior clinical response to adjuvant therapy. On the other hand, an activated immune system, in addition to limiting tumor initiation and progression, could also exert selective pressure to promote the growth of less immunogenic tumors, as a pivotal immunoediting process. But it remains unclear how cancer cell signaling regulates tumor immunogenicity and how to mitigate HNSCC-potentiated TIL suppression. In this review, we will revisit the prognostic role of TILs in HNSCC, and collectively discuss how cancer cell machinery impacts upon the plasticity of TILs. Copyright © 2016 Elsevier Ltd. All rights reserved.

Innate lymphoid cells in graft-versus-host disease.

PubMed

Konya, V; Mjösberg, J

2015-11-01

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. © 2015 The Authors. American Journal of Transplantation published by Wiley Periodicals, Inc. on behalf of American Society of Transplant Surgeons.

Tissue-Resident Lymphocytes in Solid Organ Transplantation: Innocent Passengers or the Key to Organ Transplant Survival?

PubMed

Prosser, Amy C; Kallies, Axel; Lucas, Michaela

2018-03-01

Short-term outcomes of solid organ transplantation have improved dramatically over the past several decades; however, long-term survival has remained static over the same period, and chronic rejection remains a major cause of graft failure. The importance of donor, or "passenger," lymphocytes to the induction of tolerance to allografts was recognized in the 1990s, but their precise contribution to graft acceptance or rejection has not been elucidated. Recently, specialized populations of tissue-resident lymphocytes in nonlymphoid organs have been described. These lymphocytes include tissue-resident memory T cells, regulatory T cells, γδ T cells, invariant natural killer T cells, and innate lymphoid cells. These cells reside in commonly transplanted solid organs, including the liver, kidneys, heart, and lung; however, their contribution to graft acceptance or rejection has not been examined in detail. Similarly, it is unclear whether tissue-resident cells derived from the pool of recipient-derived lymphocytes play a specific role in transplantation biology. This review summarizes the evidence for the roles of tissue-resident lymphocytes in transplant immunology, focussing on their features, functions, and relevance for solid organ transplantation, with specific reference to liver, kidney, heart, and lung transplantation.

Investigation of Macrophage Differentiation and Cytokine Production in an Undergraduate Immunology Laboratory

ERIC Educational Resources Information Center

Berkes, Charlotte; Chan, Leo Li-Ying

2015-01-01

We have developed a semester-long laboratory project for an undergraduate immunology course in which students study multiple aspects of macrophage biology including differentiation from progenitors in the bone marrow, activation upon stimulation with microbial ligands, expression of cell surface markers, and modulation of cytokine production. In…

Immunological Prevention of Spontaneous Mammary Carcinoma in Transgenic Mice

DTIC Science & Technology

2001-08-01

respectively, and a sera Mouse Typer Iso- TUBO cell inhibition was found in BALB/c mice injected with typing kit (Bio-Rad, Richmond , CA) as previously described...Curr. Opin. Immunol., 6: 41. Lapp6, M. A., and Prehn . R. T. Immunologic surveillance at the macroscopic level: 414-419. 1994. nonselective

21 CFR 866.5560 - Lactic dehydrogenase immunological test system.

Code of Federal Regulations, 2011 CFR

2011-04-01

... immunological test system is a device that consists of the reagents used to measure by immunochemical techniques... found in a variety of conditions, including megaloblastic anemia (decrease in the number of mature red blood cells), myocardial infarction (heart disease), and some forms of leukemia (cancer of the blood...

21 CFR 866.5560 - Lactic dehydrogenase immunological test system.

Code of Federal Regulations, 2013 CFR

2013-04-01

... immunological test system is a device that consists of the reagents used to measure by immunochemical techniques... found in a variety of conditions, including megaloblastic anemia (decrease in the number of mature red blood cells), myocardial infarction (heart disease), and some forms of leukemia (cancer of the blood...

21 CFR 866.5560 - Lactic dehydrogenase immunological test system.

Code of Federal Regulations, 2014 CFR

2014-04-01

... immunological test system is a device that consists of the reagents used to measure by immunochemical techniques... found in a variety of conditions, including megaloblastic anemia (decrease in the number of mature red blood cells), myocardial infarction (heart disease), and some forms of leukemia (cancer of the blood...

21 CFR 866.5560 - Lactic dehydrogenase immunological test system.

Code of Federal Regulations, 2012 CFR

2012-04-01

... immunological test system is a device that consists of the reagents used to measure by immunochemical techniques... found in a variety of conditions, including megaloblastic anemia (decrease in the number of mature red blood cells), myocardial infarction (heart disease), and some forms of leukemia (cancer of the blood...

Molecular analyses of dinosaur osteocytes support the presence of endogenous molecules.

PubMed

Schweitzer, Mary Higby; Zheng, Wenxia; Cleland, Timothy P; Bern, Marshall

2013-01-01

The discovery of soft, transparent microstructures in dinosaur bone consistent in morphology with osteocytes was controversial. We hypothesize that, if original, these microstructures will have molecular features in common with extant osteocytes. We present immunological and mass spectrometry evidence for preservation of proteins comprising extant osteocytes (Actin, Tubulin, PHEX, Histone H4) in osteocytes recovered from two non-avian dinosaurs. Furthermore, antibodies to DNA show localized binding to these microstructures, which also react positively with DNA intercalating stains propidium iodide (PI) and 4',6'-diamidino-2-phenylindole dihydrochloride (DAPI). Each antibody binds dinosaur cells in patterns similar to extant cells. These data are the first to support preservation of multiple proteins and to present multiple lines of evidence for material consistent with DNA in dinosaurs, supporting the hypothesis that these structures were part of the once living animals. We propose mechanisms for preservation of cells and component molecules, and discuss implications for dinosaurian cellular biology. Copyright © 2012 Elsevier Inc. All rights reserved.

Acute myeloblastic leukemia with minimal myeloid differentiation (FAB AML-M0): a study of eleven cases.

PubMed

Sempere, A; Jarque, I; Guinot, M; Palau, J; García, R; Sanz, G F; Gomis, F; Pérez-Sirvent, M L; Senent, L; Sanz, M A

1993-12-01

The main clinical, morphological, cytochemical, immunological features and therapy results of eleven patients diagnosed as acute myeloblastic leukemia M0 (AML-M0) are reported here. There were no clinical characteristics, abnormalities on physical examination or initial laboratory parameters that distinguished these eleven patients. Bone marrow aspirates were hypocellular in four patients. The leukemic cells were undifferentiated by light microscopy and myeloperoxidase (MPO) and/or Sudan Black B (SBB) stains were negative in all cases. Myeloid differentiation antigens were present on the leukemic cells of all eleven patients, whereas B and T cell markers were clearly negative except for CD4 and CD7 antigens. Whatever the treatment employed survival was very short. Eight of the eleven patients were treated and two achieved complete remission (CR) but only one of them is alive in continuous CR. Our results like those previously reported, suggest that AML-M0 patients have a very poor prognosis with standard induction therapies and should perhaps be considered for experimental therapeutic approaches.

Epstein-Barr Virus in Gastric Carcinoma

PubMed Central

Nishikawa, Jun; Yoshiyama, Hironori; Iizasa, Hisashi; Kanehiro, Yuichi; Nakamura, Munetaka; Nishimura, Junichi; Saito, Mari; Okamoto, Takeshi; Sakai, Kouhei; Suehiro, Yutaka; Yamasaki, Takahiro; Oga, Atsunori; Yanai, Hideo; Sakaida, Isao

2014-01-01

The Epstein-Barr virus (EBV) is detected in about 10% of gastric carcinoma cases throughout the world. In EBV-associated gastric carcinoma, all tumor cells harbor the clonal EBV genome. Gastric carcinoma associated with EBV has distinct clinicopathological features, occurs predominately in men and in younger-aged individuals, and presents a generally diffuse histological type. Most cases of EBV-associated gastric carcinoma exhibit a histology rich in lymphocyte infiltration. The immunological reactiveness in the host may represent a relatively preferable prognosis in EBV-positive cases. This fact highlights the important role of EBV in the development of EBV-associated gastric carcinoma. We have clearly proved direct infection of human gastric epithelialcells by EBV. The infection was achieved by using a recombinant EBV. Promotion of growth by EBV infection was observed in the cells. Considerable data suggest that EBV may directly contribute to the development of EBV-associated GC. This tumor-promoting effect seems to involve multiple mechanisms, because EBV affects several host proteins and pathways that normally promote apoptosis and regulate cell proliferation. PMID:25386788

Autoimmune retinopathy with RPE hypersensitivity and 'negative ERG' in X-linked hyper-IgM syndrome.

PubMed

Schuster, Andreas; Apfelstedt-Sylla, Eckart; Pusch, Carsten M; Zrenner, Eberhart; Thirkill, Charles E

2005-01-01

To report the clinical, electrophysiological, and immunological features of a patient with X-linked hyper-IgM immunodeficiency syndrome type 1 (HIGM1) accompanied by a novel type of autoimmune retinopathy, including retinal pigment epithelium (RPE) hypersensitivity. Comprehensive ophthalmological examinations, electrophysiological function testing, and inquiries into the immunological status of a 13-year-old presenting with subacute loss of vision in association with a molecularly confirmed diagnosis of HIGM1 were performed. The patient was genotyped by a PCR-based sequence tag content mapping strategy to define the genetic defect within the causative X-HIM gene TNFSF5. Since conventional allogenic bone marrow transplantation has been reported to cure HIGM1, a peripheral blood stem-cell transplantation was performed. (1) The patient's reduced visual acuity included prolonged dark adaptation and visual field constriction. Electrophysiology revealed a 'negative ERG' indicating post-receptoral dysfunction. (2) Initial immunological examination of the patient's serum identified abnormal antibody activity with components of the photoreceptors and the inner nuclear layer. The patient later developed indications of RPE hypersensitivity. A massively reduced light-peak to dark-trough ratio of the EOG slow oscillations (L/D ratio) corresponded to impaired RPE-photoreceptor complex function. (3) Molecular genetic analyses revealed the patient to be nullizygous for the tumor necrosis factor ligand member 5 gene (TNFSF5; CD40LG). A large chromosomal deletion of approximately 27.6-32.3 kb in size was identified in Xq26. (4) The transplant with its associated immunomodulation appeared to worsen rather than improve the patient's condition. The fundus appearance and electrophysiological function testing revealed indications of atypical retinal degeneration. However, the clinical course and the serological findings were consistent with those of ocular autoimmunity involving both antiretinal activity and RPE hypersensitivity. In this case, peripheral stem-cell transfusion with its associated chemotherapy failed to benefit the patient's vision; indications of autoimmunity appeared to increase following this treatment.

Controlling the Immunological Crosstalk during Conception and Pregnancy: HLA-G in Reproduction

PubMed Central

Lynge Nilsson, Line; Djurisic, Snezana; Hviid, Thomas Vauvert F.

2014-01-01

In several years after its discovery in the placenta, the human leukocyte antigen (HLA) class Ib protein, HLA-G, was not given much attention, nor was it assigned great importance. As time has unraveled, HLA-G has proven to have distinctive functions and an unforeseen and possibly important role in reproduction. HLA-G is characterized mainly by its low polymorphism and restricted tissue distribution in non-pathological conditions. In fact, its expression pattern is primarily limited to extravillous cytotrophoblast cells at the maternal-fetal interface during pregnancy. Due to low polymorphism, almost the same protein is expressed by virtually all individuals. It is these unique features that make HLA-G differ from its highly polymorphic HLA class Ia counterparts, the HLA-A, -B, and -C molecules. Its function, seemingly diverse, is typically receptor-mediated, and involves interactions with a wide range of immune cells. As the expression of HLA-G primarily is limited to gestation, this has given rise to the hypothesis that HLA-G plays an important role in the immunological tolerance of the fetus by the mother. In keeping with this, it might not be surprising that polymorphisms in the HLA-G gene, and levels of HLA-G expression, have been linked to reproductive failure and pre-eclampsia. Based on recent studies, we speculate that HLA-G might be involved in mechanisms in reproductive immunology even before conception because HLA-G can be detected in the genital tract and in the blood of non-pregnant women, and is present in seminal fluid from men. In addition, HLA-G expression has been found in the pre-implanted embryo. Therefore, we propose that a combined contribution from the mother, the father, and the embryo/fetus is likely to be important. Furthermore, this review presents important aspects of HLA-G in relation to reproduction: from genetics to physiological effects, from pregnancy and pregnancy complications to a short discussion on future possible means of preventative measures and therapy. PMID:24860568

Long term evaluation of mesenchymal stem cell therapy in a feline model of chronic allergic asthma

PubMed Central

Trzil, Julie E; Masseau, Isabelle; Webb, Tracy L; Chang, Chee-hoon; Dodam, John R; Cohn, Leah A; Liu, Hong; Quimby, Jessica M; Dow, Steven W; Reinero, Carol R

2014-01-01

Background Mesenchymal stem cells (MSCs) decrease airway eosinophilia, airway hyperresponsiveness (AHR), and remodeling in murine models of acutely induced asthma. We hypothesized that MSCs would diminish these hallmark features in a chronic feline asthma model. Objective To document effects of allogeneic, adipose-derived MSCs on airway inflammation, airway hyperresponsiveness (AHR), and remodeling over time and investigate mechanisms by which MSCs alter local and systemic immunologic responses in chronic experimental feline allergic asthma. Methods Cats with chronic, experimentally-induced asthma received six intravenous infusions of MSCs (0.36–2.5X10E7 MSCs/infusion) or placebo bimonthly at the time of study enrollment. Cats were evaluated at baseline and longitudinally for one year. Outcome measures included: bronchoalveolar lavage fluid cytology to assess airway eosinophilia; pulmonary mechanics and clinical scoring to assess AHR; and thoracic computed tomographic (CT) scans to assess structural changes (airway remodeling). CT scans were evaluated using a scoring system for lung attenuation (LA) and bronchial wall thickening (BWT). To assess mechanisms of MSC action, immunologic assays including allergen-specific IgE, cellular IL-10 production, and allergen-specific lymphocyte proliferation were performed. Results There were no differences between treatment groups or over time with respect to airway eosinophilia or AHR. However, significantly lower LA and BWT scores were noted in CT images of MSC-treated animals compared to placebo-treated cats at month 8 of the study (LA p=0.0311; BWT p=0.0489). No differences were noted between groups in the immunologic assays. Conclusions and Clinical Relevance When administered after development of chronic allergic feline asthma, MSCs failed to reduce airway inflammation and AHR. However, repeated administration of MSCs at the start of study did reduce computed tomographic measures of airway remodeling by month 8, though the effect was not sustained at month 12. Further study of MSC therapy including repeated MSC administration is warranted to assess impact on remodeling in chronic asthma. PMID:25220646

IL-2 induces a WAVE2-dependent pathway for actin reorganization that enables WASp-independent human NK cell function.

PubMed

Orange, Jordan S; Roy-Ghanta, Sumita; Mace, Emily M; Maru, Saumya; Rak, Gregory D; Sanborn, Keri B; Fasth, Anders; Saltzman, Rushani; Paisley, Allison; Monaco-Shawver, Linda; Banerjee, Pinaki P; Pandey, Rahul

2011-04-01

Wiskott-Aldrich syndrome (WAS) is a primary immunodeficiency associated with an increased susceptibility to herpesvirus infection and hematologic malignancy as well as a deficiency of NK cell function. It is caused by defective WAS protein (WASp). WASp facilitates filamentous actin (F-actin) branching and is required for F-actin accumulation at the NK cell immunological synapse and NK cell cytotoxicity ex vivo. Importantly, the function of WASp-deficient NK cells can be restored in vitro after exposure to IL-2, but the mechanisms underlying this remain unknown. Using a WASp inhibitor as well as cells from patients with WAS, we have defined a direct effect of IL-2 signaling upon F-actin that is independent of WASp function. We found that IL-2 treatment of a patient with WAS enhanced the cytotoxicity of their NK cells and the F-actin content at the immunological synapses formed by their NK cells. IL-2 stimulation of NK cells in vitro activated the WASp homolog WAVE2, which was required for inducing WASp-independent NK cell function, but not for baseline activity. Thus, WAVE2 and WASp define parallel pathways to F-actin reorganization and function in human NK cells; although WAVE2 was not required for NK cell innate function, it was accessible through adaptive immunity via IL-2. These results demonstrate how overlapping cytoskeletal activities can utilize immunologically distinct pathways to achieve synonymous immune function.

IL-2 induces a WAVE2-dependent pathway for actin reorganization that enables WASp-independent human NK cell function

PubMed Central

Orange, Jordan S.; Roy-Ghanta, Sumita; Mace, Emily M.; Maru, Saumya; Rak, Gregory D.; Sanborn, Keri B.; Fasth, Anders; Saltzman, Rushani; Paisley, Allison; Monaco-Shawver, Linda; Banerjee, Pinaki P.; Pandey, Rahul

2011-01-01

Wiskott-Aldrich syndrome (WAS) is a primary immunodeficiency associated with an increased susceptibility to herpesvirus infection and hematologic malignancy as well as a deficiency of NK cell function. It is caused by defective WAS protein (WASp). WASp facilitates filamentous actin (F-actin) branching and is required for F-actin accumulation at the NK cell immunological synapse and NK cell cytotoxicity ex vivo. Importantly, the function of WASp-deficient NK cells can be restored in vitro after exposure to IL-2, but the mechanisms underlying this remain unknown. Using a WASp inhibitor as well as cells from patients with WAS, we have defined a direct effect of IL-2 signaling upon F-actin that is independent of WASp function. We found that IL-2 treatment of a patient with WAS enhanced the cytotoxicity of their NK cells and the F-actin content at the immunological synapses formed by their NK cells. IL-2 stimulation of NK cells in vitro activated the WASp homolog WAVE2, which was required for inducing WASp-independent NK cell function, but not for baseline activity. Thus, WAVE2 and WASp define parallel pathways to F-actin reorganization and function in human NK cells; although WAVE2 was not required for NK cell innate function, it was accessible through adaptive immunity via IL-2. These results demonstrate how overlapping cytoskeletal activities can utilize immunologically distinct pathways to achieve synonymous immune function. PMID:21383498

Role of Immunologic Disturbance in Human Oncogenesis: Some Facts and Fancies*

PubMed Central

Kaplan, Henry S.

1971-01-01

A brief review is presented of the evidence linking the development of certain types of neoplasms, and of the malignant lymphomas in particular, to chronic immunosuppression in animals and man and to the naturally occurring human immunologic deficiency states. The discussion then focuses on Hodgkin's disease and considers recent evidence concerning the relation between the clinical stage of the disease and its associated defect in cell-mediated immunity. Finally, the prior occurrence of infectious mononucleosis in some cases of Hodgkin's disease is considered in the context of the hypothesis that the neoplastic cells of Hodgkin's disease may evolve from a chronic immunologic reaction, analogous to that of graft-versus-host, stemming from the induction of antigenic alteration in a subpopulation of lymphocytes by certain types of non-neoplastic viral infections. PMID:4401360

Regenerative immunology: the immunological reaction to biomaterials.

PubMed

Cravedi, Paolo; Farouk, Samira; Angeletti, Andrea; Edgar, Lauren; Tamburrini, Riccardo; Duisit, Jerome; Perin, Laura; Orlando, Giuseppe

2017-12-01

Regenerative medicine promises to meet two of the most urgent needs of modern organ transplantation, namely immunosuppression-free transplantation and an inexhaustible source of organs. Ideally, bioengineered organs would be manufactured from a patient's own biomaterials-both cells and the supporting scaffolding materials in which cells would be embedded and allowed to mature to eventually regenerate the organ in question. While some groups are focusing on the feasibility of this approach, few are focusing on the immunogenicity of the scaffolds that are being developed for organ bioengineering purposes. This review will succinctly discuss progress in the understanding of immunological characteristics and behavior of different scaffolds currently under development, with emphasis on the extracellular matrix scaffolds obtained decellularized animal or human organs which seem to provide the ideal template for bioengineering purposes. © 2017 Steunstichting ESOT.

Nijmegen breakage syndrome.

PubMed Central

van der Burgt, I; Chrzanowska, K H; Smeets, D; Weemaes, C

1996-01-01

Nijmegen breakage syndrome (NBS), a rare autosomal recessive condition also known as ataxia telangiectasia (AT) variants V1 and V2, is characterised by microcephaly, typical facies, short stature, immunodeficiency, and chromosomal instability. We report the clinical, immunological, chromosomal, and cell biological findings in 42 patients who are included in the NBS Registry in Nijmegen. The immunological, chromosomal, and cell biological findings resemble those in AT, but the clinical findings are quite different. NBS appears to be a separate entity not allelic with AT. Images PMID:8929954

Liposomes containing NY‑ESO‑1/tetanus toxoid and adjuvant peptides targeted to human dendritic cells via the Fc receptor for cancer vaccines.

PubMed

Cruz, Luis J; Rueda, Felix; Simón, Lorena; Cordobilla, Begoña; Albericio, Fernando; Domingo, Joan C

2014-04-01

To improve the immunological response against tumors, a vaccine based on nanoliposomes targeted to the Fcg-receptor was developed to enhance the immunogenicity of tumor-associated antigens (TAAs). Using human dendritic cells in vitro, a fragment of the TAA NY-ESO-1 combined with a T-helper peptide from the tetanus toxoid encapsulated in nanoliposomes was evaluated. In addition, peptides Palm-IL-1 and MAP-IFN-g were coadministered as adjuvants to enhance the immunological response. Coadministration of Palm-IL-1 or MAP-IFN-g peptide adjuvants and the hybrid NY-ESO-1-tetanus toxoid (soluble or encapsulated in nanoliposomes without targeting) increased immunogenicity. However, the most potent immunological response was obtained when the peptide adjuvants were encapsulated in liposomes targeted to human dendritic cells via the Fc receptor. This targeted vaccine strategy is a promising tool to activate and deliver antigens to dendritic cells, thus improving immunotherapeutic response in situations in which the immune system is frequently compromised, as in advanced cancers.

Regulatory immune cells and functions in autoimmunity and transplantation immunology.

PubMed

Papp, Gabor; Boros, Peter; Nakken, Britt; Szodoray, Peter; Zeher, Margit

2017-05-01

In physiological circumstances, various tolerogenic mechanisms support the protection of self-structures during immune responses. However, quantitative and/or qualitative changes in regulatory immune cells and mediators can evoke auto-reactive immune responses, and upon susceptible genetic background, along with the presence of other concomitant etiological factors, autoimmune disease may develop. In transplant immunology, tolerogenic mechanisms are also critical, since the balance between of alloantigen-reactive effector cells and the regulatory immune cells will ultimately determine whether a graft is accepted or rejected. Better understanding of the immunological tolerance and the potential modulations of immune regulatory processes are crucial for developing effective therapies in autoimmune diseases as well as in organ transplantation. In this review, we focus on the novel insights regarding the impaired immune regulation and other relevant factors contributing to the development of auto-reactive and graft-reactive immune responses in autoimmune diseases and transplant rejection, respectively. We also address some promising approaches for modification of immune-regulatory processes and tolerogenic mechanisms in autoimmunity and solid organ transplantation, which may be beneficial in future therapeutic strategies. Copyright © 2017 Elsevier B.V. All rights reserved.

Setting the proportion of CD4+ and CD8+ T-cells co-cultured with canine macrophages infected with Leishmania chagasi.

PubMed

Viana, Kelvinson Fernandes; Aguiar-Soares, Rodrigo Dian Oliveira; Ker, Henrique Gama; Resende, Lucilene Aparecida; Souza-Fagundes, Elaine Maria; Dutra, Walderez Ornelas; Fujiwara, Ricardo Toshio; da Silveira-Lemos, Denise; Sant'Ana, Rita de Cássia Oliveira; Wardini, Amanda Brito; Araújo, Márcio Sobreira Silva; Martins-Filho, Olindo Assis; Reis, Alexandre Barbosa; Giunchetti, Rodolfo Cordeiro

2015-07-30

New methods for evaluating the canine immune system are necessary, not only to monitor immunological disorders, but also to provide insights for vaccine evaluations and therapeutic interventions, reducing the costs of assays using dog models, and provide a more rational way for analyzing the canine immune response. The present study intended to establish an in vitro toll to assess the parasitological/immunological status of dogs, applicable in pre-clinical trials of vaccinology, prognosis follow-up and therapeutics analysis of canine visceral leishmaniasis. We have evaluated the performance of co-culture systems of canine Leishmania chagasi-infected macrophages with different cell ratios of total lymphocytes or purified CD4(+) and CD8(+) T-cells. Peripheral blood mononuclear cells from uninfected dogs were used for the system set up. Employing the co-culture systems of L. chagasi-infected macrophages and purified CD4(+) or CD8(+) T-cell subsets we observed a microenvironment compatible with the expected status of the analyzed dogs. In this context, it was clearly demonstrated that, at this selected T-cell:target ratio, the adaptive immune response of uninfected dogs, composed by L. chagasi-unprimed T-cells was not able to perform the in vitro killing of L. chagasi-infected macrophages. Our data demonstrated that the co-culture system with T-cells from uninfected dogs at 1:5 and 1:2 ratio did not control the infection, yielding to patent in vitro parasitism (≥ 80%), low NO production (≤ 5 μM) and IL-10 modulated (IFN-γ/IL-10 ≤ 2) immunological profile in vitro. CD4(+) or CD8(+) T-cells at 1:5 or 1:2 ratio to L. chagasi-infected macrophages seems to be ideal for in vitro assays. This co-culture system may have great potential as a canine immunological analysis method, as well as in vaccine evaluations, prognosis follow-up and therapeutic interventions. Copyright © 2015 Elsevier B.V. All rights reserved.

Immunological abnormalities associated with hereditary haemorrhagic telangiectasia.

PubMed

Guilhem, A; Malcus, C; Clarivet, B; Plauchu, H; Dupuis-Girod, S

2013-10-01

Hereditary haemorrhagic telangiectasia (HHT) is a genetic disorder related to mutations in one of the coreceptors to the transforming growth factor-β superfamily (ALK1 or endoglin). Besides the obvious vascular symptoms (epistaxis and arteriovenous malformations), patients have an unexplained high risk of severe bacterial infections. The aim of the study was to assess the main immunological functions of patients with HHT using the standard biological tests for primary immunodeficiencies. A prospective single-centre study of 42 consecutive adult patients with an established diagnosis of HHT was conducted at the National French HHT Reference Center (Lyon). Lymphocyte subpopulations and proliferation capacity, immunoglobulin levels and neutrophil and monocyte phagocytosis, oxidative burst and chemotaxis were assessed. Innate immunity was not altered in patients with HHT. With regard to adaptive immunity, significant changes were seen in immunological parameters: primarily, a lymphopenia in patients with HHT compared with healthy control subjects affecting mean CD4 (642 cells μL(-1) vs. 832 cells μL(-1) , P < 0.001), CD8 (295 cells μL(-1) vs. 501 cells μL(-1) , P < 0.0001) and natural killer (NK) cells (169 cells μL(-1) vs. 221 cells μL(-1) , P < 0.01), associated with increased levels of immunoglobulins G and A. This lymphopenia mainly concerned naïve T cells. Proliferation capacities of lymphocytes were normal. Lymphopenic patients had a higher frequency of iron supplementation but no increase in infection rate. Lower levels of immunoglobulin M and a higher rate of pulmonary arteriovenous malformations were found amongst patients with a history of severe infection. Patients with HHT exhibit immunological abnormalities including T CD4, T CD8 and NK cell lymphopenia and increased levels of immunoglobulins G and A. The observed low level of immunoglobulin M requires further investigation to determine whether it is a specific risk factor for infection in HHT. © 2013 The Association for the Publication of the Journal of Internal Medicine.

Random Evolution of Idiotypic Networks: Dynamics and Architecture

NASA Astrophysics Data System (ADS)

Brede, Markus; Behn, Ulrich

The paper deals with modelling a subsystem of the immune system, the so-called idiotypic network (INW). INWs, conceived by N.K. Jerne in 1974, are functional networks of interacting antibodies and B cells. In principle, Jernes' framework provides solutions to many issues in immunology, such as immunological memory, mechanisms for antigen recognition and self/non-self discrimination. Explaining the interconnection between the elementary components, local dynamics, network formation and architecture, and possible modes of global system function appears to be an ideal playground of statistical mechanics. We present a simple cellular automaton model, based on a graph representation of the system. From a simplified description of idiotypic interactions, rules for the random evolution of networks of occupied and empty sites on these graphs are derived. In certain biologically relevant parameter ranges the resultant dynamics leads to stationary states. A stationary state is found to correspond to a specific pattern of network organization. It turns out that even these very simple rules give rise to a multitude of different kinds of patterns. We characterize these networks by classifying `static' and `dynamic' network-patterns. A type of `dynamic' network is found to display many features of real INWs.

[Acute hybrid leukemia. Review of the literature and presentation of a case].

PubMed

Guzzini, F; Angelopoulos, N; Banfi, L; Coppetti, D; Ceppi, M; Camerone, G

1990-03-01

In the last years, the development of immunophenotypic and molecular analyses allowed to recognize several cases of hybrid acute leukemia (AL), whose blast cell display both lymphoid and myeloid features. Hybrid, or mixed-lineage, AL seems to have distinct clinical manifestations and hematological findings, and is mainly characterized by resistance to chemotherapy and poor prognosis. We report on a patient with AL, which showed a very rapid switch from the lymphoblastic phenotype exhibited at presentation to a myelomonoblastic one, appeared at first relapse, and lastly progressed to an undifferentiated leukemia in the terminal phase. Together with this morphologic and cytochemical evolution, leukemic cells expressed, besides the primary early-B antigens, new immunological markers related to T-lymphocytic and myeloid lineages. Based on this observation and current understanding of the ontogenesis of hematologic malignancies, we discuss biological mechanisms which are likely to underlie hybrid leukemia.

Ultrastructural analysis of Phytomonas species from Euphorbia pinea reveals trans-cytoplasmic filaments 10 nm in diameter.

PubMed

Page, A M; Lagnado, J R

2000-10-01

Phytomonas sp. derived from Euphorbia pinea are digenetic plant trypanosomes that are transmitted by the squashbug Stenocephalus agilis and exist exclusively as promastigotes. The stable sub-pellicular microtubular array, the flagellar axoneme and the paraflagellar rod represent the major cytoskeletal components common to all trypanosomes. The work described in this paper examines in detail the ultrastructural morphology of the organism and highlights a number of novel structural features, and in particular, the presence of some detergent-resistant proteins which take the form of bundles of trans-cytoplasmic filaments of ca. 10 nm in diameter, seen in cells from both log- and stationary-phase cultures. The ultrastructural morphology and immunological cross-reactivity of these filaments are described, and their relationship to filamentous bundles previously reported in stationary-phase cultures of Crithidia fasciculata and to intermediate filaments of animal cells is discussed.

Tonsillectomy as a Treatment for Psoriasis: A Review

PubMed Central

Wu, Wiggin; Debbaneh, Maya; Moslehi, Homayoun; Koo, John; Liao, Wilson

2015-01-01

Psoriasis is a chronic skin disorder that affects 1% to 3% of the general population worldwide. Streptococcal infection, especially streptococcal pharyngitis, has been shown to be a significant trigger of psoriasis in some patients, possibly by sensitizing T cells to keratin epitopes in the skin. Due to the role of the palatine tonsils as an immunological organ that may generate autoreactive T cells, tonsillectomy has been investigated as a treatment for psoriasis. Tonsillectomy originally gained acceptance in Japan as a treatment for palmoplantar pustulosis, a condition that shares features with pustular psoriasis. Subsequently, tonsillectomy has been used for the treatment of plaque psoriasis and guttate psoriasis. Recently, the first randomized, controlled clinical trial of tonsillectomy was performed. Here, we review the available evidence for the benefit of tonsillectomy as a treatment for palmoplantar pustulosis and psoriasis. We also discuss molecular studies aimed at understanding the role of tonsils in skin disease. PMID:24283892

Detecting proteins in highly autofluorescent cells using quantum dot antibody conjugates.

PubMed

Orcutt, Karen M; Ren, Shanshan; Gundersen, Kjell

2009-01-01

We have applied quantum dot (Qdot) antibody conjugates as a biomolecular probe for cellular proteins important in biogeochemical cycling in the sea. Conventional immunological methods have been hampered by the strong autofluorescence found in cyanobacteria cells. Qdot conjugates provide an ideal alternative for studies that require long-term imaging of cells such as detection of low abundance cellular antigens by fluorescence microscopy. The advantage of Qdot labeled probes over conventional immunological methods is the photostability of the probe. Phycoerythrin bleaches in cyanobacterial cells under prolonged UV or blue light excitation, which means that the semiconducting nanocrystal probe, the Qdot, can yield a strong fluorescent signal without interference from cellular pigments.

In vivo and in vitro studies into the immunological changes following iodine 131 therapy for Graves' disease.

PubMed

Wilson, R; McKillop, J H; Jenkins, C; Thomson, J A

1991-01-01

Radio-iodine therapy for Graves' disease is followed by immunological changes in addition to effects on thyroid hormone production. The present study examined these changes and the mechanisms responsible for them. Of the 15 patients enrolled in the study, 10 became hypothyroid in the first year after iodine 131 therapy. Patients who became hypothyroid had a tendency to show a rise in serum thyrotropin receptor antibody levels (30 +/- 14 to 40 +/- 9 units; NS) and a significant rise in immunoglobulin production (324 +/- 153 to 740 +/- 200 ng/ml; P less than 0.0005) from mitogen-stimulated peripheral blood lymphocytes (a measure of B-cell activity) 2 months after iodine 131 therapy. The increases were not seen in the patients who remained euthyroid at 1 year. In vitro studies suggested that the rise in B-cell activity is due to a fall in suppressor T cell numbers, a change shown to occur following iodine 131 therapy in previous studies. Our results indicate that immunological changes do arise after iodine 131 therapy for Graves' disease but appear to be confined to patients who subsequently became hypothyroid. It is not possible from this study to determine whether the immunological changes appear as a consequence of thyroidal destruction leading to hypothyroidism or whether they contribute directly to it.

Immunohistochemical analysis of immune response in breast cancer and melanoma patients after laser immunotherapy

NASA Astrophysics Data System (ADS)

Nordquist, Robert E.; Bishop, Shelly L.; Ferguson, Halie; Vaughan, Melville B.; Jose, Jessnie; Kastl, Katherine; Nguyen, Long; Li, Xiaosong; Liu, Hong; Chen, Wei R.

2011-03-01

Laser immunotherapy (LIT) has shown great promise in pre-clinical studies and preliminary clinical trials. It could not only eradicate treated local tumors but also cause regression and elimination of untreated metastases at distant sites. Combining a selective photothermal therapy with an active immunological stimulation, LIT can induce systemic anti-tumor immune responses. Imiquimod (IMQ), a toll-like receptor agonist, was used for the treatment of late-stage melanoma patients and glycated chitosan (GC), a biological immunological modulator, was used for the treatment of late-stage breast cancer patients, in combination of irradiation of a near-infrared laser light. To observe the immunological changes before and after LIT treatment, the pathological tissues of melanoma and breast cancer patients were processed for immunohistochemical analysis. Our results show that LIT changed the expressions of several crucial T cell types. Specifically, we observed significant decreases of CD3+ T-cells and a significant increase of CD4+,CD8+, and CD68+ T-cells in the tumor samples after LIT treatment. While not conclusive, our study could shed light on one the possible mechanisms of anti-tumor immune responses induced by LIT. Further studies will be conducted to identify immunological biomarkers associated with LIT-induced clinical response.

Immunologic Memory Induced by a Glycoconjugate Vaccine in a Murine Adoptive Lymphocyte Transfer Model

PubMed Central

Guttormsen, Hilde-Kari; Wetzler, Lee M.; Finberg, Robert W.; Kasper, Dennis L.

1998-01-01

We have developed an adoptive cell transfer model in mice to study the ability of a glycoprotein conjugate vaccine to induce immunologic memory for the polysaccharide moiety. We used type III capsular polysaccharide from the clinically relevant pathogen group B streptococci conjugated to tetanus toxoid (GBSIII-TT) as our model vaccine. GBS are a major cause of neonatal infections in humans, and type-specific antibodies to the capsular polysaccharide protect against invasive disease. Adoptive transfer of splenocytes from mice immunized with the GBSIII-TT conjugate vaccine conferred anti-polysaccharide immunologic memory to naive recipient mice. The transfer of memory occurred in a dose-dependent manner. The observed anamnestic immune response was characterized by (i) more rapid kinetics, (ii) isotype switching from immunoglobulin M (IgM) to IgG, and (iii) 10-fold-higher levels of type III-specific IgG antibody than for the primary response in animals with cells transferred from placebo-immunized mice. The adoptive cell transfer model described in this paper can be used for at least two purposes: (i) to evaluate conjugate vaccines with different physicochemical properties for their ability to induce immunologic memory and (ii) to study the cellular interactions required for an immune response to these molecules. PMID:9573085

[Impact of highly active antiretroviral therapy in the clinical, immunological and virological response from AIDS patients].

PubMed

Reyes Corcho, Andrés; Mosquera Fernández, Miguel A; Bouza Jiménez, Yanelka; Pérez Avila, Jorge; Hernández, Vivian; Jam Morales, Blas; Alvarez Amador, Gustavo; Bouza Jiménez, Yadira

2007-01-01

A longitudinal prospective study was made to evaluate the clinical, immunological and virological response of a cohort of 34 AIDS patients in Cienfuegos provinces, who had been treated with highly active antiretroviral therapy (HAART). Males comprised 67.6% of the total number and average age was 32 years. Sexual infection path was identified in 91.2% of cases. The CD4+ T counting under 200 cells defined AIDS in 79.4% of individuals. Twenty six patients suffered minor opportunistic infections (76.5%) whereas 32.4% got sick due to some major opportunistic disease prior to the therapy. After this therapy, these frequencies lowered to 20.6% and 11.8% respectively. Average CD4+ counting at the starting of HAART was 196 cell/mm3 and exceeded 400 cells in the rest of further countings. From a PVC average of 15 251 copies/mL one year after therapy, this figure reduced to 8 048 copies at 2 years. Only 10 cases required hospitalization after a HAART (29.4%). Treatment adherence reached over 80% and was correlated to immunological restoration. Survival after one year was 100% and only 2 patients died in the following 4 years. The positive impact of HAART on the frequency of opportunistic infections, immunological restoration and survival was proved.

The dynamics of health in wild field vole populations: a haematological perspective

PubMed Central

Beldomenico, Pablo M.; Telfer, Sandra; Gebert, Stephanie; Lukomski, Lukasz; Bennett, Malcolm; Begon, Michael

2010-01-01

Summary Pathogens have been proposed as potentially important drivers of population dynamics, but while a few studies have investigated the impact of specific pathogens, the wealth of information provided by general indices of health has hardly been exploited. By evaluating haematological parameters in wild populations, our knowledge of the dynamics of health and infection may be better understood. Here, haematological dynamics in natural populations of field voles are investigated to determine environmental and host factors associated with indicators of inflammatory response (counts of monocytes and neutrophils) and of condition: measures of immunological investment (lymphocyte counts) and aerobic capacity (red blood cell counts). Individuals from three field vole populations were sampled monthly for 2 years. Comparisons with individuals kept under controlled conditions facilitated interpretation of field data. Mixed effects models were developed for each cell type to evaluate separately the effects of various factors on post-juvenile voles and mature breeding females. There were three well-characterized ‘physiological’ seasons. The immunological investment appeared lowest in winter (lowest lymphocyte counts), but red blood cells were at their highest levels and indices of inflammatory response at their lowest. Spring was characterized by a fall in red blood cell counts and peaks in indicators of inflammatory response. During the course of summer—autumn, red blood cell counts recovered, the immunological investment increased and the indicators of inflammatory response decreased. Poor body condition appeared to affect the inflammatory response (lower neutrophil and monocyte peaks) and the immunological investment (lower lymphocyte counts), providing evidence that the capacity to fight infection is dependent upon host condition. Breeding early in the year was most likely in females in better condition (high lymphocyte and red blood cell counts). All the haematological parameters were affected adversely by high population densities. PMID:18564292

Modulation of Human Allogeneic and Syngeneic Pluripotent Stem Cells and Immunological Implications for Transplantation

PubMed Central

Sackett, S.D.; Brown, M.E.; Tremmel, D.M.; Ellis, T.; Burlingham, W.J.; Odorico, J.S.

2016-01-01

Tissues derived from induced pluripotent stem cells (iPSCs) are a promising source of cells for building various regenerative medicine therapies; from simply transplanting cells to reseeding decellularized organs to reconstructing multicellular tissues. Although reprogramming strategies for producing iPSCs have improved, the clinical use of iPSCs is limited by the presence of unique human leukocyte antigen (HLA) genes, the main immunologic barrier to transplantation. In order to overcome the immunological hurdles associated with allogeneic tissues and organs, the generation of patient-histocompatible iPSCs (autologous or HLA-matched cells) provides an attractive platform for personalized medicine. However, concerns have been raised as to the fitness, safety and immunogenicity of iPSC derivatives because of variable differentiation potential of different lines and the identification of genetic and epigenetic aberrations that can occur during the reprogramming process. In addition, significant cost and regulatory barriers may deter commercialization of patient specific therapies in the short-term. Nonetheless, recent studies provide some evidence of immunological benefit for using autologous iPSCs. Yet, more studies are needed to evaluate the immunogenicity of various autologous and allogeneic human iPSC-derived cell types as well as test various methods to abrogate rejection. Here, we present perspectives of using allogeneic vs autologous iPSCs for transplantation therapies and the advantages and disadvantages of each related to differentiation potential, immunogenicity, genetic stability and tumorigenicity. We also review the current literature on the immunogenicity of syngeneic iPSCs and discuss evidence that questions the feasibility of HLA-matched iPSC banks. Finally, we will discuss emerging methods of abrogating or reducing host immune responses to PSC derivatives. PMID:26970668

Modulation of human allogeneic and syngeneic pluripotent stem cells and immunological implications for transplantation.

PubMed

Sackett, S D; Brown, M E; Tremmel, D M; Ellis, T; Burlingham, W J; Odorico, J S

2016-04-01

Tissues derived from induced pluripotent stem cells (iPSCs) are a promising source of cells for building various regenerative medicine therapies; from simply transplanting cells to reseeding decellularized organs to reconstructing multicellular tissues. Although reprogramming strategies for producing iPSCs have improved, the clinical use of iPSCs is limited by the presence of unique human leukocyte antigen (HLA) genes, the main immunologic barrier to transplantation. In order to overcome the immunological hurdles associated with allogeneic tissues and organs, the generation of patient-histocompatible iPSCs (autologous or HLA-matched cells) provides an attractive platform for personalized medicine. However, concerns have been raised as to the fitness, safety and immunogenicity of iPSC derivatives because of variable differentiation potential of different lines and the identification of genetic and epigenetic aberrations that can occur during the reprogramming process. In addition, significant cost and regulatory barriers may deter commercialization of patient specific therapies in the short-term. Nonetheless, recent studies provide some evidence of immunological benefit for using autologous iPSCs. Yet, more studies are needed to evaluate the immunogenicity of various autologous and allogeneic human iPSC-derived cell types as well as test various methods to abrogate rejection. Here, we present perspectives of using allogeneic vs. autologous iPSCs for transplantation therapies and the advantages and disadvantages of each related to differentiation potential, immunogenicity, genetic stability and tumorigenicity. We also review the current literature on the immunogenicity of syngeneic iPSCs and discuss evidence that questions the feasibility of HLA-matched iPSC banks. Finally, we will discuss emerging methods of abrogating or reducing host immune responses to PSC derivatives. Copyright © 2016 Elsevier Inc. All rights reserved.

The immunological response and post-treatment survival of DC-vaccinated melanoma patients are associated with increased Th1/Th17 and reduced Th3 cytokine responses.

PubMed

Durán-Aniotz, Claudia; Segal, Gabriela; Salazar, Lorena; Pereda, Cristián; Falcón, Cristián; Tempio, Fabián; Aguilera, Raquel; González, Rodrigo; Pérez, Claudio; Tittarelli, Andrés; Catalán, Diego; Nervi, Bruno; Larrondo, Milton; Salazar-Onfray, Flavio; López, Mercedes N

2013-04-01

Immunization with autologous dendritic cells (DCs) loaded with a heat shock-conditioned allogeneic melanoma cell lysate caused lysate-specific delayed type hypersensitivity (DTH) reactions in a number of patients. These responses correlated with a threefold prolonged long-term survival of DTH(+) with respect to DTH(-) unresponsive patients. Herein, we investigated whether the immunological reactions associated with prolonged survival were related to dissimilar cellular and cytokine responses in blood. Healthy donors and melanoma patient's lymphocytes obtained from blood before and after vaccinations and from DTH biopsies were analyzed for T cell population distribution and cytokine release. Peripheral blood lymphocytes from melanoma patients have an increased proportion of Th3 (CD4(+) TGF-β(+)) regulatory T lymphocytes compared with healthy donors. Notably, DTH(+) patients showed a threefold reduction of Th3 cells compared with DTH(-) patients after DCs vaccine treatment. Furthermore, DCs vaccination resulted in a threefold augment of the proportion of IFN-γ releasing Th1 cells and in a twofold increase of the IL-17-producing Th17 population in DTH(+) with respect to DTH(-) patients. Increased Th1 and Th17 cell populations in both blood and DTH-derived tissues suggest that these profiles may be related to a more effective anti-melanoma response. Our results indicate that increased proinflammatory cytokine profiles are related to detectable immunological responses in vivo (DTH) and to prolonged patient survival. Our study contributes to the understanding of immunological responses produced by DCs vaccines and to the identification of follow-up markers for patient outcome that may allow a closer individual monitoring of patients.

Differential segregation in a cell-cell contact interface: the dynamics of the immunological synapse.

PubMed Central

Burroughs, Nigel John; Wülfing, Christoph

2002-01-01

Receptor-ligand couples in the cell-cell contact interface between a T cell and an antigen-presenting cell form distinct geometric patterns and undergo spatial rearrangement within the contact interface. Spatial segregation of the antigen and adhesion receptors occurs within seconds of contact, central aggregation of the antigen receptor then occurring over 1-5 min. This structure, called the immunological synapse, is becoming a paradigm for localized signaling. However, the mechanisms driving its formation, in particular spatial segregation, are currently not understood. With a reaction diffusion model incorporating thermodynamics, elasticity, and reaction kinetics, we examine the hypothesis that differing bond lengths (extracellular domain size) is the driving force behind molecular segregation. We derive two key conditions necessary for segregation: a thermodynamic criterion on the effective bond elasticity and a requirement for the seeding/nucleation of domains. Domains have a minimum length scale and will only spontaneously coalesce/aggregate if the contact area is small or the membrane relaxation distance large. Otherwise, differential attachment of receptors to the cytoskeleton is required for central aggregation. Our analysis indicates that differential bond lengths have a significant effect on synapse dynamics, i.e., there is a significant contribution to the free energy of the interaction, suggesting that segregation by differential bond length is important in cell-cell contact interfaces and the immunological synapse. PMID:12324401

Comparison of Immunological Characteristics of Mesenchymal Stem Cells Derived from Human Embryonic Stem Cells and Bone Marrow

PubMed Central

Fu, Xin; Chen, Yao; Xie, Fang-Nan; Dong, Ping; Liu, Wen-bo; Cao, Yilin

2015-01-01

Mesenchymal stem cell (MSC) has great potential for both regenerative medicine and immunotherapy due to its multipotency and immunomodulatory property. The derivation of MSCs from human tissues involves an invasive procedure and the obtained MSCs often suffer from inconsistent quality. To overcome these issues, the approaches of deriving a highly potent and replenishable population of MSCs from human embryonic stem cells (hESCs) were established. However, few studies compared the immunological characteristics of MSCs derived from hESCs with tissue-derived MSCs or demonstrated differences and the underlying mechanisms. Here, we differentiated H9 hESCs into MSC-like cells (H9-MSCs) through an embryoid body outgrowth method and compared the immunological characteristics of H9-MSCs with bone marrow-derived MSCs (BMSCs). Both sources of derived cells exhibited typical MSC morphologies and surface marker expressions, as well as multipotency to differentiate into osteogenic and adipogenic lineages. A immunological characterization study showed that H9-MSCs and BMSCs had similar immunoprivileged properties without triggering allogeneic lymphocyte proliferation as well as equivalent immunosuppressive effects on T-cell proliferation induced by either cellular or mitogenic stimuli. Flow cytometry analysis revealed a lower expression of human major histocompatability complex class II molecule human lymphocyte antigen (HLA)-DR and a higher expression of coinhibitory molecule B7-H1 in H9-MSCs than in BMSCs. Interferon gamma (IFN-γ) is a proinflammatory cytokine that can induce the expression of HLA class II molecules in many cell types. Our results showed that pretreatment of H9-MSCs and BMSCs with IFN-γ did not change their immunogenicity and immunosuppressive abilities, but increased the difference between H9-MSCs and BMSCs for their expression of HLA-DR. Further detection of expression of molecules involved in IFN-γ signaling pathways suggested that the lower expression of HLA-DR in H9-MSCs could be partially attributed to the lower expression and the less nuclear translocation of its transcriptional factor CIITA. The present study provides evidence that the hESC-derived MSCs share similar immunogenicity and immunosuppressive abilities with BMSCs, but differ in the expression profile of immunological markers and the responsiveness to certain inflammatory cytokines, which suggests that H9-MSCs could be a safe and efficient candidate for MSC treatment in patients with inflammatory disorders. PMID:25256849

A high dose of intravenous immunoglobulin increases CD94 expression on natural killer cells in women with recurrent spontaneous abortion.

PubMed

Shimada, Shigeki; Takeda, Masamitsu; Nishihira, Jun; Kaneuchi, Masanori; Sakuragi, Noriaki; Minakami, Hisanori; Yamada, Hideto

2009-11-01

A high dose of intravenous immunoglobulin (HIVIg) therapy is effective in various diseases such as autoimmune diseases, and also is expected to have efficacy in recurrent spontaneous abortion (RSA). The aim of this study was to understand immunological mechanisms of this therapy. By flowcytometric analyses, we examined phenotypic changes of a variety of immunological cells including natural killer (NK) cells, cytotoxic T cells, regulatory T cells and macrophages in peripheral blood of RSA women with HIVIg therapy (n = 8). Expression percentages of inhibitory CD94 on NK cells significantly (P = 0.01) increased after the therapy (58.8 +/- 21.4% versus 71.0 +/- 17.6%). Mechanisms of possible efficacy of HIVIg therapy for RSA may include enhancement of CD94 expression and subsequent suppression of NK cell cytotoxicity.

Overcoming immunological barriers in regenerative medicine.

PubMed

Zakrzewski, Johannes L; van den Brink, Marcel R M; Hubbell, Jeffrey A

2014-08-01

Regenerative therapies that use allogeneic cells are likely to encounter immunological barriers similar to those that occur with transplantation of solid organs and allogeneic hematopoietic stem cells (HSCs). Decades of experience in clinical transplantation hold valuable lessons for regenerative medicine, offering approaches for developing tolerance-induction treatments relevant to cell therapies. Outside the field of solid-organ and allogeneic HSC transplantation, new strategies are emerging for controlling the immune response, such as methods based on biomaterials or mimicry of antigen-specific peripheral tolerance. Novel biomaterials can alter the behavior of cells in tissue-engineered constructs and can blunt host immune responses to cells and biomaterial scaffolds. Approaches to suppress autoreactive immune cells may also be useful in regenerative medicine. The most innovative solutions will be developed through closer collaboration among stem cell biologists, transplantation immunologists and materials scientists.

Interfaces of Malignant and Immunologic Clonal Dynamics in Ovarian Cancer.

PubMed

Zhang, Allen W; McPherson, Andrew; Milne, Katy; Kroeger, David R; Hamilton, Phineas T; Miranda, Alex; Funnell, Tyler; Little, Nicole; de Souza, Camila P E; Laan, Sonya; LeDoux, Stacey; Cochrane, Dawn R; Lim, Jamie L P; Yang, Winnie; Roth, Andrew; Smith, Maia A; Ho, Julie; Tse, Kane; Zeng, Thomas; Shlafman, Inna; Mayo, Michael R; Moore, Richard; Failmezger, Henrik; Heindl, Andreas; Wang, Yi Kan; Bashashati, Ali; Grewal, Diljot S; Brown, Scott D; Lai, Daniel; Wan, Adrian N C; Nielsen, Cydney B; Huebner, Curtis; Tessier-Cloutier, Basile; Anglesio, Michael S; Bouchard-Côté, Alexandre; Yuan, Yinyin; Wasserman, Wyeth W; Gilks, C Blake; Karnezis, Anthony N; Aparicio, Samuel; McAlpine, Jessica N; Huntsman, David G; Holt, Robert A; Nelson, Brad H; Shah, Sohrab P

2018-05-07

High-grade serous ovarian cancer (HGSC) exhibits extensive malignant clonal diversity with widespread but non-random patterns of disease dissemination. We investigated whether local immune microenvironment factors shape tumor progression properties at the interface of tumor-infiltrating lymphocytes (TILs) and cancer cells. Through multi-region study of 212 samples from 38 patients with whole-genome sequencing, immunohistochemistry, histologic image analysis, gene expression profiling, and T and B cell receptor sequencing, we identified three immunologic subtypes across samples and extensive within-patient diversity. Epithelial CD8+ TILs negatively associated with malignant diversity, reflecting immunological pruning of tumor clones inferred by neoantigen depletion, HLA I loss of heterozygosity, and spatial tracking between T cell and tumor clones. In addition, combinatorial prognostic effects of mutational processes and immune properties were observed, illuminating how specific genomic aberration types associate with immune response and impact survival. We conclude that within-patient spatial immune microenvironment variation shapes intraperitoneal malignant spread, provoking new evolutionary perspectives on HGSC clonal dispersion. Copyright © 2018 Elsevier Inc. All rights reserved.

HPVdb: a data mining system for knowledge discovery in human papillomavirus with applications in T cell immunology and vaccinology

PubMed Central

Zhang, Guang Lan; Riemer, Angelika B.; Keskin, Derin B.; Chitkushev, Lou; Reinherz, Ellis L.; Brusic, Vladimir

2014-01-01

High-risk human papillomaviruses (HPVs) are the causes of many cancers, including cervical, anal, vulvar, vaginal, penile and oropharyngeal. To facilitate diagnosis, prognosis and characterization of these cancers, it is necessary to make full use of the immunological data on HPV available through publications, technical reports and databases. These data vary in granularity, quality and complexity. The extraction of knowledge from the vast amount of immunological data using data mining techniques remains a challenging task. To support integration of data and knowledge in virology and vaccinology, we developed a framework called KB-builder to streamline the development and deployment of web-accessible immunological knowledge systems. The framework consists of seven major functional modules, each facilitating a specific aspect of the knowledgebase construction process. Using KB-builder, we constructed the Human Papillomavirus T cell Antigen Database (HPVdb). It contains 2781 curated antigen entries of antigenic proteins derived from 18 genotypes of high-risk HPV and 18 genotypes of low-risk HPV. The HPVdb also catalogs 191 verified T cell epitopes and 45 verified human leukocyte antigen (HLA) ligands. Primary amino acid sequences of HPV antigens were collected and annotated from the UniProtKB. T cell epitopes and HLA ligands were collected from data mining of scientific literature and databases. The data were subject to extensive quality control (redundancy elimination, error detection and vocabulary consolidation). A set of computational tools for an in-depth analysis, such as sequence comparison using BLAST search, multiple alignments of antigens, classification of HPV types based on cancer risk, T cell epitope/HLA ligand visualization, T cell epitope/HLA ligand conservation analysis and sequence variability analysis, has been integrated within the HPVdb. Predicted Class I and Class II HLA binding peptides for 15 common HLA alleles are included in this database as putative targets. HPVdb is a knowledge-based system that integrates curated data and information with tailored analysis tools to facilitate data mining for HPV vaccinology and immunology. To our best knowledge, HPVdb is a unique data source providing a comprehensive list of HPV antigens and peptides. Database URL: http://cvc.dfci.harvard.edu/hpv/ PMID:24705205

HPVdb: a data mining system for knowledge discovery in human papillomavirus with applications in T cell immunology and vaccinology.

PubMed

Zhang, Guang Lan; Riemer, Angelika B; Keskin, Derin B; Chitkushev, Lou; Reinherz, Ellis L; Brusic, Vladimir

2014-01-01

High-risk human papillomaviruses (HPVs) are the causes of many cancers, including cervical, anal, vulvar, vaginal, penile and oropharyngeal. To facilitate diagnosis, prognosis and characterization of these cancers, it is necessary to make full use of the immunological data on HPV available through publications, technical reports and databases. These data vary in granularity, quality and complexity. The extraction of knowledge from the vast amount of immunological data using data mining techniques remains a challenging task. To support integration of data and knowledge in virology and vaccinology, we developed a framework called KB-builder to streamline the development and deployment of web-accessible immunological knowledge systems. The framework consists of seven major functional modules, each facilitating a specific aspect of the knowledgebase construction process. Using KB-builder, we constructed the Human Papillomavirus T cell Antigen Database (HPVdb). It contains 2781 curated antigen entries of antigenic proteins derived from 18 genotypes of high-risk HPV and 18 genotypes of low-risk HPV. The HPVdb also catalogs 191 verified T cell epitopes and 45 verified human leukocyte antigen (HLA) ligands. Primary amino acid sequences of HPV antigens were collected and annotated from the UniProtKB. T cell epitopes and HLA ligands were collected from data mining of scientific literature and databases. The data were subject to extensive quality control (redundancy elimination, error detection and vocabulary consolidation). A set of computational tools for an in-depth analysis, such as sequence comparison using BLAST search, multiple alignments of antigens, classification of HPV types based on cancer risk, T cell epitope/HLA ligand visualization, T cell epitope/HLA ligand conservation analysis and sequence variability analysis, has been integrated within the HPVdb. Predicted Class I and Class II HLA binding peptides for 15 common HLA alleles are included in this database as putative targets. HPVdb is a knowledge-based system that integrates curated data and information with tailored analysis tools to facilitate data mining for HPV vaccinology and immunology. To our best knowledge, HPVdb is a unique data source providing a comprehensive list of HPV antigens and peptides. Database URL: http://cvc.dfci.harvard.edu/hpv/.

A controlled clinical trial to evaluate the effect of GanedenBC(30) on immunological markers.

PubMed

Kimmel, M; Keller, D; Farmer, S; Warrino, D E

2010-03-01

GanedenBC(30), a probiotic, has been shown to significantly increase T-cell production of TNF-alpha after ex vivo exposure to a strain of adenovirus (AdenoVI) or influenza A (H3N2 Texas strain [FluTex]). The current controlled study was designed to further evaluate the effect of GanedenBC(30) on immunological marker levels following viral exposure. Ten healthy subjects' baseline immunological marker levels were analyzed. Subjects consumed 1 capsule/day of GanedenBC(30) for 28 days and returned for post-treatment immunological marker evaluation. Subjects' baseline measurements served as their own control. All subjects completed the study with no adverse events; however, one subject was excluded from the final analysis based on a reasonable consideration as an outlier. CD3+CD69+ cells, IL-6, IL-8, interferon-gamma (IFN-gamma) and TNF-alpha levels were increased after exposure to AdenoVI and FluTex. IL-1beta levels also increased after exposure to AdenoVI but were decreased after ex vivo exposure to FluTex. CD3+CD69+ cells increased significantly (P = 0.023) after exposure to both viral strains. Differences in IL-8 levels after FluTex exposure achieved statistical significance (P = 0.039) as did IFN-gamma levels after AdenoVI exposure (P = 0.039). A regimen of one capsule per day containing 500 million CFU of GanedenBC30 may be a safe and effective option for enhancing the immunological response to common viral respiratory tract infections. 2010 Prous Science, S.A.U. or its licensors. All rights reserved.

The top ten clues to understand the origin of chronic lymphocytic leukemia (CLL).

PubMed

García-Muñoz, Ricardo; Feliu, Jesús; Llorente, Luis

2015-01-01

The fundamental task of the immune system is to protect the individual from infectious organisms without serious injury to self. The essence of acquired immunity is molecular self/non self discrimination. Chronic lymphocytic leukemia is characterized by a global failure of immune system that begins with the failure of immunological tolerance mechanisms (autoimmunity) and finish with the incapacity to response to non-self antigens (immunodeficiency). Immunological tolerance mechanisms are involved in chronic lymphocytic leukemia (CLL) development. During B cell development some self-reactive B cells acquire a special BCR that recognize their own BCR. This self-autoantibody-self BCR interaction promotes survival, differentiation and proliferation of self-reactive B cells. Continuous self-autoantibody-self BCR interaction cross-linking induces an increased rate of surface BCR elimination, CD5+ expression, receptor editing and anergy. Unfortunately, some times this mechanisms increase genomic instability and promote additional genetic damage that immortalize self-reactive B cells and convert them into CLL like clones with the capability of clonal evolution and transformed CLL B cells. This review summarizes the immunological effects of continuous self-autoantibody-self BCR interaction cross-linking in the surface of self-reactive B cells and their role in CLL development. Copyright © 2014 Elsevier Ltd. All rights reserved.

Regionally compartmentalized resident memory T cells mediate naturally acquired protection against pneumococcal pneumonia.

PubMed

Smith, N Ms; Wasserman, G A; Coleman, F T; Hilliard, K L; Yamamoto, K; Lipsitz, E; Malley, R; Dooms, H; Jones, M R; Quinton, L J; Mizgerd, J P

2018-01-01

As children age, they become less susceptible to the diverse microbes causing pneumonia. These microbes are pathobionts that infect the respiratory tract multiple times during childhood, generating immunological memory. To elucidate mechanisms of such naturally acquired immune protection against pneumonia, we modeled a relevant immunological history in mice by infecting their airways with mismatched serotypes of Streptococcus pneumoniae (pneumococcus). Previous pneumococcal infections provided protection against a heterotypic, highly virulent pneumococcus, as evidenced by reduced bacterial burdens and long-term sterilizing immunity. This protection was diminished by depletion of CD4 + cells prior to the final infection. The resolution of previous pneumococcal infections seeded the lungs with CD4 + resident memory T (T RM ) cells, which responded to heterotypic pneumococcus stimulation by producing multiple effector cytokines, particularly interleukin (IL)-17A. Following lobar pneumonias, IL-17-producing CD4 + T RM cells were confined to the previously infected lobe, rather than dispersed throughout the lower respiratory tract. Importantly, pneumonia protection also was confined to that immunologically experienced lobe. Thus regionally localized memory cells provide superior local tissue protection to that mediated by systemic or central memory immune defenses. We conclude that respiratory bacterial infections elicit CD4 + T RM cells that fill a local niche to optimize heterotypic protection of the affected tissue, preventing pneumonia.

The Human Leukocyte Antigen–presented Ligandome of B Lymphocytes*

PubMed Central

Hassan, Chopie; Kester, Michel G. D.; de Ru, Arnoud H.; Hombrink, Pleun; Drijfhout, Jan Wouter; Nijveen, Harm; Leunissen, Jack A. M.; Heemskerk, Mirjam H. M.; Falkenburg, J. H. Frederik; van Veelen, Peter A.

2013-01-01

Peptides presented by human leukocyte antigen (HLA) molecules on the cell surface play a crucial role in adaptive immunology, mediating the communication between T cells and antigen presenting cells. Knowledge of these peptides is of pivotal importance in fundamental studies of T cell action and in cellular immunotherapy and transplantation. In this paper we present the in-depth identification and relative quantification of 14,500 peptide ligands constituting the HLA ligandome of B cells. This large number of identified ligands provides general insight into the presented peptide repertoire and antigen presentation. Our uniquely large set of HLA ligands allowed us to characterize in detail the peptides constituting the ligandome in terms of relative abundance, peptide length distribution, physicochemical properties, binding affinity to the HLA molecule, and presence of post-translational modifications. The presented B-lymphocyte ligandome is shown to be a rich source of information by the presence of minor histocompatibility antigens, virus-derived epitopes, and post-translationally modified HLA ligands, and it can be a good starting point for solving a wealth of specific immunological questions. These HLA ligands can form the basis for reversed immunology approaches to identify T cell epitopes based not on in silico predictions but on the bona fide eluted HLA ligandome. PMID:23481700

Impact of sequencing depth and read length on single cell RNA sequencing data of T cells.

PubMed

Rizzetto, Simone; Eltahla, Auda A; Lin, Peijie; Bull, Rowena; Lloyd, Andrew R; Ho, Joshua W K; Venturi, Vanessa; Luciani, Fabio

2017-10-06

Single cell RNA sequencing (scRNA-seq) provides great potential in measuring the gene expression profiles of heterogeneous cell populations. In immunology, scRNA-seq allowed the characterisation of transcript sequence diversity of functionally relevant T cell subsets, and the identification of the full length T cell receptor (TCRαβ), which defines the specificity against cognate antigens. Several factors, e.g. RNA library capture, cell quality, and sequencing output affect the quality of scRNA-seq data. We studied the effects of read length and sequencing depth on the quality of gene expression profiles, cell type identification, and TCRαβ reconstruction, utilising 1,305 single cells from 8 publically available scRNA-seq datasets, and simulation-based analyses. Gene expression was characterised by an increased number of unique genes identified with short read lengths (<50 bp), but these featured higher technical variability compared to profiles from longer reads. Successful TCRαβ reconstruction was achieved for 6 datasets (81% - 100%) with at least 0.25 millions (PE) reads of length >50 bp, while it failed for datasets with <30 bp reads. Sufficient read length and sequencing depth can control technical noise to enable accurate identification of TCRαβ and gene expression profiles from scRNA-seq data of T cells.

Exploiting fluorescence for multiplex immunoassays on protein microarrays

NASA Astrophysics Data System (ADS)

Herbáth, Melinda; Papp, Krisztián; Balogh, Andrea; Matkó, János; Prechl, József

2014-09-01

Protein microarray technology is becoming the method of choice for identifying protein interaction partners, detecting specific proteins, carbohydrates and lipids, or for characterizing protein interactions and serum antibodies in a massively parallel manner. Availability of the well-established instrumentation of DNA arrays and development of new fluorescent detection instruments promoted the spread of this technique. Fluorescent detection has the advantage of high sensitivity, specificity, simplicity and wide dynamic range required by most measurements. Fluorescence through specifically designed probes and an increasing variety of detection modes offers an excellent tool for such microarray platforms. Measuring for example the level of antibodies, their isotypes and/or antigen specificity simultaneously can offer more complex and comprehensive information about the investigated biological phenomenon, especially if we take into consideration that hundreds of samples can be measured in a single assay. Not only body fluids, but also cell lysates, extracted cellular components, and intact living cells can be analyzed on protein arrays for monitoring functional responses to printed samples on the surface. As a rapidly evolving area, protein microarray technology offers a great bulk of information and new depth of knowledge. These are the features that endow protein arrays with wide applicability and robust sample analyzing capability. On the whole, protein arrays are emerging new tools not just in proteomics, but glycomics, lipidomics, and are also important for immunological research. In this review we attempt to summarize the technical aspects of planar fluorescent microarray technology along with the description of its main immunological applications.

Effects of dietary administration of stinging nettle (Urtica dioica) on the growth performance, biochemical, hematological and immunological parameters in juvenile and adult Victoria Labeo (Labeo victorianus) challenged with Aeromonas hydrophila.

PubMed

Ngugi, Charles C; Oyoo-Okoth, Elijah; Mugo-Bundi, James; Orina, Paul Sagwe; Chemoiwa, Emily Jepyegon; Aloo, Peninah A

2015-06-01

We investigated effects of dietary administration of stinging nettle (Urtica dioica) on growth performance, biochemical, hematological and immunological parameters in juvenile and adult Victoria Labeo (Labeo victorianus) against Aeromonas hydrophila. Fish were divided into 4 groups and fed for 4 and 16 weeks with 0%, 1%, 2% and 5% of U. dioica incorporated into the diet. Use of U. dioica in the diet resulted in improved biochemical, hematological and immunological parameters. Among the biochemical parameters; plasma cortisol, glucose, triglyceride and cholesterol decreased while total protein and albumin in fish increased with increasing dietary inclusion of U. dioica. Among the haematology parameters: red blood cell (RBC), white blood cell (WBC) counts, haematocrit (Htc), mean cell haemoglobin (MCH), mean cell haemoglobin concentration (MCHC) and netrophiles increased with increasing dietary inclusion levels of U. dioica, some depending on the fish age. Serum immunoglobulins, lysozyme activity and respiratory burst were the main immunological parameters in the adult and juvenile L. victorianus measured and they all increased with increasing herbal inclusion of U. dioica in the diet. Dietary incorporation of U. dioica at 5% showed significantly higher relative percentage survival (up to 95%) against A. hydrophila. The current results demonstrate that using U. dioica can stimulate fish immunity and make L. victorianus more resistant to bacterial infection (A. hydrophila). Copyright © 2015 Elsevier Ltd. All rights reserved.

Human-Induced Pluripotent Stem Cell Technology and Cardiomyocyte Generation: Progress and Clinical Applications.

PubMed

Di Baldassarre, Angela; Cimetta, Elisa; Bollini, Sveva; Gaggi, Giulia; Ghinassi, Barbara

2018-05-25

Human-induced pluripotent stem cells (hiPSCs) are reprogrammed cells that have hallmarks similar to embryonic stem cells including the capacity of self-renewal and differentiation into cardiac myocytes. The improvements in reprogramming and differentiating methods achieved in the past 10 years widened the use of hiPSCs, especially in cardiac research. hiPSC-derived cardiac myocytes (CMs) recapitulate phenotypic differences caused by genetic variations, making them attractive human disease models and useful tools for drug discovery and toxicology testing. In addition, hiPSCs can be used as sources of cells for cardiac regeneration in animal models. Here, we review the advances in the genetic and epigenetic control of cardiomyogenesis that underlies the significant improvement of the induced reprogramming of somatic cells to CMs; the methods used to improve scalability of throughput assays for functional screening and drug testing in vitro; the phenotypic characteristics of hiPSCs-derived CMs and their ability to rescue injured CMs through paracrine effects; we also cover the novel approaches in tissue engineering for hiPSC-derived cardiac tissue generation, and finally, their immunological features and the potential use in biomedical applications.

Gut microbial metabolites limit the frequency of autoimmune T cells and protect against type 1 diabetes.

PubMed

Mariño, Eliana; Richards, James L; McLeod, Keiran H; Stanley, Dragana; Yap, Yu Anne; Knight, Jacinta; McKenzie, Craig; Kranich, Jan; Oliveira, Ana Carolina; Rossello, Fernando J; Krishnamurthy, Balasubramanian; Nefzger, Christian M; Macia, Laurence; Thorburn, Alison; Baxter, Alan G; Morahan, Grant; Wong, Lee H; Polo, Jose M; Moore, Robert J; Lockett, Trevor J; Clarke, Julie M; Topping, David L; Harrison, Leonard C; Mackay, Charles R

2017-05-01

Gut dysbiosis might underlie the pathogenesis of type 1 diabetes. In mice of the non-obese diabetic (NOD) strain, we found that key features of disease correlated inversely with blood and fecal concentrations of the microbial metabolites acetate and butyrate. We therefore fed NOD mice specialized diets designed to release large amounts of acetate or butyrate after bacterial fermentation in the colon. Each diet provided a high degree of protection from diabetes, even when administered after breakdown of immunotolerance. Feeding mice a combined acetate- and butyrate-yielding diet provided complete protection, which suggested that acetate and butyrate might operate through distinct mechanisms. Acetate markedly decreased the frequency of autoreactive T cells in lymphoid tissues, through effects on B cells and their ability to expand populations of autoreactive T cells. A diet containing butyrate boosted the number and function of regulatory T cells, whereas acetate- and butyrate-yielding diets enhanced gut integrity and decreased serum concentration of diabetogenic cytokines such as IL-21. Medicinal foods or metabolites might represent an effective and natural approach for countering the numerous immunological defects that contribute to T cell-dependent autoimmune diseases.

EPIPOX: Immunoinformatic Characterization of the Shared T-Cell Epitome between Variola Virus and Related Pathogenic Orthopoxviruses.

PubMed

Molero-Abraham, Magdalena; Glutting, John-Paul; Flower, Darren R; Lafuente, Esther M; Reche, Pedro A

2015-01-01

Concerns that variola viruses might be used as bioweapons have renewed the interest in developing new and safer smallpox vaccines. Variola virus genomes are now widely available, allowing computational characterization of the entire T-cell epitome and the use of such information to develop safe and yet effective vaccines. To this end, we identified 124 proteins shared between various species of pathogenic orthopoxviruses including variola minor and major, monkeypox, cowpox, and vaccinia viruses, and we targeted them for T-cell epitope prediction. We recognized 8,106, and 8,483 unique class I and class II MHC-restricted T-cell epitopes that are shared by all mentioned orthopoxviruses. Subsequently, we developed an immunological resource, EPIPOX, upon the predicted T-cell epitome. EPIPOX is freely available online and it has been designed to facilitate reverse vaccinology. Thus, EPIPOX includes key epitope-focused protein annotations: time point expression, presence of leader and transmembrane signals, and known location on outer membrane structures of the infective viruses. These features can be used to select specific T-cell epitopes suitable for experimental validation restricted by single MHC alleles, as combinations thereof, or by MHC supertypes.

EPIPOX: Immunoinformatic Characterization of the Shared T-Cell Epitome between Variola Virus and Related Pathogenic Orthopoxviruses

PubMed Central

Molero-Abraham, Magdalena; Glutting, John-Paul; Flower, Darren R.; Lafuente, Esther M.; Reche, Pedro A.

2015-01-01

Concerns that variola viruses might be used as bioweapons have renewed the interest in developing new and safer smallpox vaccines. Variola virus genomes are now widely available, allowing computational characterization of the entire T-cell epitome and the use of such information to develop safe and yet effective vaccines. To this end, we identified 124 proteins shared between various species of pathogenic orthopoxviruses including variola minor and major, monkeypox, cowpox, and vaccinia viruses, and we targeted them for T-cell epitope prediction. We recognized 8,106, and 8,483 unique class I and class II MHC-restricted T-cell epitopes that are shared by all mentioned orthopoxviruses. Subsequently, we developed an immunological resource, EPIPOX, upon the predicted T-cell epitome. EPIPOX is freely available online and it has been designed to facilitate reverse vaccinology. Thus, EPIPOX includes key epitope-focused protein annotations: time point expression, presence of leader and transmembrane signals, and known location on outer membrane structures of the infective viruses. These features can be used to select specific T-cell epitopes suitable for experimental validation restricted by single MHC alleles, as combinations thereof, or by MHC supertypes. PMID:26605344

Hematology/immunology (M110 series). [human hemodynamic response to weightlessness simulation

NASA Technical Reports Server (NTRS)

1973-01-01

The hematology/immunology experiments in the Skylab mission study various aspects of the red blood cell, including its metabolism and life span, and blood volume changes under zero gravity conditions to determine the precise mechanism of the transient changes which have been seen on the relatively brief missions of the past.

Understanding immunology via engineering design: the role of mathematical prototyping.

PubMed

Klinke, David J; Wang, Qing

2012-01-01

A major challenge in immunology is how to translate data into knowledge given the inherent complexity and dynamics of human physiology. Both the physiology and engineering communities have rich histories in applying computational approaches to translate data obtained from complex systems into knowledge of system behavior. However, there are some differences in how disciplines approach problems. By referring to mathematical models as mathematical prototypes, we aim to highlight aspects related to the process (i.e., prototyping) rather than the product (i.e., the model). The objective of this paper is to review how two related engineering concepts, specifically prototyping and "fitness for use," can be applied to overcome the pressing challenge in translating data into improved knowledge of basic immunology that can be used to improve therapies for disease. These concepts are illustrated using two immunology-related examples. The prototypes presented focus on the beta cell mass at the onset of type 1 diabetes and the dynamics of dendritic cells in the lung. This paper is intended to illustrate some of the nuances associated with applying mathematical modeling to improve understanding of the dynamics of disease progression in humans.

The host immunological response to cancer therapy: An emerging concept in tumor biology.

PubMed

Voloshin, Tali; Voest, Emile E; Shaked, Yuval

2013-07-01

Almost any type of anti-cancer treatment including chemotherapy, radiation, surgery and targeted drugs can induce host molecular and cellular immunological effects which, in turn, can lead to tumor outgrowth and relapse despite an initial successful therapy outcome. Tumor relapse due to host immunological effects is attributed to angiogenesis, tumor cell dissemination from the primary tumors and seeding at metastatic sites. This short review will describe the types of host cells that participate in this process, the types of factors secreted from the host following therapy that can promote tumor re-growth, and the possible implications of this unique and yet only partially-known process. It is postulated that blocking these specific immunological effects in the reactive host in response to cancer therapy may aid in identifying new host-dependent targets for cancer, which in combination with conventional treatments can prolong therapy efficacy and extend survival. Additional studies investigating this specific research direction-both in preclinical models and in the clinical setting are essential in order to advance our understanding of how tumors relapse and evade therapy. Copyright © 2013 Elsevier Inc. All rights reserved.

Spectrum and immunophenotyping of 653 patients with B-cell chronic lymphoproliferative disorders in China: A single-centre analysis.

PubMed

Miao, Yi; Cao, Lei; Sun, Qian; Li, Xiao-Tong; Wang, Yan; Qiao, Chun; Wang, Li; Wang, Rong; Qiu, Hai-Rong; Xu, Wei; Li, Jian-Yong; Wu, Yu-Jie; Fan, Lei

2018-02-01

The incidence of B-cell chronic lymphoproliferative disorders (B-CLPDs) is significantly lower in China than that in western countries. There have been studies involving small cohorts with conflicting results regarding the spectrum of B-CLPDs in China, and the types and immunophenotyping of B-CLPDs in China remain largely unexplored. We conducted a retrospective analysis of 653 cases of B-CLPDs seen in our centre from 2011 to 2015. Four-colour flow cytometry was used to determine the expression of each immunological marker, and the diagnostic values of the immunological markers were also investigated. Chronic lymphocytic leukaemia (CLL) was the most common type of B-CLPD, which was consistent with that in west countries. However, the proportions of CLL (55.9%), follicular lymphoma (2.6%), and hairy cell leukaemia (0.2%) were lower, while the proportion of lymphoplasmacytic lymphoma/WaldenstrÖm macroglobulinaemia (5.4%) was higher in China, as compared with western countries. With respect to immunophenotypic characteristics, CD23 (31.7%) was more frequently expressed in mantle cell lymphoma (MCL) in our cohort than that in western countries. Immunophenotyping was useful in differentiating MCL from CLL or B-cell prolymphocytic leukaemia and lymphoplasmacytic lymphoma/WaldenstrÖm macroglobulinaemia from splenic marginal zone lymphoma. CD200 was of better diagnostic performance (accuracy: 94.6%) in differentiating CLL from MCL compared with CD23 (accuracy: 93.3%). Some cases of B-CPLDs, however, had no definite diagnoses, which were diagnosed as CD5 + B-CPLDs unclassified (7.7%) and CD5 - B-CPLDs unclassified (15.8%). This is the largest study that systematically explores the spectrum and immunophenotyping of B-CLPDs in Asia, confirming that spectrum of B-CLPDs in China was different from that in western countries. The immunophenotypic features of B-CLPDs were similar between China and western countries, although a few disparities exist. Cases with no definite diagnoses warrant further studies in the future. Copyright © 2017 John Wiley & Sons, Ltd.

Relationship Between Clinical and Immunological Features with Magnetic Resonance Imaging Abnormalities in Female Patients with Neuropsychiatric Systemic Lupus Erythematosus

PubMed Central

Wang, Hai-Peng; Wang, Cui-Yan; Pan, Zheng-Lun; Zhao, Jun-Yu; Zhao, Bin

2016-01-01

Background: Conventional magnetic resonance imaging (MRI) is the preferred neuroimaging method in the evaluation of neuropsychiatric systemic lupus erythematosus (NPSLE). The purpose of this study was to investigate the association between clinical and immunological features with MRI abnormalities in female patients with NPSLE, to screen for the value of conventional MRI in NPSLE. Methods: A total of 59 female NPSLE patients with conventional MRI examinations were enrolled in this retrospective study. All patients were classified into different groups according to MRI abnormalities. Both clinical and immunological features were compared between MRI abnormal and normal groups. One-way analysis of variance was used to compare the systemic lupus erythematosus disease activity index (SLEDAI) score for MRI abnormalities. Multivariate logistic regression analysis investigated the correlation between immunological features, neuropsychiatric manifestations, and MRI abnormalities. Results: Thirty-six NPSLE patients (61%) showed a variety of MRI abnormalities. There were statistically significant differences in SLEDAI scores (P < 0.001), incidence of neurologic disorders (P = 0.001), levels of 24-h proteinuria (P = 0.001) and immunoglobulin M (P = 0.004), and incidence of acute confusional state (P = 0.002), cerebrovascular disease (P = 0.004), and seizure disorder (P = 0.028) between MRI abnormal and normal groups. In the MRI abnormal group, SLEDAI scores for cerebral atrophy (CA), cortex involvement, and restricted diffusion (RD) were much higher than in the MRI normal group (P < 0.001, P = 0.002, P = 0.038, respectively). Statistically significant positive correlations between seizure disorder and cortex involvement (odds ratio [OR] = 14.90; 95% confidence interval [CI], 1.50–151.70; P = 0.023) and cerebrovascular disease and infratentorial involvement (OR = 10.00; 95% CI, 1.70–60.00; P = 0.012) were found. Conclusions: MRI abnormalities in NPSLE, especially CA, cortex involvement, and RD might be markers of high systemic lupus erythematosus activity. Some MRI abnormalities might correspond to neuropsychiatric manifestations and might be helpful in understanding the pathophysiology of NPSLE. PMID:26904988

Memory-like Responses of Natural Killer Cells

PubMed Central

Cooper, Megan A.; Yokoyama, Wayne M.

2010-01-01

Summary Natural killer (NK) cells are lymphocytes with the capacity to produce cytokines and kill target cells upon activation. NK cells have long been categorized as members of the innate immune system and as such have been thought to follow the ‘rules’ of innate immunity, including the principle that they have no immunologic memory, a property thought to be strictly limited to adaptive immunity. However, recent studies have suggested that NK cells have the capacity to alter their behavior based on prior activation. This property is analogous to adaptive immune memory; however, some NK cell memory-like functions are not strictly antigen-dependent and can be demonstrated following cytokine stimulation. Here we discuss the recent evidence that NK cells can exhibit properties of immunologic memory, focusing on the ability of cytokines to non-specifically induce memory-like NK cells with enhanced responses to restimulation. PMID:20536571

A Lower Baseline CD4/CD8 T-Cell Ratio Is Independently Associated with Immunodiscordant Response to Antiretroviral Therapy in HIV-Infected Subjects

PubMed Central

Rosado-Sánchez, I.; Herrero-Fernández, I.; Álvarez-Ríos, A. I.; Genebat, M.; Abad-Carrillo, M. A.; Ruiz-Mateos, E.; Pulido, F.; González-García, J.; Montero, M.; Bernal-Morell, E.; Vidal, F.; Leal, M.

2017-01-01

ABSTRACT We explored if baseline CD4/CD8 T-cell ratio is associated with immunodiscordant response to antiretroviral therapy in HIV-infected subjects. Comparing immunodiscordant and immunoconcordant subjects matched by pretreatment CD4 counts, we observed a lower pretreatment CD4/CD8 T-cell ratio in immunodiscordant subjects. Furthermore, pretreatment CD4/CD8 T-cell ratio, but not CD4 counts, correlated with the main immunological alterations observed in immunodiscordants, including increased regulatory T-cell (Treg) frequency and T-cell turnover-related markers. Then, in a larger cohort, only baseline CD4/CD8 T-cell ratio was independently associated with immunodiscordance, after adjusting by the viral CXCR4-tropic HIV variants. Our results suggest that the CD4/CD8 T-cell ratio could be an accurate biomarker of the subjacent immunological damage triggering immunodiscordance. PMID:28559274

Primary vs. Secondary Antibody Deficiency: Clinical Features and Infection Outcomes of Immunoglobulin Replacement

PubMed Central

Duraisingham, Sai S.; Buckland, Matthew; Dempster, John; Lorenzo, Lorena; Grigoriadou, Sofia; Longhurst, Hilary J.

2014-01-01

Secondary antibody deficiency can occur as a result of haematological malignancies or certain medications, but not much is known about the clinical and immunological features of this group of patients as a whole. Here we describe a cohort of 167 patients with primary or secondary antibody deficiencies on immunoglobulin (Ig)-replacement treatment. The demographics, causes of immunodeficiency, diagnostic delay, clinical and laboratory features, and infection frequency were analysed retrospectively. Chemotherapy for B cell lymphoma and the use of Rituximab, corticosteroids or immunosuppressive medications were the most common causes of secondary antibody deficiency in this cohort. There was no difference in diagnostic delay or bronchiectasis between primary and secondary antibody deficiency patients, and both groups experienced disorders associated with immune dysregulation. Secondary antibody deficiency patients had similar baseline levels of serum IgG, but higher IgM and IgA, and a higher frequency of switched memory B cells than primary antibody deficiency patients. Serious and non-serious infections before and after Ig-replacement were also compared in both groups. Although secondary antibody deficiency patients had more serious infections before initiation of Ig-replacement, treatment resulted in a significant reduction of serious and non-serious infections in both primary and secondary antibody deficiency patients. Patients with secondary antibody deficiency experience similar delays in diagnosis as primary antibody deficiency patients and can also benefit from immunoglobulin-replacement treatment. PMID:24971644

Hepatitis E and Pregnancy- Understanding the pathogenesis

PubMed Central

Navaneethan, Udayakumar; Mohajer, Mayar Al; Shata, Mohamed T

2008-01-01

Hepatitis E virus (HEV) is a single-stranded RNA virus that causes large-scale epidemics of acute viral hepatitis, particularly in developing countries. In men and non pregnant women, the disease is usually self-limited and has a case-fatality rate of less than <0.1%. However in pregnant women particularly from certain geographic areas in India, HEV infection is more severe, often leading to fulminant hepatic failure and death in a significant proportion of patients. In contrast, reports from Egypt, Europe and the USA have shown that the course and severity of viral hepatitis during pregnancy is not different from that in non-pregnant women. The reasons for this geographical difference are not clear. The high mortality rate in pregnancy has been thought to be secondary to the associated hormonal (estrogen and progesterone) changes during pregnancy and consequent immunological changes. These immunological changes include down regulation of p65 component of NF κB with a predominant Th2 bias in the T-cell response along with host susceptibility factors, mediated by HLA expression. Thus far, researchers were unable to explain the high HEV morbidity in pregnancy, why it is different from other hepatitis viruses such as hepatitis A with similar epidemiological features, and the reason behind the difference in HEV morbidity in pregnant women in different geographical regions. The recent developments in understanding the immune response to HEV have encouraged us to review possible mechanisms for these differences. Further research in the immunology of HEV and pregnancy is required to conquer this disease in the near future. PMID:18662274

Interpreting T-Cell Cross-reactivity through Structure: Implications for TCR-Based Cancer Immunotherapy.

PubMed

Antunes, Dinler A; Rigo, Maurício M; Freitas, Martiela V; Mendes, Marcus F A; Sinigaglia, Marialva; Lizée, Gregory; Kavraki, Lydia E; Selin, Liisa K; Cornberg, Markus; Vieira, Gustavo F

2017-01-01

Immunotherapy has become one of the most promising avenues for cancer treatment, making use of the patient's own immune system to eliminate cancer cells. Clinical trials with T-cell-based immunotherapies have shown dramatic tumor regressions, being effective in multiple cancer types and for many different patients. Unfortunately, this progress was tempered by reports of serious (even fatal) side effects. Such therapies rely on the use of cytotoxic T-cell lymphocytes, an essential part of the adaptive immune system. Cytotoxic T-cells are regularly involved in surveillance and are capable of both eliminating diseased cells and generating protective immunological memory. The specificity of a given T-cell is determined through the structural interaction between the T-cell receptor (TCR) and a peptide-loaded major histocompatibility complex (MHC); i.e., an intracellular peptide-ligand displayed at the cell surface by an MHC molecule. However, a given TCR can recognize different peptide-MHC (pMHC) complexes, which can sometimes trigger an unwanted response that is referred to as T-cell cross-reactivity. This has become a major safety issue in TCR-based immunotherapies, following reports of melanoma-specific T-cells causing cytotoxic damage to healthy tissues (e.g., heart and nervous system). T-cell cross-reactivity has been extensively studied in the context of viral immunology and tissue transplantation. Growing evidence suggests that it is largely driven by structural similarities of seemingly unrelated pMHC complexes. Here, we review recent reports about the existence of pMHC "hot-spots" for cross-reactivity and propose the existence of a TCR interaction profile (i.e., a refinement of a more general TCR footprint in which some amino acid residues are more important than others in triggering T-cell cross-reactivity). We also make use of available structural data and pMHC models to interpret previously reported cross-reactivity patterns among virus-derived peptides. Our study provides further evidence that structural analyses of pMHC complexes can be used to assess the intrinsic likelihood of cross-reactivity among peptide-targets. Furthermore, we hypothesize that some apparent inconsistencies in reported cross-reactivities, such as a preferential directionality, might also be driven by particular structural features of the targeted pMHC complex. Finally, we explain why TCR-based immunotherapy provides a special context in which meaningful T-cell cross-reactivity predictions can be made.

Interpreting T-Cell Cross-reactivity through Structure: Implications for TCR-Based Cancer Immunotherapy

PubMed Central

Antunes, Dinler A.; Rigo, Maurício M.; Freitas, Martiela V.; Mendes, Marcus F. A.; Sinigaglia, Marialva; Lizée, Gregory; Kavraki, Lydia E.; Selin, Liisa K.; Cornberg, Markus; Vieira, Gustavo F.

2017-01-01

Immunotherapy has become one of the most promising avenues for cancer treatment, making use of the patient’s own immune system to eliminate cancer cells. Clinical trials with T-cell-based immunotherapies have shown dramatic tumor regressions, being effective in multiple cancer types and for many different patients. Unfortunately, this progress was tempered by reports of serious (even fatal) side effects. Such therapies rely on the use of cytotoxic T-cell lymphocytes, an essential part of the adaptive immune system. Cytotoxic T-cells are regularly involved in surveillance and are capable of both eliminating diseased cells and generating protective immunological memory. The specificity of a given T-cell is determined through the structural interaction between the T-cell receptor (TCR) and a peptide-loaded major histocompatibility complex (MHC); i.e., an intracellular peptide–ligand displayed at the cell surface by an MHC molecule. However, a given TCR can recognize different peptide–MHC (pMHC) complexes, which can sometimes trigger an unwanted response that is referred to as T-cell cross-reactivity. This has become a major safety issue in TCR-based immunotherapies, following reports of melanoma-specific T-cells causing cytotoxic damage to healthy tissues (e.g., heart and nervous system). T-cell cross-reactivity has been extensively studied in the context of viral immunology and tissue transplantation. Growing evidence suggests that it is largely driven by structural similarities of seemingly unrelated pMHC complexes. Here, we review recent reports about the existence of pMHC “hot-spots” for cross-reactivity and propose the existence of a TCR interaction profile (i.e., a refinement of a more general TCR footprint in which some amino acid residues are more important than others in triggering T-cell cross-reactivity). We also make use of available structural data and pMHC models to interpret previously reported cross-reactivity patterns among virus-derived peptides. Our study provides further evidence that structural analyses of pMHC complexes can be used to assess the intrinsic likelihood of cross-reactivity among peptide-targets. Furthermore, we hypothesize that some apparent inconsistencies in reported cross-reactivities, such as a preferential directionality, might also be driven by particular structural features of the targeted pMHC complex. Finally, we explain why TCR-based immunotherapy provides a special context in which meaningful T-cell cross-reactivity predictions can be made. PMID:29046675

Interleukin-6 and granulocyte-macrophage colony-stimulating factor in apical periodontitis: correlation with clinical and histologic findings of the involved teeth.

PubMed

Radics, T; Kiss, C; Tar, I; Márton, I J

2003-02-01

Apical periodontitis is characterized by the presence of immunocompetent cells producing a wide variety of inflammatory mediators. Releasing cytokines with long-range action, such as interleukin-6 (IL-6) and granulocyte-macrophage colony-stimulating factor (GM-CSF), apical periodontitis may induce changes in remote organs of the host. This study quantified the levels of IL-6 and GM-CSF in symptomatic and asymptomatic human periradicular lesions. Lesions were also characterized by size and histologic findings. Tissue samples were homogenized and supernatants were assayed using an enzyme-linked immunosorbent assay (ELISA). Correlations between cytokine levels and characteristic features (as single variables) of the lesions were analysed. There was a trend for higher levels of IL-6 and GM-CSF in symptomatic than in asymptomatic lesions, but the difference was not significant. Levels also tended to be higher in large than in small lesions, in polymorphonuclear (PMN) cell-rich than in PMN cell-poor samples, and in epithelialized than in non-epithelialized lesions. Significantly higher levels of IL-6 (778.1 +/- 220.5 pg/microg) and GM-CSF (363.3 +/- 98.4 pg/microg) were found in samples coincidentally possessing symptomatic and epithelialized features than in asymptomatic, small, PMN cell-poor, non-epithelialized lesions (IL-6: 45.2 +/- 13.1 pg/microg and GM-CSF: 135.1 +/- 26.4 pg/microg). These results suggest that symptomatic lesions containing epithelial cells represent an immunologically active stage of apical periodontitis, whereas asymptomatic, small, PMN cell-poor, non-epithelialized lesions represent healing apical lesions.

Advances in mechanisms of asthma, allergy, and immunology in 2011.

PubMed

Boyce, Joshua A; Bochner, Bruce; Finkelman, Fred D; Rothenberg, Marc E

2012-02-01

2011 was marked by rapid progress in the identification of basic mechanisms of allergic disease and the translation of these mechanisms into human cell systems. Studies published in the Journal of Allergy and Clinical Immunology this year provided new insights into the molecular determinants of allergenicity, as well as the environmental, cellular, and genetic factors involved in sensitization to allergens. Several articles focused on mechanisms of allergen immunotherapy and the development of novel strategies to achieve tolerance to allergens. Additional studies identified substantial contributions from T(H)17-type cells and cytokines to human disease pathogenesis. Finally, new therapeutic applications of anti-IgE were identified. The highlights of these studies and their potential clinical implications are summarized in this review. Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

[Metaphors of immunology: war and peace].

PubMed

Löwy, I

1996-01-01

Immunology has always relied on metaphorical language. In its early beginnings, it varied between bellicose images and images that stressed the interaction of immunity mechanisms with the organism's physiological functions overall. In the late nineteenth century, white blood globules were not only compared to 'border police' assigned to rebuffing intruders -- an army formed to combat the invaders -- but were also described as a physiological mechanism for eliminating aged, dead cells, at times exterminators of foreign bodies. Antibodies were described as very powerful, deadly weapons but also as an integral part of mechanisms that allowed cells to assimilate food. This duality of images holds true today. The article analyzes the emergence and development of these images, relating them to the redefinition of immunology as a science of the self and non-self and dissecting them in light of recent events, such as the Aids epidemic.

Renal and adrenal tumors: Pathology, radiology, ultrasonography, therapy, immunology

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lohr, E.; Leder, L.D.

1987-01-01

Aspects as diverse as radiology, pathology, urology, pediatrics and immunology have been brought together in one book. The most up-do-date methods of tumor diagnosis by CT, NMR, and ultrasound are covered, as are methods of catheter embolization and radiation techniques in case of primarily inoperable tumors. Contents: Pathology of Renal and Adrenal Neoplasms; Ultrasound Diagnosis of Renal and Pararenal Tumors; Computed-Body-Tomography of Renal Carcinoma and Perirenal Masses; Magnetic Resonance Imaging of Renal Mass Lesions; I-125 Embolotherapy of Renal Tumors; Adrenal Mass Lesions in Infants and Children; Computed Tomography of the Adrenal Glands; Scintigraphic Studies of Renal and Adrenal Function; Surgicalmore » Management of Renal Cell Carcinoma; Operative Therapy of Nephroblastoma; Nonoperative Treatment of Renal Cell Carcinoma; Prenatal Wilms' Tumor; Congenital Neuroblastoma; Nonsurgical Management of Wilms' Tumor; Immunologic Aspects of Malignant Renal Disease.« less

Molecular basis of Trypanosoma cruzi and Leishmania interaction with their host(s): exploitation of immune and defense mechanisms by the parasite leading to persistence and chronicity, features reminiscent of immune system evasion strategies in cancer diseases.

PubMed

Ouaissi, Ali; Ouaissi, Mehdi

2005-01-01

A number of features occurring during host-parasite interactions in Chagas disease caused by the protozoan parasite, Trypanosoma cruzi, and Leishmaniasis, caused by a group of kinetoplastid protozoan parasites are reminiscent of those observed in cancer diseases. In fact,although the cancer is not a single disease, and that T.cruzi and Leishmania are sophisticated eukaryotic parasites presenting a high level of genotypic variability the growth of the parasites in their host and that of cancer cells share at least one common feature, that is their mutual capacity for rapid cell division. Surprisingly, the parasitic diseases and cancers share some immune evasion strategies. Consideration of these immunological alterations must be added to the evaluation of the pathogenic processes. The molecular and functional characterization of virulence factors and the study of their effect on the arms of the immune system have greatly improved understanding of the regulation of immune effectors functions. The purpose of this review is to analyze some of the current data related to the regulatory components or processes originating from the parasite that control or interfere with host cell physiology. Attempts are also made to delineate some similarities between the immune evasion strategies that parasites and tumors employ. The elucidation of the mode of action of parasite virulence factors toward the host cell allow not only provide us with a more comprehensive view of the host-parasite relationships but may also represent a step forward in efforts aimed to identify new target molecules for therapeutic intervention.

Immunological features underlying viral hemorrhagic fevers.

PubMed

Messaoudi, Ilhem; Basler, Christopher F

2015-10-01

Several enveloped RNA viruses of the arenavirus, bunyavirus, filovirus and flavivirus families are associated with a syndrome known as viral hemorrhagic fever (VHF). VHF is characterized by fever, vascular leakage, coagulation defects and multi organ system failure. VHF is currently viewed as a disease precipitated by viral suppression of innate immunity, which promotes systemic virus replication and excessive proinflammatory cytokine responses that trigger the manifestations of severe disease. However, the mechanisms by which immune dysregulation contributes to disease remain poorly understood. Infection of nonhuman primates closely recapitulates human VHF, notably Ebola and yellow fever, thereby providing excellent models to better define the immunological basis for this syndrome. Here we review the current state of our knowledge and suggest future directions that will better define the immunological mechanisms underlying VHF. Copyright © 2015 Elsevier Ltd. All rights reserved.

Influence of space flight conditions on phenotypes and functionality of nephritic immune cells of fish (Xiphophorus helleri)

NASA Astrophysics Data System (ADS)

Piepenbreier, K.; Renn, J.; Fischer, R.; Goerlich, R.

Microgravity is considered to directly perturb a number of immunological and haematological parameters in mammalians, and therefore is of fundamental importance in space biology. The viviparous teleost Xiphophorus helleri (swordtail) was used as a "lower vertebrate model" in the shuttle missions STS-89 (Small Payload) and STS-90 (NEUROLAB). When developing a regenerative aquatic system (like the Closed Equilibrated Biological Aquatic System - C.E.B.A.S.) to produce food fish on long-term space missions, we have to make sure that microgravity and other space conditions do not endanger the animals' health. Immunological aspects are very important in this field. The major research targets were immunological research of accessory (monocytes) and immunoreactive cells (lymphocytes) of the kidney from X. helleri, which were exposed to microgravity in comparison to ground control animals. Cell cycle analysis of the main haematopoetic organ (kidney), cell behaviour, cell cytochemistry, phagocytic ability and in vitro stimulation of immunoreactive cells from kidney after return to earth were investigated. The results are also important for basic research in immunotoxicology and developmental biology. As there is an interrelation between immune cells and bone metabolism, the investigations are also interesting for space medicine. Acknowledgement: This work was supported by the German Aerospace Center (DLR) (50 WB 9412, 50 WB 9996) and the National Aeronautics and Space Administration (NASA 98HEDS-02-418)

Signet-ring cell lymphoma of T-cell origin. An immunocytochemical and ultrastructural study relating giant vacuole formation to cytoplasmic sequestration of surface membrane.

PubMed

Grogan, T M; Richter, L C; Payne, C M; Rangel, C S

1985-09-01

In contrast to previous accounts of signet-ring lymphoma as a B-cell neoplasm, we report a case of signet-ring, large-cell lymphoma of T-cell lineage. Immunologic and ultrastructural studies were performed on a subcutaneous mass noted initially, as well as on an enlarged lymph node that developed later, in a 69-year-old man. Immunologic assessment indicated strong expression of T-helper antigen (Leu 3a + b), universal T-antigens (Leu 1, 5), and Ia. There was an absence of T-suppressor/cytotoxic antigen (Leu 2a), universal T-antigens (Leu 4, 9), and immunoglobulin light and heavy chains. Collectively, these findings indicate a mature T-cell lymphoma of T-helper type in an activated (Ia+) state. In contrast to previous reports of T-cell and Ia occurring solely as surface antigens, we demonstrated pools of cytoplasmic Leu 1, 3, 5 and Ia that displaced the nucleus. The ultrastructure of the giant cytoplasmic vacuoles was identical to the microvesicle-containing vacuoles reported in signet-ring cell lymphomas of B-cell lineage. In our case of T-cell lineage, we found substantial evidence of endocytosis by the neoplastic cells and numerous giant multivesicular bodies. The pools of cytoplasmic T and Ia antigens may result from abnormal internalization of surface T-antigens or the sequestration of T-antigen-containing Golgi-derived vesicles. Our combined immunologic and ultrastructural findings suggest that aberrant membrane recycling may be the common denominator of signet-ring formation in both B- and T-cell signet-ring lymphomas.

[Development of an incubation system for an inverted microscopy for long-term observation of cell cultures using chamber slides].

PubMed

Feicht, W; Buchner, A; Riesenberg, R

2001-05-01

Trifunctional bispecific antibodies open up new immunological possibilities in tumour treatment. Prior to clinical application, comprehensive investigations using animal models and in vitro examinations need to be done. To investigate long-term interactions between various immunologically active blood cells and individual tumour cells in the presence of antibodies, we developed an incubation system for experimental cell cultures on an inverted microscope. The system consists of a perspex box with a central moisture chamber with integrated water reservoir, external air circulation heating, and a CO2 supply. The sterile cell cultures are located in the wells of a slide positioned within a depression in the water reservoir. The newly developed incubation system enables continuous observation over the long term of experiments under optimal cell cultures conditions in combination with modern video techniques.

Changes in immunological profile as a function of urbanization and lifestyle

PubMed Central

Mbow, Moustapha; de Jong, Sanne E; Meurs, Lynn; Mboup, Souleymane; Dieye, Tandakha Ndiaye; Polman, Katja; Yazdanbakhsh, Maria

2014-01-01

Differences in lifestyle and break with natural environment appear to be associated with changes in the immune system resulting in various adverse health effects. Although genetics can have a major impact on the immune system and disease susceptibility, the contribution of environmental factors is thought to be substantial. Here, we investigated the immunological profile of healthy volunteers living in a rural and an urban area of a developing African country (Senegal), and in a European country (the Netherlands). Using flow cytometry, we investigated T helper type 1 (Th1), Th2, Th17, Th22 and regulatory T cells, as well as CD4+ T-cell and B-cell activation markers, and subsets of memory T and B cells in the peripheral blood. Rural Senegalese had significantly higher frequencies of Th1, Th2 and Th22 cells, memory CD4+ T and B cells, as well as activated CD4+ T and B cells compared with urban Senegalese and urban Dutch people. Within the Senegalese population, rural paritcipants displayed significantly higher frequencies of Th2 and Th22 cells, as well as higher pro-inflammatory and T-cell activation and memory profiles compared with the urban population. The greater magnitude of immune activation and the enlarged memory pool, together with Th2 polarization, seen in rural participants from Africa, followed by urban Africans and Europeans suggest that environmental changes may define immunological footprints, which could have consequences for disease patterns in general and vaccine responses in particular. PMID:24924958

Tumor-infiltrating lymphocytes predict response to chemotherapy in patients with advance non-small cell lung cancer.

PubMed

Liu, Hui; Zhang, Tiantuo; Ye, Jin; Li, Hongtao; Huang, Jing; Li, Xiaodong; Wu, Benquan; Huang, Xubing; Hou, Jinghui

2012-10-01

Accumulating preclinical evidence suggests that anticancer immune responses contribute to the success of chemotherapy. The predictive significance of tumor-infiltrating lymphocytes (TILs) for response to neoadjuvant chemotherapy in non-small cell lung cancer (NSCLC) remains unknown. The aim of this study was to investigate the prognostic and predictive value of TIL subtypes in patients with advanced NSCLC treated with platinum-based chemotherapy. In total, 159 patients with stage III and IV NSCLC were retrospectively enrolled. The prevalence of CD3(+), CD4(+), CD8(+) and Foxp3(+) TILs was assessed by immunohistochemistry in tumor tissue obtained before chemotherapy. The density of TILs subgroups was treated as dichotomous variables using the median values as cutoff. Survival curves were estimated by the Kaplan-Meier method, and differences in overall survival between groups were determined using the Log-rank test. Prognostic effects of TIL subsets density were evaluated by Cox regression analysis. The presence of CD3(+), CD4(+), CD8(+), and FOXP3(+) TILs was not correlated with any clinicopathological features. Neither the prevalence of TILs nor combined analysis displayed obvious prognostic performances for overall survival in Cox regression model. Instead, higher FOXP3(+)/CD8(+) ratio in tumor sites was an independent factor for poor response to platinum-based chemotherapy in overall cohort. These findings suggest that immunological CD8(+) and FOXP3(+)Tregs cell infiltrate within tumor environment is predictive of response to platinum-based neoadjuvant chemotherapy in advanced NSCLC patients. The understanding of the clinical relevance of the microenvironmental immunological milieu might provide an important clue for the design of novel strategies in cancer immunotherapy.

Distinct Cytokine and Chemokine Profiles in Autism Spectrum Disorders

PubMed Central

Han, Yvonne M. Y.; Cheung, Winnie K. Y.; Wong, Chun Kwok; Sze, Sophia L.; Cheng, Timmy W. S.; Yeung, Michael K.; Chan, Agnes S.

2017-01-01

Previous studies have shown that immunological factors are involved in the pathogenesis of autism spectrum disorders (ASDs). However, this research has been conducted almost exclusively in Western contexts, and only a handful of studies on immune measures have been conducted in Asian populations, such as Chinese populations. The present study examined whether immunological abnormalities are associated with cognitive deficits and problem behaviors in Chinese children with ASD and whether these children show different immunological profiles. Thirteen typically developing (TD) children and 22 children with ASD, aged 6–17 years, participated voluntarily in the study. Executive functions and short-term memory were measured using neuropsychological tests, and behavioral measures were assessed using parent ratings. The children were also assessed on immunological measures, specifically, the levels of cytokines and chemokines in the blood serum. Children with ASD showed greater deficits in cognitive functions, as well as altered levels of immunological measures, including CCL2, CCL5, and CXCL9 levels, compared to TD children, and the cognitive functions and associated behavioral deficits of children with ASD were significantly associated with different immunological measures. The children were further sub-classified into ASD with only autistic features (ASD-only) or ASD comorbid with attention deficit hyperactivity disorder (ASD + ADHD). The comorbidity results showed that there were no differences between the two groups of ASD children in any of the cognitive or behavioral measures. However, the results pertaining to immunological measures showed that the children with ASD-only and ASD + ADHD exhibited distinct cytokine and chemokine profiles and that abnormal immunologic function was associated with cognitive functions and inattention/hyperactivity symptoms. These results support the notion that altered immune functions may play a role in the selective cognitive and behavioral symptoms of ASD. PMID:28167942

Prolymphocytic leukaemia: surface morphology in 21 cases as seen by scanning electron microscopy and comparison with B-type CLL and CLL in 'prolymphocytoid' transformation.

PubMed

Polliack, A; Leizerowitz, R; Berrebi, A; Gamliel, H; Galili, N; Gurfel, D; Catovsky, D

1984-08-01

The surface architecture of leukaemic cells obtained from 21 cases of proven prolymphocytic leukaemia (PLL) and eight cases of chronic lymphocytic leukaemia (CLL) with 'prolymphocytoid' transformation (PL-CLL) was compared with the cell surface morphology of leukaemic cells obtained from 46 cases of B-type CLL, using the scanning electron microscope (SEM). All cases were defined by cytochemistry, immunological markers and transmission electron microscopy prior to SEM examination. B-CLL cells showed the well-recognized spectrum of surface architecture described in earlier studies. The majority of cells had moderate numbers of short microvilli, although in a minority, cells with relatively smooth surfaces predominated. In seven of the eight cases of PL-CLL, cells were villous in nature and in this respect similar to CLL cells; however, more cells with dense microvilli were seen. The prolymphocytic cells were recognized by their larger size and in 18 of the 19 cases of B-derived PLL, villous cells predominated. Two cases of T-derived PLL showed variable cell surface morphology ranging from smooth to moderately villous. It appears that B-PLL cells are most frequently villous and display more surface microvilli than B-CLL cells. B-prolymphocytes display the surface features regarded as characteristic for neoplastic B-cells as seen in patients with B-type lymphoma and leukaemia.

A Journey with Elie Metchnikoff: From Innate Cell Mechanisms in Infectious Diseases to Quantum Biology

PubMed Central

Merien, Fabrice

2016-01-01

Many reviews of Elie Metchnikoff’s work have been published, all unanimously acknowledging the significant contributions of his cellular theory to the fields of immunology and infectious diseases. In 1883, he published a key paper describing phagocytic cells in frogs. His descriptions were not just about phagocytes involved in host defense, he also described how these specialized cells eliminated degenerating or dying cells of the host. This perspective focuses on key concepts developed by Metchnikoff by presenting relevant excerpts of his 1883 paper and matching these concepts with challenges of modern immunology. A new approach to macrophage polarization is included to introduce some creative thinking about the exciting emerging area of quantum biology. PMID:27379227

Imaging Vesicular Traffic at the Immune Synapse.

PubMed

Bouchet, Jérôme; Del Río-Iñiguez, Iratxe; Alcover, Andrés

2017-01-01

Immunological synapse formation is the result of a profound T cell polarization process that involves the coordinated action of the actin and microtubule cytoskeleton, as well as intracellular vesicle traffic. Endosomal vesicle traffic ensures the targeting of the T cell receptor (TCR) and various signaling molecules to the synapse, being necessary for the generation of signaling complexes downstream of the TCR. Here we describe the microscopy imaging methods that we currently use to unveil how TCR and signaling molecules are associated with endosomal compartments and deliver their cargo to the immunological synapse.

Acute Leukemia with a Translocation T(4;11)(q21;q23): a Distinct Clinicopathological Entity: Report of a Case with Cytogenetic Clonal Evolution and Review of 146 Cases of the Literature.

PubMed

Léglise, M C; Rivière, D; Brière, J

1990-01-01

We present a cytogenetic clonal evolution that correlates morphological and immunological shifts in a case of a patient with a t(4;11) (q21;q23) acute leukemia. We take this opportunity to review 146 cases reported so far, with special reference to morphology, immunophenotyping, cytogenetics, clinical characteristics and evolution. Particular features are underlined, and prognosis, leukemic stem cell origin, chromosomal breakpoints and genes involved are discussed. A relationship between this type of leukemia and exposure to carcinogens is suggested by a high rate of secondary leukemia in adults and a high frequency in newborns and infants.

Pediatric common variable immunodeficiency: immunologic and phenotypic associations with switched memory B cells.

PubMed

Yong, Pierre L; Orange, Jordan S; Sullivan, Kathleen E

2010-08-01

Recent studies suggest that patients with common variable immunodeficiency (CVID) and low numbers of switched memory B cells have lower IgG levels and higher rates of autoimmune disease, splenomegaly, and granulomatous disease; however, no prior literature has focused exclusively on pediatric cases. We examined the relationship between switched memory B cells and clinical and immunologic manifestations of CVID in a pediatric population. Forty-five patients were evaluated. Patients were categorized as Group I (<5 switched memory B cells/ml, n = 24) or Group II (> or =5 switched memory B cells/mL, n = 21). CD3(+) T-cell counts and CD19(+) B-cell levels were lower among Group I patients. Only those in Group I had meningitis, sepsis, bronchiectasis, granulomatous lung disease, autoimmune cytopenias, or hematologic malignancies. Segregation of pediatric patients into high risk (Group I) and average risk (Group II) may assist in targeting surveillance appropriately.

Functional and molecular alterations in T Cells induced by CCL5.

PubMed

Cridge, T J; Horowitz, K M; Marinucci, M N; Rose, K M; Wells, M; Werner, M T; Kurt, Robert A

2006-01-01

To delineate whether, and the extent to which, CCL5 could impact T cell function we examined cytokine production and proliferative ability following CCL5 treatment in vitro. We report a decreased ability of splenic T cells to produce IFN-? and TNF-a as well as proliferate in response to crosslinking with antibody to CD3 after 72, but not 24 hours of CCL5 exposure. To identify a mechanism by which CCL5 modulated T cell function, we examined T cell receptor translocation and lipid raft clustering. After exposure to CCL5, T cells were less efficient at translocating the TCR and clustering lipid rafts. Since TCR translocation and lipid raft clustering are required for creation of an immunological synapse, these data suggest that extended exposure to CCL5 may impact T cell effector function by modulating the ability to create a functional immunological synapse.

Endometrial Stromal Cells and Immune Cell Populations Within Lymph Nodes in a Nonhuman Primate Model of Endometriosis

PubMed Central

Fazleabas, A. T.; Braundmeier, A. G.; Markham, R.; Fraser, I. S.; Berbic, M.

2011-01-01

Mounting evidence suggests that immunological responses may be altered in endometriosis. The baboon (Papio anubis) is generally considered the best model of endometriosis pathogenesis. The objective of the current study was to investigate for the first time immunological changes within uterine and peritoneal draining lymph nodes in a nonhuman primate baboon model of endometriosis. Paraffin-embedded femoral lymph nodes were obtained from 22 normally cycling female baboons (induced endometriosis n = 11; control n = 11). Immunohistochemical staining was performed with antibodies for endometrial stromal cells, T cells, immature and mature dendritic cells, and B cells. Lymph nodes were evaluated using an automated cellular imaging system. Endometrial stromal cells were significantly increased in lymph nodes from animals with induced endometriosis, compared to control animals (P = .033). In animals with induced endometriosis, some lymph node immune cell populations including T cells, dendritic cells and B cells were increased, suggesting an efficient early response or peritoneal drainage. PMID:21617251

Revisiting the B-cell compartment in mouse and humans: more than one B-cell subset exists in the marginal zone and beyond.

PubMed

Garraud, Olivier; Borhis, Gwenoline; Badr, Gamal; Degrelle, Séverine; Pozzetto, Bruno; Cognasse, Fabrice; Richard, Yolande

2012-11-29

The immunological roles of B-cells are being revealed as increasingly complex by functions that are largely beyond their commitment to differentiate into plasma cells and produce antibodies, the key molecular protagonists of innate immunity, and also by their compartmentalisation, a more recently acknowledged property of this immune cell category. For decades, B-cells have been recognised by their expression of an immunoglobulin that serves the function of an antigen receptor, which mediates intracellular signalling assisted by companion molecules. As such, B-cells were considered simple in their functioning compared to the other major type of immune cell, the T-lymphocytes, which comprise conventional T-lymphocyte subsets with seminal roles in homeostasis and pathology, and non-conventional T-lymphocyte subsets for which increasing knowledge is accumulating. Since the discovery that the B-cell family included two distinct categories - the non-conventional, or extrafollicular, B1 cells, that have mainly been characterised in the mouse; and the conventional, or lymph node type, B2 cells - plus the detailed description of the main B-cell regulator, FcγRIIb, and the function of CD40(+) antigen presenting cells as committed/memory B-cells, progress in B-cell physiology has been slower than in other areas of immunology. Cellular and molecular tools have enabled the revival of innate immunity by allowing almost all aspects of cellular immunology to be re-visited. As such, B-cells were found to express "Pathogen Recognition Receptors" such as TLRs, and use them in concert with B-cell signalling during innate and adaptive immunity. An era of B-cell phenotypic and functional analysis thus began that encompassed the study of B-cell microanatomy principally in the lymph nodes, spleen and mucosae. The novel discovery of the differential localisation of B-cells with distinct phenotypes and functions revealed the compartmentalisation of B-cells. This review thus aims to describe novel findings regarding the B-cell compartments found in the mouse as a model organism, and in human physiology and pathology. It must be emphasised that some differences are noticeable between the mouse and human systems, thus increasing the complexity of B-cell compartmentalisation. Special attention will be given to the (lymph node and spleen) marginal zones, which represent major crossroads for B-cell types and functions and a challenge for understanding better the role of B-cell specificities in innate and adaptive immunology.

A RICKETTSIAL INFECTION IN CANADIAN VOLES

PubMed Central

Baker, James A.

1946-01-01

From apparently normal voles captured on Grosse Isle, Province of Quebec, Canada, an infective agent has been grown in embryonated eggs, and by inoculation an inapparent infection was established in voles, mice, guinea pigs, hamsters, and rats. No growth of the agent was obtained in the absence of living cells, and the manner of its development in the yolk sac of embryonated eggs, as well as morphological, epidemiological, and pathogenic features, indicates a rickettsial nature. The inability to transmit infection by either cage or intrauterine contact points to a vector, and mites are shown to have a probable part in the epidemiology. Mice infected with the vole agent resist lethal doses of the Karp strain of scrub typhus, and certain epidemiological, morphological, and immunological features support the relationship indicated by the mouse tests. It is therefore concluded that voles on this island have an inapparent infection due to a rickettsia that may be related to the rickettsia of scrub typhus. PMID:19871552

Characterisation of a C1qtnf5 Ser163Arg Knock-In Mouse Model of Late-Onset Retinal Macular Degeneration

PubMed Central

Shu, Xinhua; Luhmann, Ulrich F. O.; Aleman, Tomas S.; Barker, Susan E.; Lennon, Alan; Tulloch, Brian; Chen, Mei; Xu, Heping; Jacobson, Samuel G.; Ali, Robin; Wright, Alan F.

2011-01-01

A single founder mutation resulting in a Ser163Arg substitution in the C1QTNF5 gene product causes autosomal dominant late-onset retinal macular degeneration (L-ORMD) in humans, which has clinical and pathological features resembling age-related macular degeneration. We generated and characterised a mouse “knock-in” model carrying the Ser163Arg mutation in the orthologous murine C1qtnf5 gene by site-directed mutagenesis and homologous recombination into mouse embryonic stem cells. Biochemical, immunological, electron microscopic, fundus autofluorescence, electroretinography and laser photocoagulation analyses were used to characterise the mouse model. Heterozygous and homozygous knock-in mice showed no significant abnormality in any of the above measures at time points up to 2 years. This result contrasts with another C1qtnf5 Ser163Arg knock-in mouse which showed most of the features of L-ORMD but differed in genetic background and targeting construct. PMID:22110650

Immunology and immunity against infection: General rules

NASA Astrophysics Data System (ADS)

Zinkernagel, Rolf M.

2005-12-01

Simplified and generalizable rules of immune responses against infections or vaccines have been summarized into 20 statements previously (Scand. J. Immunol. 60 (2004) 9-13) and are restated in a slightly different form here. The key terms of immunology (e.g. specificity, tolerance and memory) are explained in terms of their co-evolutionary importance in the equilibrium between infectious agents and diseases with higher vertebrate hosts. Specificity is best defined by protective antibodies or protective activated T cells; e.g. serotype specific neutralizing antibodies against polio viruses represent the discriminatory power of an immune response very well indeed. Tolerance is reviewed in terms of reactivity rather than self-nonself discrimination. Immune respones are deleted against antigens expressed at sufficient levels within the lymphoheamopoetic system, but may well exist at both, the T and the B cell level against antigens strictly outside of secondary lymphatic organs. In this respect the immune system behaves identically against virus infections and against self antigens. Persistent virus infections delete responsive T cells, once eliminated immune T cell responses wane, if a virus keeps outside of secondary lymphatic tissues no immune response is induced. Immunological memory is usually defined as earlier and greater responses but this does not correlate with protective immunity stringently. It is summarized here that pre-existing titers of protective neutralizing antibodies or pre-existence of activated T cells are the correlates of protection acute cytopathic lethal infections and toxins or against intracellular parasites. It is concluded that many discrepancies and uncertainties in immunological research derive from model situations and experimental results that are correctly measured but cannot be related to co-evolutionary contexts, i.e. survival.

The host immunological response to cancer therapy: An emerging concept in tumor biology

DOE Office of Scientific and Technical Information (OSTI.GOV)

Voloshin, Tali; Voest, Emile E.; Shaked, Yuval, E-mail: yshaked@tx.technion.ac.il

Almost any type of anti-cancer treatment including chemotherapy, radiation, surgery and targeted drugs can induce host molecular and cellular immunological effects which, in turn, can lead to tumor outgrowth and relapse despite an initial successful therapy outcome. Tumor relapse due to host immunological effects is attributed to angiogenesis, tumor cell dissemination from the primary tumors and seeding at metastatic sites. This short review will describe the types of host cells that participate in this process, the types of factors secreted from the host following therapy that can promote tumor re-growth, and the possible implications of this unique and yet onlymore » partially-known process. It is postulated that blocking these specific immunological effects in the reactive host in response to cancer therapy may aid in identifying new host-dependent targets for cancer, which in combination with conventional treatments can prolong therapy efficacy and extend survival. Additional studies investigating this specific research direction—both in preclinical models and in the clinical setting are essential in order to advance our understanding of how tumors relapse and evade therapy. -- Highlights: • Cancer therapy induces host molecular and cellular pro-tumorigenic effects. • Host effects in response to therapy may promote tumor relapse and metastasis. • The reactive host consists of immunological mediators promoting tumor re-growth. • Blocking therapy-induced host mediators may improve outcome.« less

Lessons from reproductive immunology for other fields of immunology and clinical approaches.

PubMed

Markert, Udo R; Fitzgerald, Justine S; Seyfarth, Lydia; Heinzelmann, Joana; Varosi, Frauke; Voigt, Sandra; Schleussner, Ekkehard; Seewald, Hans-Joachim

2005-01-01

Reproduction is indispensable to evolution and, thus, life. Nonetheless, it overcomes common rules known to established life. Immunology of reproduction, and especially the tolerance of two genetically distinct organisms and their fruitful symbiosis, is one of the most imposing paradox of life. Mechanisms, which are physiologically used for induction of said tolerance, are frequently abused by pathogens or tumors intending to escape the host's immune response. Understanding the regulation of immune responses in pregnancy and the invasion of allogeneic fetus-derived trophoblast cells into the decidua may lead to new therapeutic concepts. In transplantation, knowledge concerning local physiological immunotolerance may be useful for the development of new therapies, which do not require a general immune suppression of the patient. In immunological disorders, such as autoimmune diseases or allergies, immune deviations occur which are either prevented during pregnancy or have parallels to pregnancy. Vice versa, lessons from other fields of immunology may also offer new notions for the comprehension of reproductive immunology and may lead to new therapies for the treatment of pregnancy-related problems.

Modulatory efficacy of green tea polyphenols on glycoconjugates and immunological markers in 4-Nitroquinoline 1-oxide-induced oral carcinogenesis-A therapeutic approach.

PubMed

Srinivasan, Periasamy; Sabitha, Kuruvimalai Ekambaram; Shyamaladevi, Chennam Srinivasulu

2006-08-25

Green tea polyphenols (GTP) has been used as a chemopreventive agent world wide against chemically induced cancer. The present study is aimed to understand the therapeutic action of GTP on glycoconjugates and immunological markers in 4-Nitroquinoline 1-oxide (4-NQO)-induced oral cancer over a period of 30 days at 200mg/kg, p.o., Oral cancer was induced by painting 4-NQO for 8 weeks followed by administration of GTP after 22 weeks, for 30 days. Glycoconjugates such as hexose, hexosamine, sialicacid, fucose and mucoprotein were analysed. Expression of glycoconjugates was examined through histology and SDS-PAGE. Immunological markers such as circulating immune complex and mast cell density were studied. Oral cancer-induced animals showed a significant increase in levels of glycoconjugates and its expression, similar to that observed for immunological markers. Treatment with GTP altered the expression of glycoconjugates as well as immunological markers. The results suggest that GTP modulates both the expression of glycoconjugates and immunological markers resulting in regression of oral cancer.

Immunological changes in human skeletal muscle and blood after eccentric exercise and multiple biopsies

PubMed Central

Malm, Christer; Nyberg, Pernilla; Engström, Marianne; Sjödin, Bertil; Lenkei, Rodica; Ekblom, Björn; Lundberg, Ingrid

2000-01-01

A role of the immune system in muscular adaptation to physical exercise has been suggested but data from controlled human studies are scarce. The present study investigated immunological events in human blood and skeletal muscle by immunohistochemistry and flow cytometry after eccentric cycling exercise and multiple biopsies. Immunohistochemical detection of neutrophil- (CD11b, CD15), macrophage- (CD163), satellite cell- (CD56) and IL-1β-specific antigens increased similarly in human skeletal muscle after eccentric cycling exercise together with multiple muscle biopsies, or multiple biopsies only. Changes in immunological variables in blood and muscle were related, and monocytes and natural killer (NK) cells appeared to have governing functions over immunological events in human skeletal muscle. Delayed onset muscle soreness, serum creatine kinase activity and C-reactive protein concentration were not related to leukocyte infiltration in human skeletal muscle. Eccentric cycling and/or muscle biopsies did not result in T cell infiltration in human skeletal muscle. Modes of stress other than eccentric cycling should therefore be evaluated as a myositis model in human. Based on results from the present study, and in the light of previously published data, it appears plausible that muscular adaptation to physical exercise occurs without preceding muscle inflammation. Nevertheless, leukocytes seem important for repair, regeneration and adaptation of human skeletal muscle. PMID:11080266

Age-Related Changes in Immunological Factors and Their Relevance in Allergic Disease Development During Childhood.

PubMed

Chang, Woo Sung; Kim, Eun Jin; Lim, Yeon Mi; Yoon, Dankyu; Son, Jo Young; Park, Jung Won; Hong, Soo Jong; Cho, Sang Heon; Lee, Joo Shil

2016-07-01

Allergic diseases are triggered by Th2-mediated immune reactions to allergens and orchestrated by various immunological factors, including immune cells and cytokines. Although many reports have suggested that childhood is the critical period in the onset of allergic diseases and aging leads to alter the susceptibility of an individual to allergic diseases, age-related changes in various immunological factors in healthy individuals as well as their difference between healthy and allergic children have not yet been established. We investigated the ratio of Th1/Th2 cells and the levels of 22 allergy-related cytokines across all age groups in individuals who were classified as clinically non-atopic and healthy. We also examined their differences between healthy and allergic children to evaluate immunological changes induced by the development of allergic diseases during childhood. The Th1/Th2 ratio rose gradually during the growth period including childhood, reaching peak values in the twenties-thirties age group. Th1/Th2 ratios were significantly lower in allergic children than in healthy controls, whereas 14 of 22 cytokines were significantly higher in allergic children than in healthy controls. On the other hand, there were no differences in Th1/Th2 ratios and cytokines between healthy and allergic adolescents. In this study, age-related changes in Th1/Th2 ratios were found in normal controls across all age groups, and decreases in Th1/Th2 ratio were observed with increasing of 14 cytokines in allergic children. The results of this study may be helpful as reference values for both monitoring immunological changes according to aging in healthy individuals and distinguishing between normal and allergic subjects in terms of immune cells and soluble factors.

Immunological and molecular epidemiological characteristics of acute and fulminant viral hepatitis A.

PubMed

Hussain, Zahid; Husain, Syed A; Almajhdi, Fahad N; Kar, Premashis

2011-05-23

Hepatitis A virus is an infection of liver; it is hyperendemic in vast areas of the world including India. In most cases it causes an acute self limited illness but rarely fulminant. There is growing concern about change in pattern from asymptomatic childhood infection to an increased incidence of symptomatic disease in the adult population. In-depth analysis of immunological, viral quantification and genotype of acute and fulminant hepatitis A virus. Serum samples obtained from 1009 cases of suspected acute viral hepatitis was employed for different biochemical and serological examination. RNA was extracted from blood serum, reverse transcribed into cDNA and amplified using nested PCR for viral quantification, sequencing and genotyping. Immunological cell count from freshly collected whole blood was carried out by fluorescence activated cell sorter. Fulminant hepatitis A was mostly detected with other hepatic viruses. CD8+ T cells count increases in fulminant hepatitis to a significantly high level (P = 0.005) compared to normal healthy control. The immunological helper/suppressor (CD4+/CD8+) ratio of fulminant hepatitis was significantly lower compared to acute cases. The serologically positive patients were confirmed by RT-PCR and total of 72 (69.2%) were quantified and sequenced. The average quantitative viral load of fulminant cases was significantly higher (P < 0.05). There was similar genotypic distribution in both acute and fulminant category, with predominance of genotype IIIA (70%) compared to IA (30%). Immunological factors in combination with viral load defines the severity of the fulminant hepatitis A. Phylogenetic analysis of acute and fulminant hepatitis A confirmed genotypes IIIA as predominant against IA with no preference of disease severity.

Immunological and molecular epidemiological characteristics of acute and fulminant viral hepatitis A

PubMed Central

2011-01-01

Background Hepatitis A virus is an infection of liver; it is hyperendemic in vast areas of the world including India. In most cases it causes an acute self limited illness but rarely fulminant. There is growing concern about change in pattern from asymptomatic childhood infection to an increased incidence of symptomatic disease in the adult population. Objective In-depth analysis of immunological, viral quantification and genotype of acute and fulminant hepatitis A virus. Methods Serum samples obtained from 1009 cases of suspected acute viral hepatitis was employed for different biochemical and serological examination. RNA was extracted from blood serum, reverse transcribed into cDNA and amplified using nested PCR for viral quantification, sequencing and genotyping. Immunological cell count from freshly collected whole blood was carried out by fluorescence activated cell sorter. Results Fulminant hepatitis A was mostly detected with other hepatic viruses. CD8+ T cells count increases in fulminant hepatitis to a significantly high level (P = 0.005) compared to normal healthy control. The immunological helper/suppressor (CD4+/CD8+) ratio of fulminant hepatitis was significantly lower compared to acute cases. The serologically positive patients were confirmed by RT-PCR and total of 72 (69.2%) were quantified and sequenced. The average quantitative viral load of fulminant cases was significantly higher (P < 0.05). There was similar genotypic distribution in both acute and fulminant category, with predominance of genotype IIIA (70%) compared to IA (30%). Conclusions Immunological factors in combination with viral load defines the severity of the fulminant hepatitis A. Phylogenetic analysis of acute and fulminant hepatitis A confirmed genotypes IIIA as predominant against IA with no preference of disease severity. PMID:21605420

Newtonian cell interactions shape natural killer cell education.

PubMed

Goodridge, Jodie P; Önfelt, Björn; Malmberg, Karl-Johan

2015-09-01

Newton's third law of motion states that for every action on a physical object there is an equal and opposite reaction. The dynamic change in functional potential of natural killer (NK) cells during education bears many features of such classical mechanics. Cumulative physical interactions between cells, under a constant influence of homeostatic drivers of differentiation, lead to a reactive spectrum that ultimately shapes the functionality of each NK cell. Inhibitory signaling from an array of self-specific receptors appear not only to suppress self-reactivity but also aid in the persistence of effector functions over time, thereby allowing the cell to gradually build up a functional potential. Conversely, the frequent non-cytolytic interactions between normal cells in the absence of such inhibitory signaling result in continuous stimulation of the cells and attenuation of effector function. Although an innate cell, the degree to which the fate of the NK cell is predetermined versus its ability to adapt to its own environment can be revealed through a Newtonian view of NK cell education, one which is both chronological and dynamic. As such, the development of NK cell functional diversity is the product of qualitatively different physical interactions with host cells, rather than simply the sum of their signals or an imprint based on intrinsically different transcriptional programs. © 2015 The Authors. Immunological Reviews Published by John Wiley & Sons Ltd.

Biomaterials innovation for next generation ex vivo immune tissue engineering.

PubMed

Singh, Ankur

2017-06-01

Primary and secondary lymphoid organs are tissues that facilitate differentiation of B and T cells, leading to the induction of adaptive immune responses. These organs are present in the body from birth and are also recognized as locations where self-reactive B and T cells can be eliminated during the natural selection process. Many insights into the mechanisms that control the process of immune cell development and maturation in response to infection come from the analysis of various gene-deficient mice that lack some or all hallmark features of lymphoid tissues. The complexity of such animal models limits our ability to modulate the parameters that control the process of immune cell development, differentiation, and immunomodulation. Engineering functional, living immune tissues using biomaterials can grant researchers the ability to reproduce immunological events with tunable parameters for more rapid development of immunotherapeutics, cell-based therapy, and enhancing our understanding of fundamental biology as well as improving efforts in regenerative medicine. Here the author provides his review and perspective on the bioengineering of primary and secondary lymphoid tissues, and biomaterials innovation needed for the construction of these immune organs in tissue culture plates and on-chip. Copyright © 2017 Elsevier Ltd. All rights reserved.

Induction of innate immunity in control of mucosal transmission of HIV.

PubMed

Wang, Yufei; Lehner, Thomas

2011-09-01

To present evidence of the role of innate mucosal immunity and to harness this arm of immunity in protection against HIV infection. Dendritic cells, monocytes, natural killer (NK) cells and γδ T cells are critical in innate immunity, which is mediated by Toll-like receptor (TLR) and recently identified stress pathways. Complement factors, cytokines and chemokines have diverse functions usually affecting HIV infection indirectly. A novel group of innate intracellular HIV restriction factors has been identified - APOBEC3G, TRIM5α and tetherin - all of which are upregulated by type I interferons and some by vaccination and TLR agonists. Whereas innate immunity conventionally lacks memory, recent evidence suggests that some of the cells and intracellular factors may express immunological memory-like features. Innate mucosal immunity may provide early effective control of HIV transmission and replication. Some vaccines can enhance innate immune factors, such as APOBEC3G and control HIV during the eclipse period, allowing full weight of neutralizing and/or cytotoxic T cells to develop and prevent mucosal HIV infection. The next generation of vaccines should be designed to target both innate and adaptive immune memory responses.

Mucosal-associated invariant T cells in autoimmunity, immune-mediated diseases and airways disease.

PubMed

Hinks, Timothy S C

2016-05-01

Mucosal-associated invariant T (MAIT) cells are a novel class of innate-like T cells, expressing a semi-invariant T-cell receptor (TCR) and able to recognize small molecules presented on the non-polymorphic MHC-related protein 1. Their intrinsic effector-memory phenotype, enabling secretion of pro-inflammatory cytokines, and their relative abundance in humans imply a significant potential to contribute to autoimmune processes. However, as MAIT cells were unknown until recently and specific immunological tools were unavailable, little is known of their roles in disease. Here I review observations from clinical studies and animal models of autoimmune and immune-mediated diseases including the roles of MAIT cells in systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease and airways diseases. MAIT cell deficiencies are frequently observed in peripheral blood, and at sites of disease such as the airways in asthma. However, MAIT cells have a specific sensitivity to suppression by therapeutic corticosteroids that may confound many of these observations, as may the tendency of the surface marker CD161 to activation-induced down-regulation. Nonetheless, the dependence on bacteria for the development of MAIT cells suggests a potentially important protective role linking the influences of early life microbial exposures and subsequent development of autoimmunity. Conversely, MAIT cells could contribute to chronic inflammation either through TCR-independent activation, or potentially by TCR recognition of as yet undiscovered ligands. Future research will be greatly facilitated by the immunological tools that are now available, including murine genetic models and human and murine specific tetramers. © 2016 The Authors. Immunology published by John Wiley & Sons Ltd.

PTSD is associated with an increase in aged T cell phenotypes in adults living in Detroit

PubMed Central

Aiello, Allison E.; Dowd, Jennifer B.; Jayabalasingham, Bamini; Feinstein, Lydia; Uddin, Monica; Simanek, Amanda M.; Cheng, Caroline K.; Galea, Sandro; Wildman, Derek E.; Koenen, Karestan; Pawelec, Graham

2016-01-01

Background Psychosocial stress is thought to play a key role in the acceleration of immunological aging. This study investigated the relationship between lifetime and past-year history of post-traumatic stress disorder (PTSD) and the distribution of T cell phenotypes thought to be characteristic of immunological aging. Methods Data were from 85 individuals who participated in the community-based Detroit Neighborhood Health Study. Immune markers assessed included the CD4:CD8 ratio, the ratio of late-differentiated effector (CCR7-CD45RA+CD27-CD28-) to naïve (CCR7+CD45RA+CD27+CD28+) T cells, the percentage of KLRG1-expressing cells, and the percentage of CD57-expressing cells. Results In models adjusted for age, gender, race/ethnicity, education, smoking status, and medication use, we found that past-year PTSD was associated with statistically significant differences in the CD8+ T cell population, including a higher ratio of late-differentiated effector to naïve T cells, a higher percentage of KLRG1+ cells, and a higher percentage of CD57+ cells. The percentage of CD57+ cells in the CD4 subset was also significantly higher and the CD4:CD8 ratio significantly lower among individuals who had experienced past-year PTSD. Lifetime PTSD was also associated with differences in several parameters of immune aging. Conclusions PTSD is associated with an aged immune phenotype and should be evaluated as a potential catalyzer of accelerated immunological aging in future studies. PMID:26894484

Cre-mediated cell ablation contests mast cell contribution in models of antibody- and T cell-mediated autoimmunity.

PubMed

Feyerabend, Thorsten B; Weiser, Anne; Tietz, Annette; Stassen, Michael; Harris, Nicola; Kopf, Manfred; Radermacher, Peter; Möller, Peter; Benoist, Christophe; Mathis, Diane; Fehling, Hans Jörg; Rodewald, Hans-Reimer

2011-11-23

Immunological functions of mast cells remain poorly understood. Studies in Kit mutant mice suggest key roles for mast cells in certain antibody- and T cell-mediated autoimmune diseases. However, Kit mutations affect multiple cell types of both immune and nonimmune origin. Here, we show that targeted insertion of Cre-recombinase into the mast cell carboxypeptidase A3 locus deleted mast cells in connective and mucosal tissues by a genotoxic Trp53-dependent mechanism. Cre-mediated mast cell eradication (Cre-Master) mice had, with the exception of a lack of mast cells and reduced basophils, a normal immune system. Cre-Master mice were refractory to IgE-mediated anaphylaxis, and this defect was rescued by mast cell reconstitution. This mast cell-deficient strain was fully susceptible to antibody-induced autoimmune arthritis and to experimental autoimmune encephalomyelitis. Differences comparing Kit mutant mast cell deficiency models to selectively mast cell-deficient mice call for a systematic re-evaluation of immunological functions of mast cells beyond allergy. Copyright © 2011 Elsevier Inc. All rights reserved.

[Immunopathology of ulcerative colitis and granulomatous colitis (author's transl)].

PubMed

Bläker, F

1975-08-01

There is no convincing evidence as yet for a key role of immunological processes in the pathogenesis of unspecific colitis. However clinical findings as well as immunological data do support the hypothesis that immune reactions are involved primarily or secondarily in the pathogenesis and the clinical course of ulcerative colitis and granulomatous colitis. In such patients a specific adaptation of humoral and cell-bound immune reactions against antigenic material from the colon and other tissues has been found in peripheral blood, lymphatic tissue and bowel wall. In this context it seems to be especially noteworthy, that lymphocytes taken from patients with colitis lead to disintegration of colon epithelial cells in vitro. This cytotoxic effect of the lymphocytes is lost after colectomy or remission of the disease. Ulcerative and granulomatous colitis do have many clinical and immunological peculiarities in common. This makes one think, that possibly the same noxious factors induce differential local reactions because of different hereditary disposition.

The comparative immunology of wild and laboratory mice, Mus musculus domesticus

PubMed Central

Abolins, Stephen; King, Elizabeth C.; Lazarou, Luke; Weldon, Laura; Hughes, Louise; Drescher, Paul; Raynes, John G.; Hafalla, Julius C. R.; Viney, Mark E.; Riley, Eleanor M.

2017-01-01

The laboratory mouse is the workhorse of immunology, used as a model of mammalian immune function, but how well immune responses of laboratory mice reflect those of free-living animals is unknown. Here we comprehensively characterize serological, cellular and functional immune parameters of wild mice and compare them with laboratory mice, finding that wild mouse cellular immune systems are, comparatively, in a highly activated (primed) state. Associations between immune parameters and infection suggest that high level pathogen exposure drives this activation. Moreover, wild mice have a population of highly activated myeloid cells not present in laboratory mice. By contrast, in vitro cytokine responses to pathogen-associated ligands are generally lower in cells from wild mice, probably reflecting the importance of maintaining immune homeostasis in the face of intense antigenic challenge in the wild. These data provide a comprehensive basis for validating (or not) laboratory mice as a useful and relevant immunological model system. PMID:28466840

Centrosome docking at the immunological synapse is controlled by Lck signaling

PubMed Central

Tsun, Andy; Qureshi, Ihjaaz; Stinchcombe, Jane C.; Jenkins, Misty R.; de la Roche, Maike; Kleczkowska, Joanna; Zamoyska, Rose

2011-01-01

Docking of the centrosome at the plasma membrane directs lytic granules to the immunological synapse. To identify signals controlling centrosome docking at the synapse, we have studied cytotoxic T lymphocytes (CTLs) in which expression of the T cell receptor–activated tyrosine kinase Lck is ablated. In the absence of Lck, the centrosome is able to translocate around the nucleus toward the immunological synapse but is unable to dock at the plasma membrane. Lytic granules fail to polarize and release their contents, and target cells are not killed. In CTLs deficient in both Lck and the related tyrosine kinase Fyn, centrosome translocation is impaired, and the centrosome remains on the distal side of the nucleus relative to the synapse. These results show that repositioning of the centrosome in CTLs involves at least two distinct steps, with Lck signaling required for the centrosome to dock at the plasma membrane. PMID:21339332

AllergoOncology: Opposite outcomes of immune tolerance in allergy and cancer.

PubMed

Jensen-Jarolim, E; Bax, H J; Bianchini, R; Crescioli, S; Daniels-Wells, T R; Dombrowicz, D; Fiebiger, E; Gould, H J; Irshad, S; Janda, J; Josephs, D H; Levi-Schaffer, F; O'Mahony, L; Pellizzari, G; Penichet, M L; Redegeld, F; Roth-Walter, F; Singer, J; Untersmayr, E; Vangelista, L; Karagiannis, S N

2018-02-01

While desired for the cure of allergy, regulatory immune cell subsets and nonclassical Th2-biased inflammatory mediators in the tumour microenvironment can contribute to immune suppression and escape of tumours from immunological detection and clearance. A key aim in the cancer field is therefore to design interventions that can break immunological tolerance and halt cancer progression, whereas on the contrary allergen immunotherapy exactly aims to induce tolerance. In this position paper, we review insights on immune tolerance derived from allergy and from cancer inflammation, focusing on what is known about the roles of key immune cells and mediators. We propose that research in the field of AllergoOncology that aims to delineate these immunological mechanisms with juxtaposed clinical consequences in allergy and cancer may point to novel avenues for therapeutic interventions that stand to benefit both disciplines. © 2017 The Authors. Allergy Published by John Wiley & Sons Ltd.

Impact of folate therapy on combined immunodeficiency secondary to hereditary folate malabsorption.

PubMed

Kishimoto, Kenji; Kobayashi, Ryoji; Sano, Hirozumi; Suzuki, Daisuke; Maruoka, Hayato; Yasuda, Kazue; Chida, Natsuko; Yamada, Masafumi; Kobayashi, Kunihiko

2014-07-01

Hereditary folate malabsorption (HFM) is a rare autosomal recessive disorder. Severe folate deficiency in HFM can result in immunodeficiency. We describe a female infant with HFM who acquired severe Pneumocystis pneumonia. The objective of the present study was to elucidate her immunological phenotype and to examine the time course of immune recovery following parenteral folate therapy. The patient demonstrated a combined immunodeficiency with an impaired T cell proliferation response, pan-hypogammaglobulinemia, and an imbalanced pro-inflammatory cytokine profile. She had normal white blood cell count, normal lymphocyte subsets, and normal complement levels. Two novel mutations were identified within the SLC46A1 gene to produce a compound heterozygote. We confirmed full recovery of her immunological and neurophysiological status with parenteral folate replacement. The time course of recovery of her immunological profile varied widely, however. HFM should be recognized as a unique form of immunodeficiency. Copyright © 2014 Elsevier Inc. All rights reserved.

Advances in clinical immunology in 2015.

PubMed

Chinen, Javier; Notarangelo, Luigi D; Shearer, William T

2016-12-01

Advances in clinical immunology in the past year included the report of practice parameters for the diagnosis and management of primary immunodeficiencies to guide the clinician in the approach to these relatively uncommon disorders. We have learned of new gene defects causing immunodeficiency and of new phenotypes expanding the spectrum of conditions caused by genetic mutations such as a specific regulator of telomere elongation (RTEL1) mutation causing isolated natural killer cell deficiency and mutations in ras-associated RAB (RAB27) resulting in immunodeficiency without albinism. Advances in diagnosis included the increasing use of whole-exome sequencing to identify gene defects and the measurement of serum free light chains to identify secondary hypogammaglobulinemias. For several primary immunodeficiencies, improved outcomes have been reported after definitive therapy with hematopoietic stem cell transplantation and gene therapy. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Immune activation by nucleic acids: A role in pregnancy complications.

PubMed

Konečná, B; Lauková, L; Vlková, B

2018-04-01

Cell-free self-DNA or RNA may induce an immune response by activating specific sensing receptors. During pregnancy, placental nucleic acids present in the maternal circulation further activate these receptors due to the presence of unmethylated CpG islands. A higher concentration of cell-free foetal DNA is associated with pregnancy complications and a higher risk for foetal rejection. Cell-free foetal DNA originates from placental trophoblasts. It appears in different forms: free, bound to histones in nucleosomes, in neutrophil extracellular traps (NETs) and in extracellular vesicles (EVs). In several pregnancy complications, cell-free foetal DNA triggers the production of proinflammatory cytokines, and this production results in a cellular and humoral immune response. This review discusses preeclampsia, systemic lupus erythematosus, foetal growth restriction, gestational diabetes, rheumatoid arthritis and obesity in pregnancy from an immunological point of view and closely examines the different pathways that result in maternal inflammation. Understanding the role of cell-free nucleic acids, as well as the biogenesis of NETs and EVs, will help us to specify their functions or targets, which seem to be important in pregnancy complications. It is still not clear whether higher concentrations of cell-free nucleic acids in the maternal circulation are the cause or consequence of various complications. Therefore, further clinical studies and, even more importantly, animal experiments that focus on the involved immunological pathways are needed. © 2018 The Foundation for the Scandinavian Journal of Immunology.

Lymphatic-targeted cationic liposomes: a robust vaccine adjuvant for promoting long-term immunological memory.

PubMed

Wang, Ce; Liu, Peng; Zhuang, Yan; Li, Ping; Jiang, Boling; Pan, Hong; Liu, Lanlan; Cai, Lintao; Ma, Yifan

2014-09-22

Although retaining antigens at the injection site (the so-called "depot effect") is an important strategy for vaccine development, increasing evidence showed that lymphatic-targeted vaccine delivery with liposomes could be a promising approach for improving vaccine efficacy. However, it remains unclear whether antigen depot or lymphatic targeting would benefit long-term immunological memory, a major determinant of vaccine efficacy. In the present study, OVA antigen was encapsulated with DOTAP cationic liposomes (LP) or DOTAP-PEG-mannose liposomes (LP-Man) to generate depot or lymphatic-targeted liposome vaccines, respectively. The result of in vivo imaging showed that LP mostly accumulated near the injection site, whereas LP-Man not only effectively accumulated in draining lymph nodes (LNs) and the spleen, but also enhanced the uptake by resident antigen-presenting cells. Although LP vaccines with depot effect induced anti-OVA IgG more potently than LP-Man vaccines did on day 40 after priming, they failed to mount an effective B-cell memory response upon OVA re-challenge after three months. In contrast, lymphatic-targeted LP-Man vaccines elicited sustained antibody production and robust recall responses three months after priming, suggesting lymphatic targeting rather than antigen depot promoted the establishment of long-term memory responses. The enhanced long-term immunological memory by LP-Man was attributed to vigorous germinal center responses as well as increased Tfh cells and central memory CD4(+) T cells in the secondary lymphoid organs. Hence, lymphatic-targeted vaccine delivery with LP-Man could be an effective strategy to promote long-lasting immunological memory. Copyright © 2014 Elsevier Ltd. All rights reserved.

CD8+ T Cells Provide an Immunologic Signature of Tuberculosis in Young Children

PubMed Central

Nyendak, Melissa; Kiguli, Sarah; Zalwango, Sarah; Mori, Tomi; Mayanja-Kizza, Harriet; Balyejusa, Stephen; Null, Megan; Baseke, Joy; Mulindwa, Deo; Byrd, Laura; Swarbrick, Gwendolyn; Scott, Christine; Johnson, Denise F.; Malone, LaShaunda; Mudido-Musoke, Philipa; Boom, W. Henry; Lewinsohn, David M.; Lewinsohn, Deborah A.

2012-01-01

Rationale: The immunologic events surrounding primary Mycobacterium tuberculosis infection and development of tuberculosis remain controversial. Young children who develop tuberculosis do so quickly after first exposure, thus permitting study of immune response to primary infection and disease. We hypothesized that M. tuberculosis–specific CD8+ T cells are generated in response to high bacillary loads occurring during tuberculosis. Objectives: To determine if M. tuberculosis–specific T cells are generated among healthy children exposed to M. tuberculosis and children with tuberculosis. Methods: Enzyme-linked immunosorbent spot assays were used to measure IFN-γ production in response to M. tuberculosis–specific proteins ESAT-6/CFP-10 by peripheral blood mononuclear cells and CD8+ T cells isolated from Ugandan children hospitalized with tuberculosis (n = 96) or healthy tuberculosis contacts (n = 62). Measurements and Main Results: The proportion of positive CD8+ T-cell assays and magnitude of CD8+ T-cell responses were significantly greater among young (<5 yr) tuberculosis cases compared with young contacts (P = 0.02, Fisher exact test, P = 0.01, Wilcoxon rank-sum, respectively). M. tuberculosis–specific T-cell responses measured in peripheral blood mononuclear cells were equivalent between groups. Conclusions: Among young children, M. tuberculosis–specific CD8+ T cells develop in response to high bacillary loads, as occurs during tuberculosis, and are unlikely to be found after M. tuberculosis exposure. T-cell responses measured in peripheral blood mononuclear cells are generated after M. tuberculosis exposure alone, and thus cannot distinguish exposure from disease. In young children, IFN-γ–producing M. tuberculosis–specific CD8+ T cells provide an immunologic signature of primary M. tuberculosis infection resulting in disease. PMID:22071329

[Inflammasome and its role in immunological and inflammatory response at early stage of burns].

PubMed

Zhang, Fang; Li, Jiahui; Xia, Zhaofan

2014-06-01

Inflammasomes are large multi-protein complexes that serve as a platform for caspase-1 activation, and this process induces subsequent maturation and secretion of the proinflammatory cytokines IL-1β and IL-18, as well as pyroptosis. As an important component of the innate immune system, early activation of inflammasomes in a variety of immune cell subsets can mediate inflammatory response and immunological conditions after burn injury. Here, we review the current knowledge of inflammasomes and its role in immunological and inflammatory response at the early stage of burn injury.

[Report on the 34th meeting of the German Clinical Immunology Workgroup, Frankfurt, 03.-04.11.2006].

PubMed

Aries, P M; Witte, T; Lamprecht, P

2007-02-01

The annual meeting of the Clinical Immunology Workgroup focused on autoimmune vasculitides. The role of innate immunity, T- and B-cells, and innovative therapies for autoimmune vasculitides was discussed. Further topics of the meeting were the role of endothelial microparticles, ghrelin and leptin, regulatory and effector-memory T-cells in ANCA-associated vasculitides, as well as the lethal midline granuloma, intracytoplasmic cytokine-profile in Behcet's disease, autoantibodies in rheumatoid arthritis, polyarteritis nodosa with cranial manifestation, ILT6 as genetic marker in multiple sclerosis and Sjögren's syndrome, alpha-fodrin autoantibodies in multiple sclerosis, interferon-g autoantibodies in a patient with atypical mycobacteriosis, and autoreactive T-cells in murine lupus.

Acetylcholine-producing NK cells attenuate CNS inflammation via modulation of infiltrating monocytes/macrophages.

PubMed

Jiang, Wei; Li, Daojing; Han, Ranran; Zhang, Chao; Jin, Wei-Na; Wood, Kristofer; Liu, Qiang; Shi, Fu-Dong; Hao, Junwei

2017-07-25

The nonneural cholinergic system of immune cells is pivotal for the maintenance of immunological homeostasis. Here we demonstrate the expression of choline acetyltransferase (ChAT) and cholinergic enzymes in murine natural killer (NK) cells. The capacity for acetylcholine synthesis by NK cells increased markedly under inflammatory conditions such as experimental autoimmune encephalomyelitis (EAE), in which ChAT expression escalated along with the maturation of NK cells. ChAT + and ChAT - NK cells displayed distinctive features in terms of cytotoxicity and chemokine/cytokine production. Transfer of ChAT + NK cells into the cerebral ventricles of CX3CR1 -/- mice reduced brain and spinal cord damage after EAE induction, and decreased the numbers of CNS-infiltrating CCR2 + Ly6C hi monocytes. ChAT + NK cells killed CCR2 + Ly6C hi monocytes directly via the disruption of tolerance and inhibited the production of proinflammatory cytokines. Interestingly, ChAT + NK cells and CCR2 + Ly6C hi monocytes formed immune synapses; moreover, the impact of ChAT + NK cells was mediated by α7-nicotinic acetylcholine receptors. Finally, the NK cell cholinergic system up-regulated in response to autoimmune activation in multiple sclerosis, perhaps reflecting the severity of disease. Therefore, this study extends our understanding of the nonneural cholinergic system and the protective immune effect of acetylcholine-producing NK cells in autoimmune diseases.

Immunopathologic features of allergic contact dermatitis in humans: participation of plasmacytoid dendritic cells in the pathogenesis of the disease?

PubMed

Bangert, Christine; Friedl, Josef; Stary, Georg; Stingl, Georg; Kopp, Tamara

2003-12-01

Contrary to our abundant knowledge about the sensitization phase of human contact hypersensitivity, little is known about the cell types orchestrating the effector phase. In order to address this issue, we phenotypically analyzed biopsies from 72 h epicutaneous patch test reactions (n=10) and normal human skin (n=5) for the presence of various leukocyte differentiation antigens. The inflammatory infiltrate was dominated by CD3+/CD4+ T cells with approximately 30% of the cells coexpressing CD25 and CTLA-4, a phenotype consistent with either activated effector or regulatory T cells. In our search for professional antigen-presenting cells, we were surprised to find not only sizeable numbers of CD1a+ dendritic cells and CD1c+ dendritic cells, but also of CD123+, CD45RA+, BDCA-2+, CLA+, and CD62L+ plasmacytoid dendritic cells. Although virtually absent in normal human skin, these cells were detectable already 6 h after hapten challenge and were often found in close proximity to CD56+ natural killer cells, indicative of a functional interaction between these cell types. The detailed knowledge of the cellular composition of the inflammatory infiltrate in allergic contact dermatitis and its kinetics should form the basis for the investigation of the immunologic and molecular events operative in the perpetuation and resolution of the eczematous response.

Biotechnological and biomedical applications of mesenchymal stem cells as a therapeutic system.

PubMed

Rahimzadeh, Amirbahman; Mirakabad, Fatemeh Sadat Tabatabaei; Movassaghpour, Aliakbar; Shamsasenjan, Karim; Kariminekoo, Saber; Talebi, Mehdi; Shekari, Abolfazl; Zeighamian, Vahideh; Ghalhar, Masoud Gandomkar; Akbarzadeh, Abolfazl

2016-01-01

Mesenchymal stem cells (MSCs) are non-hematopoietic, multipotent progenitor cells which reside in bone marrow (BM), support homing of hematopoietic stem cells (HSCs) and self-renewal in the BM. These cells have the potential to differentiate into tissues of mesenchymal origin, such as fibroblasts, adipocytes, cardiomyocytes, and stromal cells. MSCs can express surface molecules like CD13, CD29, CD44, CD73, CD90, CD166, CXCL12 and toll-like receptors (TLRs). Different factors, such as TGF-β, IL-10, IDO, PGE-2, sHLA-G5, HO, and Galectin-3, secreted by MSCs, induce interaction in cell to cell immunomodulatory effects on innate and adaptive cells of the immune system. Furthermore, these cells can stimulate and increase the TH2 and regulatory T-cells through inhibitory effects on the immune system. MSCs originate from the BM and other tissues including the brain, adipose tissue, peripheral blood, cornea, thymus, spleen, fallopian tube, placenta, Wharton's jelly and umbilical cord blood. Many studies have focused on two significant features of MSC therapy: (I) MSCs can modulate T-cell-mediated immunological responses, and (II) systemically administered MSCs home in to sites of ischemia or injury. In this review, we describe the known mechanisms of immunomodulation and homing of MSCs. As a result, this review emphasizes the functional role of MSCs in modulating immune responses, their capability in homing to injured tissue, and their clinical therapeutic potential.

Dendritic cells: key to fetal tolerance?

PubMed

Blois, Sandra M; Kammerer, Ulrike; Alba Soto, Catalina; Tometten, Mareike C; Shaikly, Valerie; Barrientos, Gabriela; Jurd, Richard; Rukavina, Daniel; Thomson, Angus W; Klapp, Burghard F; Fernández, Nelson; Arck, Petra C

2007-10-01

Pregnancy is a unique event in which a fetus, despite being genetically and immunologically different from the mother (a hemi-allograft), develops in the uterus. Successful pregnancy implies avoidance of rejection by the maternal immune system. Fetal and maternal immune cells come into direct contact at the decidua, which is a highly specialized mucous membrane that plays a key role in fetal tolerance. Uterine dendritic cells (DC) within the decidua have been implicated in pregnancy maintenance. DC serve as antigen-presenting cells with the unique ability to induce primary immune responses. Just as lymphocytes comprise different subsets, DC subsets have been identified that differentially control lymphocyte function. DC may also act to induce immunologic tolerance and regulation of T cell-mediated immunity. Current understanding of DC immunobiology within the context of mammalian fetal-maternal tolerance is reviewed and discussed herein.

T Cell Receptors and the Evolution of Recognition Mechanisms in Immunity.

ERIC Educational Resources Information Center

Inchley, C. J.

1986-01-01

Discusses recent advances in the study of mammalian immunology. Explains the roles of two families of lymphocytes, the B cells and T cells. Also examines evolutionary mechanisms related to the immune system. (ML)

Towards a global human embryonic stem cell bank.

PubMed

Lott, Jason P; Savulescu, Julian

2007-08-01

An increasingly unbridgeable gap exists between the supply and demand of transplantable organs. Human embryonic stem cell technology could solve the organ shortage problem by restoring diseased or damaged tissue across a range of common conditions. However, such technology faces several largely ignored immunological challenges in delivering cell lines to large populations. We address some of these challenges and argue in favor of encouraging contribution or intentional creation of embryos from which widely immunocompatible stem cell lines could be derived. Further, we argue that current immunological constraints in tissue transplantation demand the creation of a global stem cell bank, which may hold particular promise for minority populations and other sub-groups currently marginalized from organ procurement and allocation systems. Finally, we conclude by offering a number of practical and ethically oriented recommendations for constructing a human embryonic stem cell bank that we hope will help solve the ongoing organ shortage problem.

A T-Cell Receptor Breaks the Rules | Center for Cancer Research

Cancer.gov

Most mature T cells function immunologically when a T-cell receptor (TCR) located on the cell surface encounters and engages its ligand, a major histocompatability complex (MHC), which displays a specific part of a target protein called an antigen. This antigen-presenting complex is assembled from one of the dozen or so MHC molecules that every person inherits from their parents; and the antigen fragment, called a peptide epitope, is excised from one of thousands of possible proteins—originally part of an invading pathogen or a cancer cell—that T cells are capable of identifying and attacking. The framework of an MHC molecule holding a centrally displayed or “presented” peptide is what engages the TCR and triggers T-cell action. This role of MHC molecules presenting antigens to the TCR is a central tenet of immunology, with the fit between a TCR and the MHC framework actually “hardwired” into their three-dimensional structures.

21st Nantes Actualités Transplantation: "When Stem Cells Meet Immunology".

PubMed

Anegon, Ignacio; Nguyen, Tuan Huy

2017-01-01

"When Stem Cells Meet Immunology" has been the topic of the 21st annual "Nantes Actualités en Transplantation" meeting (June 9-10, 2016, Nantes, France). This meeting brought together pioneers and leading experts in the fields of stem cells, biomaterials and immunoregulation. Presentations covered multipotent (mesenchymal and hematopoietic) and pluripotent stem cells (embryonic and induced) for regenerative medicine of incurable diseases, immunotherapy and blood transfusions. An additional focus had been immune rejections and responses of allogeneic or autologous stem cells. Conversely, stem cells are also able to directly modulate the immune response through the production of immunoregulatory molecules. Moreover, stem cells may also provide an unlimited source of immune cells (DCs, NK cells, B cells, and T cells) that can operate as "super" immune cells, for example, through genetic engineering with chimeric antigen receptors.This meeting report puts presentations into an overall context highlighting new potential biomarkers for potency prediction of mesenchymal stem cell-derived and pluripotent stem cell-derived multicellular organoids. Finally, we propose future directions arising from the flourishing encounter of stem cell and immune biology.

Chimeric Antigen Receptor- and TCR-Modified T Cells Enter Main Street and Wall Street.

PubMed

Barrett, David M; Grupp, Stephan A; June, Carl H

2015-08-01

The field of adoptive cell transfer (ACT) is currently comprised of chimeric Ag receptor (CAR)- and TCR-engineered T cells and has emerged from principles of basic immunology to paradigm-shifting clinical immunotherapy. ACT of T cells engineered to express artificial receptors that target cells of choice is an exciting new approach for cancer, and it holds equal promise for chronic infection and autoimmunity. Using principles of synthetic biology, advances in immunology, and genetic engineering have made it possible to generate human T cells that display desired specificities and enhanced functionalities. Clinical trials in patients with advanced B cell leukemias and lymphomas treated with CD19-specific CAR T cells have induced durable remissions in adults and children. The prospects for the widespread availability of engineered T cells have changed dramatically given the recent entry of the pharmaceutical industry to this arena. In this overview, we discuss some of the challenges and opportunities that face the field of ACT. Copyright © 2015 by The American Association of Immunologists, Inc.

Detection of cell mediated immune response to avian influenza viruses

USDA-ARS?s Scientific Manuscript database

In birds, lymphomyeloid tissues develop from epithelial (Bursa of Fabricus or thymus) or mesenchymal tissue which are populated by heamatopoietic stem cells. These stem cells develop directly into immunologically competent B (bursa) and T (thymus) cells. Cell-mediated immunity (CMI) is a part of the...

Immunologic memory response induced by a meningococcal serogroup C conjugate vaccine using the P64k recombinant protein as carrier.

PubMed

Guirola, María; Urquiza, Dioslaida; Alvarez, Anabel; Cannan-Haden, Leonardo; Caballero, Evelin; Guillén, Gerardo

2006-03-01

In this study, we used an adoptive lymphocyte transfer experiment to evaluate the ability of the P64k recombinant protein to recruit T-helper activity and induce immunologic memory response to the polysaccharide moiety in a meningococcal serogroup C conjugate vaccine. Adoptive transfer of splenocytes from mice immunized with the glycoconjugate conferred antipolysaccharide immunologic memory to naive recipient mice. The observed anamnestic immune response was characterized by more rapid kinetics, isotype switching from IgM to IgG and higher antipolysaccharide antibody titers compared with those reached in groups transferred with splenocytes from plain polysaccharide or phosphate-immunized mice. The memory response generated was also long lasting. Sera from mice transferred with cells from conjugate-immunized mice were the only protective in the infant rat passive protection assay, and also showed higher bactericidal titers. We demonstrated that priming the mice immune system with the glycoconjugate using the P64k protein as carrier induced a memory response to the polysaccharide, promoting a switch of the T-cell-independent response to a T-cell dependent one.

Intranasal immunization with protective antigen of Bacillus anthracis induces a long-term immunological memory response.

PubMed

Woo, Sun-Je; Kang, Seok-Seong; Park, Sung-Moo; Yang, Jae Seung; Song, Man Ki; Yun, Cheol-Heui; Han, Seung Hyun

2015-10-01

Although intranasal vaccination has been shown to be effective for the protection against inhalational anthrax, establishment of long-term immunity has yet to be achieved. Here, we investigated whether intranasal immunization with recombinant protective antigen (rPA) of Bacillus anthracis induces immunological memory responses in the mucosal and systemic compartments. Intranasal immunization with rPA plus cholera toxin (CT) sustained PA-specific antibody responses for 6 months in lung, nasal washes, and vaginal washes as well as serum. A significant induction of PA-specific memory B cells was observed in spleen, cervical lymph nodes (CLNs) and lung after booster immunization. Furthermore, intranasal immunization with rPA plus CT remarkably generated effector memory CD4(+) T cells in the lung. PA-specific CD4(+) T cells preferentially increased the expression of Th1- and Th17-type cytokines in lung, but not in spleen or CLNs. Collectively, the intranasal immunization with rPA plus CT promoted immunologic memory responses in the mucosal and systemic compartments, providing long-term immunity. Copyright © 2015 Elsevier Ltd. All rights reserved.

Ezrin tunes T-cell activation by controlling Dlg1 and microtubule positioning at the immunological synapse

PubMed Central

Lasserre, Rémi; Charrin, Stéphanie; Cuche, Céline; Danckaert, Anne; Thoulouze, Maria-Isabel; de Chaumont, Fabrice; Duong, Tarn; Perrault, Nathalie; Varin-Blank, Nadine; Olivo-Marin, Jean-Christophe; Etienne-Manneville, Sandrine; Arpin, Monique; Di Bartolo, Vincenzo; Alcover, Andrés

2010-01-01

T-cell receptor (TCR) signalling is triggered and tuned at immunological synapses by the generation of signalling complexes that associate into dynamic microclusters. Microcluster movement is necessary to tune TCR signalling, but the molecular mechanism involved remains poorly known. We show here that the membrane-microfilament linker ezrin has an important function in microcluster dynamics and in TCR signalling through its ability to set the microtubule network organization at the immunological synapse. Importantly, ezrin and microtubules are important to down-regulate signalling events leading to Erk1/2 activation. In addition, ezrin is required for appropriate NF-AT activation through p38 MAP kinase. Our data strongly support the notion that ezrin regulates immune synapse architecture and T-cell activation through its interaction with the scaffold protein Dlg1. These results uncover a crucial function for ezrin, Dlg1 and microtubules in the organization of the immune synapse and TCR signal down-regulation. Moreover, they underscore the importance of ezrin and Dlg1 in the regulation of NF-AT activation through p38. PMID:20551903

Tumor-specific antigens and immunologic adjuvants in cancer immunotherapy.

PubMed

Seremet, Teofila; Brasseur, Francis; Coulie, Pierre G

2011-01-01

T cell-based cancer immunotherapy relies on advancements made over the last 20 years on the molecular mechanisms underlying the antigenicity of tumors. This review focuses on human tumor antigens recognized by T lymphocytes, particularly the reasons why some are tumor-specific but others are not, and on the immunologic adjuvants used in clinical trials on therapeutic vaccination with defined tumor antigens.

Therapeutic Role of Hematopoietic Stem Cells in Autism Spectrum Disorder-Related Inflammation

PubMed Central

Siniscalco, Dario; Bradstreet, James Jeffrey; Antonucci, Nicola

2013-01-01

Autism and autism spectrum disorders (ASDs) are heterogeneous, severe neuro-developmental disorders with core symptoms of dysfunctions in social interactions and communication skills, restricted interests, repetitive – stereotypic verbal and non-verbal behaviors. Biomolecular evidence points to complex gene-environmental interactions in ASDs. Several biochemical processes are associated with ASDs: oxidative stress (including endoplasmic reticulum stress), decreased methylation capacity, limited production of glutathione; mitochondrial dysfunction, intestinal dysbiosis, increased toxic metal burden, and various immune abnormalities. The known immunological disorders include: T-lymphocyte populations and function, gene expression changes in monocytes, several autoimmune-related findings, high levels of N-acetylgalactosaminidase (which precludes macrophage activation), and primary immune deficiencies. These immunological observations may result in minicolumn structural changes in the brain, as well as, abnormal immune mediation of synaptic functions. Equally, these immune dysregulations serve as the rationale for immune-directed interventions such as hematopoietic stem cells (HSCs), which are pivotal in controlling chronic inflammation and in the restoration of immunological balance. These properties make them intriguing potential agents for ASD treatments. This prospective review will focus on the current state-of-the-art knowledge and challenges intrinsic in the application of HSCs for ASD-related immunological disorders. PMID:23772227

Understanding Immunology via Engineering Design: The Role of Mathematical Prototyping

PubMed Central

Klinke, David J.; Wang, Qing

2012-01-01

A major challenge in immunology is how to translate data into knowledge given the inherent complexity and dynamics of human physiology. Both the physiology and engineering communities have rich histories in applying computational approaches to translate data obtained from complex systems into knowledge of system behavior. However, there are some differences in how disciplines approach problems. By referring to mathematical models as mathematical prototypes, we aim to highlight aspects related to the process (i.e., prototyping) rather than the product (i.e., the model). The objective of this paper is to review how two related engineering concepts, specifically prototyping and “fitness for use,” can be applied to overcome the pressing challenge in translating data into improved knowledge of basic immunology that can be used to improve therapies for disease. These concepts are illustrated using two immunology-related examples. The prototypes presented focus on the beta cell mass at the onset of type 1 diabetes and the dynamics of dendritic cells in the lung. This paper is intended to illustrate some of the nuances associated with applying mathematical modeling to improve understanding of the dynamics of disease progression in humans. PMID:22973412

From Immunologically Archaic to Neoteric Glycovaccines

PubMed Central

Cavallari, Marco; De Libero, Gennaro

2017-01-01

Polysaccharides (PS) are present in the outermost surface of bacteria and readily come in contact with immune cells. They interact with specific antibodies, which in turn confer protection from infections. Vaccines with PS from pneumococci, meningococci, Haemophilus influenzae type b, and Salmonella typhi may be protective, although with the important constraint of failing to generate permanent immunological memory. This limitation has in part been circumvented by conjugating glycovaccines to proteins that stimulate T helper cells and facilitate the establishment of immunological memory. Currently, protection evoked by conjugated PS vaccines lasts for a few years. The same approach failed with PS from staphylococci, Streptococcus agalactiae, and Klebsiella. All those germs cause severe infections in humans and often develop resistance to antibiotic therapy. Thereby, prevention is of increasing importance to better control outbreaks. As only 23 of more than 90 pneumococcal serotypes and 4 of 13 clinically relevant Neisseria meningitidis serogroups are covered by available vaccines there is still tremendous clinical need for PS vaccines. This review focuses on glycovaccines and the immunological mechanisms for their success or failure. We discuss recent advances that may facilitate generation of high affinity anti-PS antibodies and confer specific immunity and long-lasting protection. PMID:28134792

Immunological Assays as an Opportunity of Assessment of Health Risks of Airborne Particle Mixture Including Nanoparticles

NASA Astrophysics Data System (ADS)

Brzicová, Táňa; Lochman, Ivo; Danihelka, Pavel; Lochmanová, Alexandra; Lach, Karel; Mička, Vladimír

2013-04-01

The aim of this pilot study was to evaluate perspectives of the assessment of nonspecific biological effects of airborne particulate matter including nanoparticles using appropriate immunological assays. We have selected various in vitro immunological assays to establish an array allowing us to monitor activation of the cell-mediated and humoral response of both the innate and adaptive immunity. To assess comprehensive interactions and effects, the assays were performed in whole blood cultures from healthy volunteers and we used an original airborne particle mixture from high pollution period in Ostrava region representing areas with one of the most polluted air in Europe. Even if certain effects were observed, the results of the immunological assays did not prove significant effects of airborne particles on immune cells' functions of healthy persons. However, obtained data do not exclude health risks of long-term exposure to airborne particles, especially in case of individuals with genetic predisposition to certain diseases or already existing disease. This study emphasizes the in vitro assessment of complex effects of airborne particles in conditions similar to actual ones in an organism exposed to particle mixture present in the polluted air.

[Clinical and experimental study of treating aplastic anemia with fetal liver cell suspension and fetal liver cell-free suspension].

PubMed

Han, J R; Yuan, S W; Ren, Q F

1990-06-01

Fresh fetal liver obtained from 3- to 6-month fetus was prepared. Fetal liver cell suspension (FLC) or fetal liver cell-free suspension (FLCF) were then transfused into two groups of patient of aplastic anemia. 15 of 21 patients of aplastic anemia treated with FLC showed reconstitution of haemopoietic function or improvement of peripheral blood pictures, while 27 of 30 patients treated with FLCF showed reconstitution or improvement. It is verified that there is a stimulating factor for CFU-CM, BFU-E, and CFU-E and also a immunologic stimulant for improving the nonspecific immunologic function of the organism as shown by clinical analysis and experimental study. It is obvious that the therapeutic effect of FLCF is much better than that of the FLC.

Immunological unresponsiveness in mice. II. Cellular basis of immunological unresponsiveness induced in foetal and neonatal mice by transfer of human gamma-globulin by the maternal route.

PubMed Central

Shinka, S; Komatsu, T; Dohi, Y; Amano, T

1979-01-01

The cellular basis of the mechanism of immunological tolerance to human gamma-globulin (H gamma G) induced in foetal and neonatal mice by materno-foetal or materno-neonatal transfer after a single injection of tolerogen (deaggregated H gamma G) into the mothers was investigated using a cell transfer system and assays of passive haemagglutinating antibodies and plaque-forming cells to H gamma G. The results demonstrated that B cells are mainly involved in the tolerance induced on the fourteenth day of gestation, whereas inactivation of T cells may account for the tolerance induced on the eighteenth day of gestation and in the neonatal stage. Treatment of the mothers with tolerogen and then anti-H gamma G serum reduced the tolerance induced on the fourteenth day of gestation, but did not affect that induced on the eighteenth day of gestation and in the neonatal stage. Cell transfer experiments showed that B-cell tolerance induced on the fourteenth day of gestation was prevented by passive antibody, while T-cell tolerance induced on the eighteenth day of gestation and in the neonatal stage was not affected by passive antibody. Assay of the anti-DNP antibody response after immunization with DNP10-H gamma G showed that treatment of mice with the tolerogen on the eighteenth day of gestation, but not the fourteenth day of gestation, inactivated H gamma G-reactive helper cells. The significance of these results is discussed in relation to the results of the cell transfer experiments described as above. PMID:89080

Myocardial aging as a T-cell–mediated phenomenon

PubMed Central

Ramos, Gustavo Campos; van den Berg, Anne; Nunes-Silva, Vânia; Weirather, Johannes; Peters, Laura; Burkard, Matthias; Friedrich, Mike; Pinnecker, Jürgen; Abeßer, Marco; Heinze, Katrin G.; Schuh, Kai; Beyersdorf, Niklas; Kerkau, Thomas; Demengeot, Jocelyne; Frantz, Stefan; Hofmann, Ulrich

2017-01-01

In recent years, the myocardium has been rediscovered under the lenses of immunology, and lymphocytes have been implicated in the pathogenesis of cardiomyopathies with different etiologies. Aging is an important risk factor for heart diseases, and it also has impact on the immune system. Thus, we sought to determine whether immunological activity would influence myocardial structure and function in elderly mice. Morphological, functional, and molecular analyses revealed that the age-related myocardial impairment occurs in parallel with shifts in the composition of tissue-resident leukocytes and with an accumulation of activated CD4+ Foxp3− (forkhead box P3) IFN-γ+ T cells in the heart-draining lymph nodes. A comprehensive characterization of different aged immune-deficient mouse strains revealed that T cells significantly contribute to age-related myocardial inflammation and functional decline. Upon adoptive cell transfer, the T cells isolated from the mediastinal lymph node (med-LN) of aged animals exhibited increased cardiotropism, compared with cells purified from young donors or from other irrelevant sites. Nevertheless, these cells caused rather mild effects on cardiac functionality, indicating that myocardial aging might stem from a combination of intrinsic and extrinsic (immunological) factors. Taken together, the data herein presented indicate that heart-directed immune responses may spontaneously arise in the elderly, even in the absence of a clear tissue damage or concomitant infection. These observations might shed new light on the emerging role of T cells in myocardial diseases, which primarily affect the elderly population. PMID:28255084

Depletion of autoreactive immunologic memory followed by autologous hematopoietic stem cell transplantation in patients with refractory SLE induces long-term remission through de novo generation of a juvenile and tolerant immune system.

PubMed

Alexander, Tobias; Thiel, Andreas; Rosen, Oliver; Massenkeil, Gero; Sattler, Arne; Kohler, Siegfried; Mei, Henrik; Radtke, Hartmut; Gromnica-Ihle, Erika; Burmester, Gerd-Rüdiger; Arnold, Renate; Radbruch, Andreas; Hiepe, Falk

2009-01-01

Clinical trials have indicated that immunoablation followed by autologous hematopoietic stem cell transplantation (ASCT) has the potential to induce clinical remission in patients with refractory systemic lupus erythematosus (SLE), but the mechanisms have remained unclear. We now report the results of a single-center prospective study of long-term immune reconstitution after ASCT in 7 patients with SLE. The clinical remissions observed in these patients are accompanied by the depletion of autoreactive immunologic memory, reflected by the disappearance of pathogenic anti-double-stranded DNA (dsDNA) antibodies and protective antibodies in serum and a fundamental resetting of the adaptive immune system. The latter comprises recurrence of CD31(+)CD45RA(+)CD4(+) T cells (recent thymic emigrants) with a doubling in absolute numbers compared with age-matched healthy controls at the 3-year follow-up (P = .016), the regeneration of thymic-derived FoxP3(+) regulatory T cells, and normalization of peripheral T-cell receptor (TCR) repertoire usage. Likewise, responders exhibited normalization of the previously disturbed B-cell homeostasis with numeric recovery of the naive B-cell compartment within 1 year after ASCT. These data are the first to demonstrate that both depletion of the autoreactive immunologic memory and a profound resetting of the adaptive immune system are required to reestablish self-tolerance in SLE.

Cell Therapy for Prophylactic Tolerance in Immunoglobulin E-mediated Allergy.

PubMed

Baranyi, Ulrike; Farkas, Andreas M; Hock, Karin; Mahr, Benedikt; Linhart, Birgit; Gattringer, Martina; Focke-Tejkl, Margit; Petersen, Arnd; Wrba, Fritz; Rülicke, Thomas; Valenta, Rudolf; Wekerle, Thomas

2016-05-01

Therapeutic strategies for the prophylaxis of IgE-mediated allergy remain an unmet medical need. Cell therapy is an emerging approach with high potential for preventing and treating immunological diseases. We aimed to develop a cell-based therapy inducing permanent allergen-specific immunological tolerance for preventing IgE-mediated allergy. Wild-type mice were treated with allergen-expressing bone marrow cells under a short course of tolerogenic immunosuppression (mTOR inhibition and costimulation blockade). Bone marrow was retrieved from a novel transgenic mouse ubiquitously expressing the major grass pollen allergen Phl p 5 as a membrane-anchored protein (BALB/c-Tg[Phlp5-GFP], here mPhl p 5). After transplantation recipients were IgE-sensitized at multiple time points with Phl p 5 and control allergen. Mice treated with mPhl p 5 bone marrow did not develop Phl p 5-specific IgE (or other isotypes) despite repeated administration of the allergen, while mounting and maintaining a strong humoral response towards the control allergen. Notably, Phl p 5-specific T cell responses and allergic airway inflammation were also completely prevented. Interestingly allergen-specific B cell tolerance was maintained independent of Treg functions indicating deletional tolerance as underlying mechanism. This proof-of-concept study demonstrates that allergen-specific immunological tolerance preventing occurrence of allergy can be established through a cell-based therapy employing allergen-expressing leukocytes. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

A very low geno2pheno false positive rate is associated with poor viro-immunological response in drug-naïve patients starting a first-line HAART.

PubMed

Armenia, Daniele; Soulie, Cathia; Di Carlo, Domenico; Fabeni, Lavinia; Gori, Caterina; Forbici, Federica; Svicher, Valentina; Bertoli, Ada; Sarmati, Loredana; Giuliani, Massimo; Latini, Alessandra; Boumis, Evangelo; Zaccarelli, Mauro; Bellagamba, Rita; Andreoni, Massimo; Marcelin, Anne-Geneviève; Calvez, Vincent; Antinori, Andrea; Ceccherini-Silberstein, Francesca; Perno, Carlo-Federico; Santoro, Maria Mercedes

2014-01-01

We previously found that a very low geno2pheno false positive rate (FPR ≤ 2%) defines a viral population associated with low CD4 cell count and the highest amount of X4-quasispecies. In this study, we aimed at evaluating whether FPR ≤ 2% might impact on the viro-immunological response in HIV-1 infected patients starting a first-line HAART. The analysis was performed on 305 HIV-1 B subtype infected drug-naïve patients who started their first-line HAART. Baseline FPR (%) values were stratified according to the following ranges: ≤ 2; 2-5; 5-10; 10-20; 20-60; >60. The impact of genotypically-inferred tropism on the time to achieve immunological reconstitution (a CD4 cell count gain from HAART initiation ≥ 150 cells/mm(3)) and on the time to achieve virological success (the first HIV-RNA measurement <50 copies/mL from HAART initiation) was evaluated by survival analyses. Overall, at therapy start, 27% of patients had FPR ≤ 10 (6%, FPR ≤ 2; 7%, FPR 2-5; 14%, FPR 5-10). By 12 months of therapy the rate of immunological reconstitution was overall 75.5%, and it was significantly lower for FPR ≤ 2 (54.1%) in comparison to other FPR ranks (78.8%, FPR 2-5; 77.5%, FPR 5-10; 71.7%, FPR 10-20; 81.8%, FPR 20-60; 75.1%, FPR >60; p = 0.008). The overall proportion of patients achieving virological success was 95.5% by 12 months of therapy. Multivariable Cox analyses showed that patients having pre-HAART FPR ≤ 2% had a significant lower relative adjusted hazard [95% C.I.] both to achieve immunological reconstitution (0.37 [0.20-0.71], p = 0.003) and to achieve virological success (0.50 [0.26-0.94], p = 0.031) than those with pre-HAART FPR >60%. Beyond the genotypically-inferred tropism determination, FPR ≤ 2% predicts both a poor immunological reconstitution and a lower virological response in drug-naïve patients who started their first-line therapy. This parameter could be useful to identify patients potentially with less chance of achieving adequate immunological reconstitution and virological undetectability.

Association between memory B-cells and clinical and immunological features of primary Sjögren's syndrome and Sicca patients.

PubMed

Barcelos, Filipe; Martins, Catarina; Papoila, Ana; Geraldes, Carlos; Cardigos, Joana; Nunes, Glória; Lopes, Teresa; Alves, Nuno; Vaz-Patto, José; Branco, Jaime; Borrego, Luís-Miguel

2018-06-01

B-cells play a pivotal role in primary Sjögren's syndrome (pSS) pathogenesis. We aim to (1) evaluate the distribution of B-lymphocyte subpopulations in pSS and Sicca patients, (2) establish cut-off points that discriminate pSS from controls, (3) evaluate the association between memory B-cells and phenotypic features in pSS. We included 57 pSS patients, 68 Sicca and 24 healthy controls. Circulating B-cells were characterized by flow cytometry as naïve and memory subsets and classified from Bm1 to Bm5. Compared to controls, pSS patients had lower percentages (29.5 vs 44.4%) and absolute numbers (47 vs 106 cells/µl) of memory B-cells. Through ROC curves, a cut-off of ≤ 58 total memory B-cells/µl yielded a specificity of 0.88 and a sensitivity of 0.60 for pSS, and was met by 59.6% of pSS patients, 38.8% of Sicca and 12.5% of controls. A cut-off of < 23.5 Switched-memory B-cells/µl yielded a specificity of 0.88 and a sensitivity of 0.54 and was met by 54.4% of pSS patients, 37.3% of Sicca and 12.5% of controls. In pSS, lower total memory B-cells count was associated with longer disease duration (14.3 vs 8.1 years, p = 0.006) and more active disease profile, as evaluated by the European League Against Rheumatism (EULAR) Sjögren's Syndrome Disease Activity Index (ESSDAI) (3.1 vs 1.4, p = 0.043). Decreased numbers of memory B-cells clearly discriminated pSS from controls and can also have prognostic value. It remains to be clarified whether Sicca patients with decreased memory B-cells represent pSS and if B-cell profiling could help in the diagnosis of pSS.

Antiglioma Immunological Memory in Response to Conditional Cytotoxic/Immune-Stimulatory Gene Therapy: Humoral and Cellular Immunity Lead to Tumor Regression

PubMed Central

Muhammad, A.K.M. Ghulam; Candolfi, Marianela; King, Gwendalyn D.; Yagiz, Kader; Foulad, David; Mineharu, Yohei; Kroeger, Kurt M.; Treuer, Katherine A.; Nichols, W. Stephen; Sanderson, Nicholas S.; Yang, Jieping; Khayznikov, Maksim; Van Rooijen, Nico; Lowenstein, Pedro R.; Castro, Maria G.

2009-01-01

Purpose Glioblastoma multiforme is a deadly primary brain cancer. Because the tumor kills due to recurrences, we tested the hypothesis that a new treatment would lead to immunological memory in a rat model of recurrent glioblastoma multiforme. Experimental Design We developed a combined treatment using an adenovirus (Ad) expressing fms-like tyrosine kinase-3 ligand (Flt3L), which induces the infiltration of immune cells into the tumor microenvironment, and an Ad expressing herpes simplex virus-1–thymidine kinase (TK), which kills proliferating tumor cells in the presence of ganciclovir. Results This treatment induced immunological memory that led to rejection of a second glioblastoma multiforme implanted in the contralateral hemisphere and of an extracranial glioblastoma multiforme implanted intradermally. Rechallenged long-term survivors exhibited anti-glioblastoma multiforme–specific T cells and displayed specific delayed-type hypersensitivity. Using depleting antibodies, we showed that rejection of the second tumor was dependent on CD8+ T cells. Circulating anti-glioma antibodies were observed when glioblastoma multiforme cells were implanted intradermally in naïve rats or in long-term survivors. However, rats bearing intracranial glioblastoma multiforme only exhibited circulating antitumoral antibodies upon treatment with Ad-Flt3L + Ad-TK. This combined treatment induced tumor regression and release of the chromatin-binding protein high mobility group box 1 in two further intracranial glioblastoma multiforme models, that is, Fisher rats bearing intracranial 9L and F98 glioblastoma multiforme cells. Conclusions Treatment with Ad-Flt3L + Ad-TK triggered systemic anti–glioblastoma multiforme cellular and humoral immune responses, and anti–glioblastoma multiforme immunological memory. Release of the chromatin-binding protein high mobility group box 1 could be used as a noninvasive biomarker of therapeutic efficacy for glioblastoma multiforme. The robust treatment efficacy lends further support to its implementation in a phase I clinical trial. PMID:19789315

Rapid reduction of hepatitis C virus-Core protein in the peripheral blood improve the immunological response in chronic hepatitis C patients.

PubMed

Kondo, Yasuteru; Ueno, Yoshiyuki; Wakui, Yuta; Ninomiya, Masashi; Kakazu, Eiji; Inoue, Jun; Kobayashi, Koju; Obara, Noriyuki; Shimosegawa, Tooru

2011-12-01

  The extracellular hepatitis C virus (HCV)-antigen, including HCV-Core protein, can suppress immune cells. Recently, the efficacy of double filtration plasmapheresis (DFPP) for chronic hepatitis C (CHC) was reported. However, the mechanism of efficacy of DFPP might not be only the reduction of HCV but also the effect of immune cells via direct and/or indirect mechanisms. The aim of this study is to analyze the virological and immunological parameters of difficult-to-treat HCV patients treated with DFPP combined with Peg-interferon and RBV (DFPP/Peg-IFN/RBV) therapy.   Twelve CHC patients were enrolled and treated with DFPP/Peg-IFN/RBV therapy. The immunological, virological and genetic parameters were studied.   All patients (4/4) treated with the major IL28B allele (T/T) could achieve complete early virological response (EVR). The amounts of HCV-Core antigen in the peripheral blood of EVR patients treated with DFPP/Peg-IFN/RBV rapidly declined in comparison to those of late virological response (LVR) patients treated with DFPP/Peg-IFN/RBV and EVR patients treated with Peg-IFN and RBV (Peg-IFN/RBV). The amount of IFN-γ produced from peripheral blood gradually increased. On the other hand, the amount of IL10 gradually decreased in the EVR patients. The frequencies of HCV-Core binding on CD3+ T cells rapidly declined in EVR patients treated with DFPP/Peg-IFN/RBV therapy. Moreover, the distributions of activated CD4(+) and CD8(+) T cells and CD16-CD56 high natural killer cells were significantly changed between before and after DFPP.   The rapid reduction of HCV-Core antigens and changes in the distribution of lymphoid cells could contribute to the favorable immunological response during DFPP/Peg-IFN/RBV therapy. © 2011 The Japan Society of Hepatology.

Comparison of immune manifestations between refractory cytopenia of childhood and aplastic anemia in children: A single-center retrospective study.

PubMed

Wu, Jun; Cheng, Yifei; Zhang, Leping

2015-12-01

This retrospective single-center study assessed the incidence and clinical features of immune manifestations of refractory cytopenia of childhood (RCC) and childhood aplastic anemia (AA). We evaluated 72 children with RCC and 123 with AA between February 2008 and March 2013. RCC was associated with autoimmune disease in 4 children, including 1 case each with autoimmune hemolytic anemia, rheumatoid arthritis, systemic lupus erythematosus, and anaphylactoid purpura. No children with AA were diagnosed with autoimmune diseases. Immune abnormalities were common in both RCC and AA; the most significant reductions were in the relative numbers of CD3-CD56+ subsets found in RCC. Despite the many similar immunologic abnormalities in AA and RCC, the rate of autoimmune disease was significantly lower in childhood AA than RCC (p=0.008, χ2=6.976). The relative numbers of natural killer cells were significantly lower in RCC patients than AA patients. By month 6, there was no significant difference in autoimmune manifestations between RCC and AA in relation to the response to immunosuppressive therapy (p=0.907, χ2=0.014). The large overlap of analogous immunologic abnormalities indicates that RCC and childhood AA may share the same pathogenesis. Copyright © 2015 Elsevier Ltd. All rights reserved.

Humoral and cell-mediated immune responses after a booster dose of HBV vaccine in HIV-infected children, adolescents and young adults.

PubMed

Giacomet, Vania; Masetti, Michela; Nannini, Pilar; Forlanini, Federica; Clerici, Mario; Zuccotti, Gian Vincenzo; Trabattoni, Daria

2018-01-01

HBV vaccine induces protective antibodies only in 23-56% of HIV-infected children. The aim of our study is to evaluate the immunologic effects of a booster dose of HBV vaccine in HIV-infected youth. 53 young HIV-infected patients in whom HBV vaccination did not elicit protective Ab titers were enrolled. All patients were on ART with optimal immunological and viral response. All patients received a booster dose of HBV vaccine (HBVAXPRO 10 μg i.m.). HBV-specific Ab titer, viral load and CD4+ T cells were measured at baseline (T0), T1, T6 and T12 months. In a subgroup of 16 patients HBV-specific cell mediated immune responses were evaluated at baseline, at T1 and T6. The booster dose induced seroconversion in 51% of patients at T1, 57% at T6, and49% at T12; seroconversion rate was significantly correlated with CD4+T cells at T0 and to the CD4 nadir. The booster dose induced HBV-specific cell mediated immunity at T6 mainly in Responders (Rs): Effector Memory CD8+T cells, HBV-specific TNFα-, IFNγ-, granzyme secreting CD8+ T cells and IL2-secreting CD4+ T cells were significantly increased in Rs compared to T0. In Non Responders (NRs), HBV-specific IL2-secreting CD4+ T cells, Central and Effector Memory CD8+ T cells were the only parameters modified at T6. Seroconversion induced by a booster dose of vaccine correlates with the development of T cell immunological memory in HIV-infected patients who did not respond to the standard immunization. Alternate immunization schedules need to be considered in NRs.

Cytomegalovirus: virological facts for clinicians.

PubMed

Bodaghi, B; Michelson, S

1999-12-01

Human cytomegalovirus (HCMV) is a complex DNA virus encoding more than 200 viral proteins. This highly adapted opportunist agent has developed several ways to evade the immune system. Among all clinical features due to HCMV, retinitis occurs especially in severely immunosuppressed patients, particularly during the end phase of HIV infection. Highly active antiretroviral therapy (HAART) has significantly reduced the incidence of this complication. However, in this HAART era, we observe the emergence of new clinical patterns in patients presenting with cicatricial HCMV retinitis. These patterns could be potentially related to immune mechanisms directed against viral antigens expressed at the surface of retinal cells that are still latently infected without any viral replication. We used a model of human retinal pigment epithelial (RPE) cells to evaluate virus-host interactions in the presence of different cytokines in the eye which play a major role in immunological or infectious conditions. Two different enzymatic pathways seem to be particularly involved during infection. Lack of tryptophan and production of nitric oxide seem to block HCMV replication in RPE cells. We propose a model to explain some of the mechanisms involved during severe immunosuppression and also after immune recovery.

[Chemically-induced scleroderma].

PubMed

Haustein, U F; Ziegler, V; Herrmann, K

1992-08-01

Scleroderma-like diseases can be induced by a number of chemical compounds, such as plastics, solvents and drugs. Contaminated rapeseed oil was the cause of the toxic oil syndrome and L-tryptophan induces the so-called eosinophilia-myalgia-syndrome. On the other hand, paraffin and silicon can trigger so-called adjuvant disease, while long-term exposure to silica can lead to idiopathic scleroderma (associated with silicosis in some cases). In addition to the clinical features, some pathogenetic data in the literature, such as genetic factors (HLA, chromosomal anomalies, enzyme deficiencies) and the metabolism of chlorinated ethylenes via reactive epoxide intermediate products, and our own findings are reported. Silica-induced scleroderma cannot be distinguished from the idiopathic form by epidemiological, clinical or immunological studies or by parameters referring to the blood vessels or collagen metabolism. In cell culture studies it has been shown that macrophages/monocytes release IL1, IL6 and TNF after ingestion of silica, which affects fibroblasts, T-helper cells and endothelial cells. Comparative results from the silicosis literature are reported. Finally, the possibly stimulating role of ionizing irradiation (uranium mining) in favouring the development of scleroderma is discussed.

Coeliac Disease With Rheumatoid Arthritis: An Unusual Association.

PubMed

Warjri, Synrang Batngen; Ete, Tony; Beyong, Taso; Barman, Bhupen; Lynrah, Kyrshanlang G; Nobin, Hage; Perme, Obang

2015-02-01

Coeliac disease has a significant association with many autoimmune disorders. It shares many common genetic and immunological features with other autoimmune diseases. Gluten, a gut-derived antigen, is the driver of the autoimmunity seen in coeliac disease. The altered intestinal permeability found in coeliac patients, coupled with a genetic predisposition and altered immunological response, may result in a systemic immune response that is directed against sites other than the gut. Gut-derived antigens may have a role in the pathogenesis of other autoimmune disorders including rheumatoid arthritis. Here we report a case of adult coeliac disease associated with rheumatoid arthritis.

The Progression of Cell Death Affects the Rejection of Allogeneic Tumors in Immune-Competent Mice – Implications for Cancer Therapy

PubMed Central

Chaurio, Ricardo A.; Muñoz, Luis E.; Maueröder, Christian; Janko, Christina; Harrer, Thomas; Fürnrohr, Barbara G.; Niederweis, Michael; Bilyy, Rostyslav; Schett, Georg; Herrmann, Martin; Berens, Christian

2014-01-01

Large amounts of dead and dying cells are produced during cancer therapy and allograft rejection. Depending on the death pathway and stimuli involved, dying cells exhibit diverse features, resulting in defined physiological consequences for the host. It is not fully understood how dying and dead cells modulate the immune response of the host. To address this problem, different death stimuli were studied in B16F10 melanoma cells by regulated inducible transgene expression of the pro-apoptotic active forms of caspase-3 (revCasp-3), Bid (tBid), and the Mycobacterium tuberculosis-necrosis inducing toxin (CpnTCTD). The immune outcome elicited for each death stimulus was assessed by evaluating the allograft rejection of melanoma tumors implanted subcutaneously in BALB/c mice immunized with dying cells. Expression of all proteins efficiently killed cells in vitro (>90%) and displayed distinctive morphological and physiological features as assessed by multiparametric flow cytometry analysis. BALB/c mice immunized with allogeneic dying melanoma cells expressing revCasp-3 or CpnTCTD showed strong rejection of the allogeneic challenge. In contrast, mice immunized with cells dying either after expression of tBid or irradiation with UVB did not, suggesting an immunologically silent cell death. Surprisingly, immunogenic cell death induced by expression of revCasp-3 or CpnTCTD correlated with elevated intracellular reactive oxygen species (ROS) levels at the time point of immunization. Conversely, early mitochondrial dysfunction induced by tBid expression or UVB irradiation accounted for the absence of intracellular ROS accumulation at the time point of immunization. Although ROS inhibition in vitro was not sufficient to abrogate the immunogenicity in our allo-immunization model, we suggest that the point of ROS generation and its intracellular accumulation may be an important factor for its role as damage associated molecular pattern in the development of allogeneic responses. PMID:25426116

Assessment of interactions of efavirenz solid drug nanoparticles with human immunological and haematological systems.

PubMed

Liptrott, Neill J; Giardiello, Marco; McDonald, Tom O; Rannard, Steve P; Owen, Andrew

2018-03-15

Recent work has developed solid drug nanoparticles (SDNs) of efavirenz that have been demonstrated, preclinically, improved oral bioavailability and the potential to enable up to a 50% dose reduction, and is currently being studied in a healthy volunteer clinical trial. Other SDN formulations are being studied for parenteral administration, either as intramuscular long-acting formulations, or for direct administration intravenously. The interaction of nanoparticles with the immunological and haematological systems can be a major barrier to successful translation but has been understudied for SDN formulations. Here we have conducted a preclinical evaluation of efavirenz SDN to assess their potential interaction with these systems. Platelet aggregation and activation, plasma coagulation, haemolysis, complement activation, T cell functionality and phenotype, monocyte derived macrophage functionality, and NK cell function were assessed in primary healthy volunteer samples treated with either aqueous efavirenz or efavirenz SDN. Efavirenz SDNs were shown not to interfere with any of the systems studied in terms of immunostimulation nor immunosuppression. Although efavirenz aqueous solution was shown to cause significant haemolysis ex vivo, efavirenz SDNs did not. No other interaction with haematological systems was observed. Efavirenz SDNs have been demonstrated to be immunologically and haematologically inert in the utilised assays. Taken collectively, along with the recent observation that lopinavir SDN formulations did not impact immunological responses, these data indicate that this type of nanoformulation does not elicit immunological consequences seen with other types of nanomaterial. The methodologies presented here provide a framework for pre-emptive preclinical characterisation of nanoparticle safety.

21 CFR 866.6020 - Immunomagnetic circulating cancer cell selection and enumeration system.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Immunomagnetic circulating cancer cell selection... Associated Antigen immunological Test Systems § 866.6020 Immunomagnetic circulating cancer cell selection and enumeration system. (a) Identification. An immunomagnetic circulating cancer cell selection and enumeration...

21 CFR 866.6020 - Immunomagnetic circulating cancer cell selection and enumeration system.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Immunomagnetic circulating cancer cell selection... Associated Antigen immunological Test Systems § 866.6020 Immunomagnetic circulating cancer cell selection and enumeration system. (a) Identification. An immunomagnetic circulating cancer cell selection and enumeration...

21 CFR 866.6020 - Immunomagnetic circulating cancer cell selection and enumeration system.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Immunomagnetic circulating cancer cell selection... Associated Antigen immunological Test Systems § 866.6020 Immunomagnetic circulating cancer cell selection and enumeration system. (a) Identification. An immunomagnetic circulating cancer cell selection and enumeration...

21 CFR 866.6020 - Immunomagnetic circulating cancer cell selection and enumeration system.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Immunomagnetic circulating cancer cell selection... Associated Antigen immunological Test Systems § 866.6020 Immunomagnetic circulating cancer cell selection and enumeration system. (a) Identification. An immunomagnetic circulating cancer cell selection and enumeration...

21 CFR 866.6020 - Immunomagnetic circulating cancer cell selection and enumeration system.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Immunomagnetic circulating cancer cell selection... Associated Antigen immunological Test Systems § 866.6020 Immunomagnetic circulating cancer cell selection and enumeration system. (a) Identification. An immunomagnetic circulating cancer cell selection and enumeration...

Prebiotics, probiotics, synbiotics, and the immune system: experimental data and clinical evidence.

PubMed

Frei, Remo; Akdis, Mübeccel; O'Mahony, Liam

2015-03-01

The intestinal immune system is constantly exposed to foreign antigens, which for the most part should be tolerated. Certain probiotics, prebiotics, and synbiotics are able to influence immune responses. In this review, we highlight the recent publications (within the last 2 years) that have substantially progressed this field. The immunological mechanisms underpinning probiotics, prebiotics, and synbiotics effects continue to be better defined with novel mechanisms being described for dendritic cells, epithelial cells, T regulatory cells, effector lymphocytes, natural killer T cells, and B cells. Many of the mechanisms being described are bacterial strain or metabolite specific, and should not be extrapolated to other probiotics or prebiotics. In addition, the timing of intervention seems to be important, with potentially the greatest effects being observed early in life. In this review, we discuss the recent findings relating to probiotics, prebiotics, and synbiotics, specifically their effects on immunological functions.

Spaceflight and Development of Immune Responses

NASA Technical Reports Server (NTRS)

Sonnenfeld, Gerald

1996-01-01

Evidence from both human and rodent studies has indicated that alterations in immunological parameters occur after space flight. The number of flight experiments has been small, and the full breadth of immunological alterations occurring after space flight remains to be established. Among the major effects on immune responses after space flight that have been reported are: alterations in lymphocyte blastogenesis and natural killer cell activity, alterations in production of cytokines, changes in leukocyte sub-population distribution, and decreases in the ability of bone marrow cells to respond to colony stimulating factors. Changes have been reported in immunological parameters of both humans and rodents. The significance of these alterations in relation to resistance to infection remains to be established. The objective of the studies contained in this project was to determine the effects of space flight on immune responses of pregnant rats and their offspring. The hypothesis was that space flight and the attendant period of microgravity will result in alteration of immunological parameters of both the pregnant rats as well as their offspring carried in utero during the flight. The parameters tested included: production of cytokines, composition of leukocyte sub- populations, response of bone marrow/liver cells to granulocyte/monocyte colony stimulating factor, and leukocyte blastogenesis. Changes in immune responses that could yield alterations in resistance to infection were determined. This yielded useful information for planning studies that could contribute to crew health. Additional information that could eventually prove useful to determine the potential for establishment of a permanent colony in space was obtained.

Is There Natural Killer Cell Memory and Can It Be Harnessed by Vaccination? Natural Killer Cells in Vaccination.

PubMed

Neely, Harold R; Mazo, Irina B; Gerlach, Carmen; von Andrian, Ulrich H

2017-12-18

Natural killer (NK) cells have historically been considered to be a part of the innate immune system, exerting a rapid response against pathogens and tumors in an antigen (Ag)-independent manner. However, over the past decade, evidence has accumulated suggesting that at least some NK cells display certain characteristics of adaptive immune cells. Indeed, NK cells can learn and remember encounters with a variety of Ags, including chemical haptens and viruses. Upon rechallenge, memory NK cells mount potent recall responses selectively to those Ags. This phenomenon, traditionally termed "immunological memory," has been reported in mice, nonhuman primates, and even humans and appears to be concentrated in discrete NK cell subsets. Because immunological memory protects against recurrent infections and is the central goal of active vaccination, it is crucial to define the mechanisms and consequences of NK cell memory. Here, we summarize the different kinds of memory responses that have been attributed to specific NK cell subsets and discuss the possibility to harness NK cell memory for vaccination purposes. Copyright © 2017 Cold Spring Harbor Laboratory Press; all rights reserved.

21 CFR 866.5520 - Immunoglobulin G (Fab fragment specific) immunological test system.

Code of Federal Regulations, 2011 CFR

2011-04-01

... multiple myeloma (tumor of bone marrow cells), Waldenstrom's macroglobulinemia (increased immunoglobulin production by the spleen and bone marrow cells), and lymphoma (tumor of the lymphoid tissues). (b...

21 CFR 866.5520 - Immunoglobulin G (Fab fragment specific) immunological test system.

Code of Federal Regulations, 2012 CFR

2012-04-01

... multiple myeloma (tumor of bone marrow cells), Waldenstrom's macroglobulinemia (increased immunoglobulin production by the spleen and bone marrow cells), and lymphoma (tumor of the lymphoid tissues). (b...

21 CFR 866.5520 - Immunoglobulin G (Fab fragment specific) immunological test system.

Code of Federal Regulations, 2013 CFR

2013-04-01

... multiple myeloma (tumor of bone marrow cells), Waldenstrom's macroglobulinemia (increased immunoglobulin production by the spleen and bone marrow cells), and lymphoma (tumor of the lymphoid tissues). (b...

21 CFR 866.5520 - Immunoglobulin G (Fab fragment specific) immunological test system.

Code of Federal Regulations, 2014 CFR

2014-04-01

... multiple myeloma (tumor of bone marrow cells), Waldenstrom's macroglobulinemia (increased immunoglobulin production by the spleen and bone marrow cells), and lymphoma (tumor of the lymphoid tissues). (b...

Spontaneous apoptosis, oxidative status and immunophenotype markers in blood lymphocytes of AIDS patients.

PubMed

Losa, G A; Graber, R

2000-01-01

Peripheral blood mononuclear cells (PBMC) from 251 HIV-positive drug abusers of known clinical stage and from 40 healthy donors were tested for conventional immunologic markers (CD3, CD4, CD8, CD19, CD14, CD16/CD56, CD45 and HLA-DR). Additional cell parameters and the occurrence of spontaneous apoptosis (programmed cell death) were investigated on freshly isolated PBMC by flow cytometric measurement of either annexin-V bound to plasma membrane phosphatidylserine or propidium iodide uptake. The activity of gamma-glutamyltransferase (gamma-GT), an ectoenzyme contributing to the synthesis of the intracellular antioxidant glutathione (GSH) and involved in early apoptosis, was also determined in these cells. Immunocompetent T-cell counts were lower in HIV+ patients, with the exception of CD8+ and HLA-DR+ lymphocytes. The external binding of annexin-V was significantly higher in HIV+ PBMC and occurred in both CD8+ and CD4+ T-lymphocyte subsets. The activity of gamma-GT, was significantly lower in the PBMC from HIV+ patients, indicating that the redox status of PBMC may be affected in HIV+ individuals. Finally, the most dominant features characterising patients receiving antiretroviral therapy were greater long-term stability in the distribution of various cell parameters excepted the level of apoptosis.

Spontaneous Apoptosis, Oxidative Status and Immunophenotype Markers in Blood Lymphocytes of AIDS Patients

PubMed Central

Losa, Gabriele A.; Graber, Riccardo

2000-01-01

Peripheral blood mononuclear cells (PBMC) from 251 HIV‐positive drug abusers of known clinical stage and from 40 healthy donors were tested for conventional immunologic markers (CD3, CD4, CD8, CD19, CD14, CD16/CD56, CD45 and HLA‐DR). Additional cell parameters and the occurrence of spontaneous apoptosis (programmed cell death) were investigated on freshly isolated PBMC by flow cytometric measurement of either annexin‐V bound to plasma membrane phosphatidylserine or propidium iodide uptake. The activity of γ‐glutamyltransferase (γ‐GT), an ectoenzyme contributing to the synthesis of the intracellular antioxidant glutathione (GSH) and involved in early apoptosis, was also determined in these cells. Immunocompetent T‐cell counts were lower in HIV+ patients, with the exception of CD8+ and HLA‐DR+ lymphocytes. The external binding of annexin‐V was significantly higher in HIV+ PBMC and occurred in both CD8+ and CD4+ T‐lymphocyte subsets. The activity of γ‐GT, was significantly lower in the PBMC from HIV+ patients, indicating that the redox status of PBMC may be affected in HIV+ individuals. Finally, the most dominant features characterising patients receiving antiretroviral therapy were greater long‐term stability in the distribution of various cell parameters excepted the level of apoptosis. PMID:11254221

Pyruvate dehydrogenase has a major role in mast cell function, and its activity is regulated by mitochondrial microphthalmia transcription factor.

PubMed

Sharkia, Israa; Hadad Erlich, Tal; Landolina, Nadine; Assayag, Miri; Motzik, Alex; Rachmin, Inbal; Kay, Gillian; Porat, Ziv; Tshori, Sagi; Berkman, Neville; Levi-Schaffer, Francesca; Razin, Ehud

2017-07-01

We have recently observed that oxidative phosphorylation-mediated ATP production is essential for mast cell function. Pyruvate dehydrogenase (PDH) is the main regulator of the Krebs cycle and is located upstream of the electron transport chain. However, the role of PDH in mast cell function has not been described. Microphthalmia transcription factor (MITF) regulates the development, number, and function of mast cells. Localization of MITF to the mitochondria and its interaction with mitochondrial proteins has not been explored. We sought to explore the role played by PDH in mast cell exocytosis and to determine whether MITF is localized in the mitochondria and involved in regulation of PDH activity. Experiments were performed in vitro by using human and mouse mast cells, as well as rat basophil leukemia cells, and in vivo in mice. The effect of PDH inhibition on mast cell function was examined. PDH interaction with MITF was measured before and after immunologic activation. Furthermore, mitochondrial localization of MITF and its effect on PDH activity were determined. PDH is essential for immunologically mediated degranulation of mast cells. After activation, PDH is serine dephosphorylated. In addition, for the first time, we show that MITF is partially located in the mitochondria and interacts with PDH. This interaction is dependent on the phosphorylation state of PDH. Furthermore, mitochondrial MITF regulates PDH activity. The association of mitochondrial MITF with PDH emerges as an important regulator of mast cell function. Our findings indicate that PDH could arise as a new target for the manipulation of allergic diseases. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Effects of microgravity on the immune system

NASA Technical Reports Server (NTRS)

Sonnenfeld, Gerald; Taylor, Gerald R.

1991-01-01

Changes in resistance to bacterial and viral infections in Apollo crew members has stimulated interest in the study of immunity and space flight. Results of studies from several laboratories in both humans and rodents have indicated alterations after space flight that include the following immunological parameters: thymus size, lymphocyte blastogenesis, interferon and interleukin production, natural killer cell activity, cytotoxic T-cell activity, leukocyte subset population distribution, response of bone marrow cells to colony stimulating factors, and delayed hypersensitivity skin test reactivity. The interactions of the immune system with other physiological systems, including muscle, bone, and the nervous system, may play a major role in the development of these immunological parameters during and after flight. There may also be direct effects of space flight on immune responses.

B cells in operational tolerance.

PubMed

Chesneau, M; Danger, R; Soulillou, J-P; Brouard, S

2018-05-01

Transplantation is currently the therapy of choice for endstage organ failure even though it requires long-term immunosuppresive therapy, with its numerous side effects, for acceptance of the transplanted organ. In rare cases however, patients develop operational tolerance, that is, graft survival without immunosuppression. Studies conducted on these patients reveal genetic, phenotypic, and functional signatures. They provide a better understanding of the immunological mechanisms involved in operational tolerance and define biomarkers that could be used to adapt immunosuppressive treatment to the individual, safely reduce immunosuppression doses, and ideally and safely guide immunosuppression withdrawal. This review summarizes studies that suggest a role for B cells as biomarkers of operational tolerance and discusses the use of B cells as a predictive tool for immunologic risk. Copyright © 2018. Published by Elsevier Inc.

Immunologic "vaccination" for the prevention of autoimmune diabetes (type 1A).

PubMed

Simone, E A; Wegmann, D R; Eisenbarth, G S

1999-03-01

Diabetes type 1A is an autoimmune condition characterized by lymphocytic infiltration of islets and selective destruction of insulin-secreting beta-cells. Numerous investigators have prevented diabetes in animal models with a variety of antigens and routes of administration. It is also now possible to identify high-risk individuals even before the appearance of autoantibodies. These advances have created the opportunity to design and begin human prevention trials. This review focuses on a variety of immunomodulatory approaches (including administration of adjuvants, autoantigens, T-cells, T-cell receptors, and DNA) that we have collectively termed immunologic "vaccination." In addition, we discuss the potential benefits and dangers of these approaches and issues relating to the design of human trials.

Rapid allergen-induced interleukin-17 and interferon-γ secretion by skin-resident memory CD8+ T cells.

PubMed

Schmidt, Jonas D; Ahlström, Malin G; Johansen, Jeanne D; Dyring-Andersen, Beatrice; Agerbeck, Christina; Nielsen, Morten M; Poulsen, Steen S; Woetmann, Anders; Ødum, Niels; Thomsen, Allan R; Geisler, Carsten; Bonefeld, Charlotte M

2017-04-01

Skin-resident memory T (T RM ) cells are associated with immunological memory in the skin. Whether immunological memory responses to allergens in the skin are solely localized to previously allergen-exposed sites or are present globally in the skin is not clear. Furthermore, the mechanisms whereby T RM cells induce rapid recall responses need further investigation. To study whether contact allergens induce local and/or global memory, and to determine the mechanisms involved in memory responses in the skin. To address these questions, we analysed responses to contact allergens in mice and humans sensitized to 2,4-dinitrofluorobenzene and nickel, respectively. Challenge responses in both mice and humans were dramatically increased at sites previously exposed to allergens as compared with previously unexposed sites. Importantly, the magnitude of the challenge response correlated with the epidermal accumulation of interleukin (IL)-17A-producing and interferon (IFN)-γ-producing T RM cells. Moreover, IL-17A and IFN-γ enhanced allergen-induced IL-1β production in keratinocytes. We show that sensitization with contact allergens induces a strong, long-lasting local memory and a weaker, temporary global immunological memory response to the allergen that is mediated by IL-17A-producing and IFN-γ-producing CD8 + T RM cells. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Altered Cytokine Gene Expression in Peripheral Blood Monocytes across the Menstrual Cycle in Primary Dysmenorrhea: A Case-Control Study

PubMed Central

Ma, Hongyue; Hong, Min; Duan, Jinao; Liu, Pei; Fan, Xinsheng; Shang, Erxin; Su, Shulan; Guo, Jianming; Qian, Dawei; Tang, Yuping

2013-01-01

Primary dysmenorrhea is one of the most common gynecological complaints in young women, but potential peripheral immunologic features underlying this condition remain undefined. In this paper, we compared 84 common cytokine gene expression profiles of peripheral blood mononuclear cells (PBMCs) from six primary dysmenorrheic young women and three unaffected controls on the seventh day before (secretory phase), and the first (menstrual phase) and the fifth (regenerative phase) days of menstruation, using a real-time PCR array assay combined with pattern recognition and gene function annotation methods. Comparisons between dysmenorrhea and normal control groups identified 11 (nine increased and two decreased), 14 (five increased and nine decreased), and 15 (seven increased and eight decreased) genes with ≥2-fold difference in expression (P<0.05) in the three phases of menstruation, respectively. In the menstrual phase, genes encoding pro-inflammatory cytokines (IL1B, TNF, IL6, and IL8) were up-regulated, and genes encoding TGF-β superfamily members (BMP4, BMP6, GDF5, GDF11, LEFTY2, NODAL, and MSTN) were down-regulated. Functional annotation revealed an excessive inflammatory response and insufficient TGF-β superfamily member signals with anti-inflammatory consequences, which may directly contribute to menstrual pain. In the secretory and regenerative phases, increased expression of pro-inflammatory cytokines and decreased expression of growth factors were also observed. These factors may be involved in the regulation of decidualization, endometrium breakdown and repair, and indirectly exacerbate primary dysmenorrhea. This first study of cytokine gene expression profiles in PBMCs from young primary dysmenorrheic women demonstrates a shift in the balance between expression patterns of pro-inflammatory cytokines and TGF-β superfamily members across the whole menstrual cycle, underlying the peripheral immunologic features of primary dysmenorrhea. PMID:23390521

Effects of isolation on interferon production and hematological and immunological parameters

NASA Technical Reports Server (NTRS)

Sonnenfeld, G.; Measel, J.; Loken, M. R.; Degioanni, J.; Follini, S.; Galvagno, A.; Montalbini, M.

1992-01-01

A 27-year-old woman was maintained in an isolated state for 131 days in Carlsbad Caverns, New Mexico. Her diet was vitamin D-depleted. Determinations on the effects of such isolation on levels and activities of peripheral blood cells that are important for hematological homeostasis and immunological function were carried out. Throughout the duration of the study, the percentage of lymphoid cells that expressed CD3, CD4, CD8, CD19, Leu 8, and other markers remained relatively constant although the absolute numbers of these cells varied. Although the percentage of natural killer (NK) cells did not vary, the activity of these cells did change. NK cell activity became elevated as the isolation study progressed. Production of interferon-gamma (IFN-gamma) in response to mitogen stimulation was higher than expected throughout the isolation periods, but returned to the normal range after termination of the isolation. Red and white cell counts dropped significantly upon entering isolation, but soon returned to normal.

Testisimmune privilege - Assumptions versus facts

PubMed Central

Kaur, G.; Mital, P.; Dufour, J.M.

2013-01-01

The testis has long enjoyed a reputation as an immunologically privileged site based on its ability to protect auto-antigenic germ cells and provide an optimal environment for the extended survival of transplanted allo- or xeno-grafts. Exploration of the role of anatomical, physiological, immunological and cellular components in testis immune privilege revealed that the tolerogenic environment of the testis is a result of the immunomodulatory factors expressed or secreted by testicular cells (mainly Sertoli cells, peritubular myoid cells, Leydig cells, and resident macrophages). The blood-testis barrier/Sertoli cell barrier, is also important to seclude advanced germ cells but its requirement in testis immune privilege needs further investigation. Testicular immune privilege is not permanent, as an effective immune response can be mounted against transplanted tissue, and bacterial/viral infections in the testis can be effectively eliminated. Overall, the cellular components control the fate of the immune response and can shift the response from immunodestructive to immunoprotective, resulting in immune privilege. PMID:25309630

Regulatory T cells in human disease and their potential for therapeutic manipulation

PubMed Central

Taams, Leonie S; Palmer, Donald B; Akbar, Arne N; Robinson, Douglas S; Brown, Zarin; Hawrylowicz, Catherine M

2006-01-01

Regulatory T cells are proposed to play a central role in the maintenance of immunological tolerance in the periphery, and studies in many animal models demonstrate their capacity to inhibit inflammatory pathologies in vivo. At a recent meeting [Clinical Application of Regulatory T Cells, 7–8 April 2005, Horsham, UK, organized by the authors of this review, in collaboration with the British Society for Immunology and Novartis] evidence was discussed that certain human autoimmune, infectious and allergic diseases are associated with impaired regulatory T-cell function. In contrast, evidence from several human cancer studies and some infections indicates that regulatory T cells may impair the development of protective immunity. Importantly, certain therapies, both those that act non-specifically to reduce inflammation and antigen-specific immunotherapies, may induce or enhance regulatory T-cell function. The purpose of this review was to summarize current knowledge on regulatory T-cell function in human disease, and to assess critically how this can be tailored to suit the therapeutic manipulation of immunity. PMID:16630018

Fatal subacute liver failure after repeated administration of sevoflurane anaesthesia.

PubMed

Zizek, David; Ribnikar, Marija; Zizek, Bogomir; Ferlan-Marolt, Vera

2010-01-01

Sevoflurane is a widely used halogenated inhalation anaesthetic. In comparison with other similar anaesthetics, it is not metabolized to potentially hepatotoxic trifluoroacetylated proteins. In this case report, we present a 66-year-old woman with breast carcinoma, who underwent sevoflurane general anaesthesia twice in 25 days. Soon after the second elective surgical procedure, jaundice and marked elevations in serum transaminases developed. The patient died 66 days thereafter. Autopsy results denied evidence of major cardiovascular abnormality, and histological examination confirmed massive liver cell necrosis with no feature of chronic liver injury. Sevoflurane anaesthesia was imputed as the cause after exclusion of other possible aetiological agents. Besides, coexistent malignant tumours found in the patient could have modulated the immunological response to the applied anaesthetic followed by fatal consequences.

Therapeutic targets and new directions for antibodies developed for ovarian cancer

PubMed Central

Bax, Heather J.; Josephs, Debra H.; Pellizzari, Giulia; Spicer, James F.; Montes, Ana; Karagiannis, Sophia N.

2016-01-01

ABSTRACT Antibody therapeutics against different target antigens are widely used in the treatment of different malignancies including ovarian carcinomas, but this disease still requires more effective agents. Improved understanding of the biological features, signaling pathways, and immunological escape mechanisms involved in ovarian cancer has emerged in the past few years. These advances, including an appreciation of the cross-talk between cancer cells and the patient's immune system, have led to the identification of new targets. In turn, potential antibody treatments with various mechanisms of action, including immune activation or toxin-delivery, that are directed at these targets have been developed. Here, we identify established as well as novel targets for antibodies in ovarian cancer, and discuss how they may provide fresh opportunities to identify interventions with enhanced therapeutic potential. PMID:27494775

Screening and Identification for Immunological Active Components from Andrographis Herba Using Macrophage Biospecific Extraction Coupled with UPLC/Q-TOF-MS.

PubMed

Wang, Yaqi; Jiao, Jiaojiao; Yang, Yuanzhen; Yang, Ming; Zheng, Qin

2018-04-30

The method of cell biospecific extraction coupled with UPLC/Q-TOF-MS has been developed as a tool for the screening and identification of potential immunological active components from Andrographis Herba (AH). In our study, a macrophage cell line (RAW264.7) was used to extract cell-combining compounds from the ethanol extract of AH. The cell binding system was then analyzed and identified by UPLC/Q-TOF-MS analysis. Finally, nine compounds, which could combine with macrophages, in an ethanol extract of AH were detected by comparing basic peak intensity (BPI) profiles of macrophages before and after treatment with AH. Then they were identified as Andrographidine E ( 1 ), Andrographidine D ( 2 ), Neoandrographolide ( 3 ), Dehydroandrographolide ( 4 ), 5, 7, 2′, 3′-tetramethoxyflavone ( 5 ), β-sitosterol ( 7 ), 5-hydroxy-7, 2′, 3′-trimethoxyflavone ( 8 ) and 5-hydroxy-7, 8, 2′, 3′-tetramethoxyflavone ( 9 ), which could classified into five flavonoids, three diterpene lactones, and one sterol. Their structures were recognized by their characteristic fragment ions and fragmentations pattern of diterpene lactones and flavonoids. Additionally, the activity of compounds 3 , 4 , and 7 was tested in vitro. Results showed that these three compounds could decrease the release of NO ( p < 0.01) in macrophages remarkably. Moreover, 3 , 4 , and 7 showed satisfactory dose-effect relationships and their IC 50 values were 9.03, 18.18, and 13.76 μg/mL, respectively. This study is the first reported work on the screening of immunological active components from AH. The potential immunological activity of flavonoids from AH has not been reported previously.

Gene correction of induced pluripotent stem cells derived from a murine model of X-linked chronic granulomatous disorder.

PubMed

Mukherjee, Sayandip; Thrasher, Adrian J

2014-01-01

Gene therapy presents an attractive alternative to allogeneic haematopoietic stem cell transplantation (HSCT) for treating patients suffering from primary immunodeficiency disorder (PID). The conceptual advantage of gene correcting a patient's autologous HSCs lies in minimizing or completely avoiding immunological complications arising from allogeneic transplantation while conferring the same benefits of immune reconstitution upon long-term engraftment. Clinical trials targeting X-linked chronic granulomatous disorder (X-CGD) have shown promising results in this context. However, long-term clinical benefits in these patients have been limited by issues of poor engraftment of gene-transduced cells coupled with transgene silencing and vector induced clonal proliferation. Novel vectors incorporating safety features such as self-inactivating (SIN) mutations in the long terminal repeats (LTRs) along with synthetic promoters driving lineage-restricted sustainable expression of the gp91phox transgene are expected to resolve the current pitfalls and require rigorous preclinical testing. In this chapter, we have outlined a protocol in which X-CGD mouse model derived induced pluripotent stem cells (iPSCs) have been utilized to develop a platform for investigating the efficacy and safety profiles of novel vectors prior to clinical evaluation.

Genetics of SCID

PubMed Central

2010-01-01

Human SCID (Severe Combined Immunodeficiency) is a prenatal disorder of T lymphocyte development, that depends on the expression of numerous genes. The knowledge of the genetic basis of SCID is essential for diagnosis (e.g., clinical phenotype, lymphocyte profile) and treatment (e.g., use and type of pre-hematopoietic stem cell transplant conditioning). Over the last years novel genetic defects causing SCID have been discovered, and the molecular and immunological mechanisms of SCID have been better characterized. Distinct forms of SCID show both common and peculiar (e.g., absence or presence of nonimmunological features) aspects, and they are currently classified into six groups according to prevalent pathophysiological mechanisms: impaired cytokine-mediated signaling; pre-T cell receptor defects; increased lymphocyte apoptosis; defects in thymus embryogenesis; impaired calcium flux; other mechanisms. This review is the updated, extended and largely modified translation of the article "Cossu F: Le basi genetiche delle SCID", originally published in Italian language in the journal "Prospettive in Pediatria" 2009, 156:228-238. PMID:21078154

Immunology Comes Full Circle in Melanoma While Specific Immunity Is Unleashed to Eliminate Metastatic Disease, Inflammatory Products of Innate Immunity Promote Resistance.

PubMed

Grimm, Elizabeth A

2016-01-01

Melanoma and many other cancers often express cells and molecular features of inflammation. Intrinsic to melanoma is the expression of a continuous cycle of cytokines and oxidative stress markers. The oxidative stress of inflammation is proposed to drive a metastatic process, not only of DNA adducts and crosslinks, but also of posttranslational oxidative modifications to lipids and proteins that we argue support growth and survival. Fortunately, numerous antioxidant agents are available clinically and we further propose that the pharmacological attenuation of these inflammatory processes, particularly the reactive nitrogen species, will restore the cancer cells to an apoptosis-permissive and growth-inhibitory state. Experimental model data using a small-molecule arginine antagonist that prevents enzymatic production of nitric oxide supports this view directly. I propose that the recognition, measurement, and regulation of such carcinogenic inflammation be considered as part of the approach to the treatment of cancer.

Hydrogel-based encapsulation of biological, functional tissue: fundamentals, technologies and applications

NASA Astrophysics Data System (ADS)

Zimmermann, H.; Ehrhart, F.; Zimmermann, D.; Müller, K.; Katsen-Globa, A.; Behringer, M.; Feilen, P. J.; Gessner, P.; Zimmermann, G.; Shirley, S. G.; Weber, M. M.; Metze, J.; Zimmermann, U.

2007-12-01

Replacing dysfunctional endocrine cells or tissues (e.g. islets, parathyroid tissue) by functional, foreign material without using immunosuppressives could soon become reality. Immunological reactions are avoided by encapsulating cells/tissues in hydrogel (e.g. alginate) microcapsules, preventing interaction of the enclosed material with the host’s immune system while permitting the unhindered passage of nutrients, oxygen and secreted therapeutic factors. Detailed investigations of the physical, physico-chemical and immunological parameters of alginate-based microcapsules have led recently to the development of a novel class of cell-entrapping microcapsules that meet the demands of biocompatibility, long-term integrity and function. This together with the development of ‘good medical practice’ microfluidic chip technology and of advanced cryopreservation technology for generation and storage of immunoisolated transplants will bring cell-based therapy to clinics and the market.

Bayesian Immunological Model Development from the Literature: Example Investigation of Recent Thymic Emigrants†

PubMed Central

Holmes, Tyson H.; Lewis, David B.

2014-01-01

Bayesian estimation techniques offer a systematic and quantitative approach for synthesizing data drawn from the literature to model immunological systems. As detailed here, the practitioner begins with a theoretical model and then sequentially draws information from source data sets and/or published findings to inform estimation of model parameters. Options are available to weigh these various sources of information differentially per objective measures of their corresponding scientific strengths. This approach is illustrated in depth through a carefully worked example for a model of decline in T-cell receptor excision circle content of peripheral T cells during development and aging. Estimates from this model indicate that 21 years of age is plausible for the developmental timing of mean age of onset of decline in T-cell receptor excision circle content of peripheral T cells. PMID:25179832

Immunology and Immunotherapy of Head and Neck Cancer

PubMed Central

Ferris, Robert L.

2015-01-01

The immune system plays a key role in the development, establishment, and progression of head and neck squamous cell carcinoma (HNSCC). A greater understanding of the dysregulation and evasion of the immune system in the evolution and progression of HNSCC provides the basis for improved therapies and outcomes for patients. HNSCC cells evade the host immune system through manipulation of their own immunogenicity, production of immunosuppressive mediators, and promotion of immunomodulatory cell types. Through the tumor's influence on the microenvironment, the immune system can be exploited to promote metastasis, angiogenesis, and growth. This article provides a brief overview of key components of the immune infiltrating cells in the tumor microenvironment, reviewing immunological principles related to head and neck cancer, including the concept of cancer immunosurveillance and immune escape. Current immunotherapeutic strategies and emerging results from ongoing clinical trials are presented. PMID:26351330

Cloning and Characterization of Inducible Nitric Oxide Synthase from Mouse Macrophages

NASA Astrophysics Data System (ADS)

Xie, Qiao-Wen; Cho, Hearn J.; Calaycay, Jimmy; Mumford, Richard A.; Swiderek, Kristine M.; Lee, Terry D.; Ding, Aihao; Troso, Tiffany; Nathan, Carl

1992-04-01

Nitric oxide (NO) conveys a variety of messages between cells, including signals for vasorelaxation, neurotransmission, and cytotoxicity. In some endothelial cells and neurons, a constitutive NO synthase is activated transiently by agonists that elevate intracellular calcium concentrations and promote the binding of calmodulin. In contrast, in macrophages, NO synthase activity appears slowly after exposure of the cells to cytokines and bacterial products, is sustained, and functions independently of calcium and calmodulin. A monospecific antibody was used to clone complementary DNA that encoded two isoforms of NO synthase from immunologically activated mouse macrophages. Liquid chromatography-mass spectrometry was used to confirm most of the amino acid sequence. Macrophage NO synthase differs extensively from cerebellar NO synthase. The macrophage enzyme is immunologically induced at the transcriptional level and closely resembles the enzyme in cytokine-treated tumor cells and inflammatory neutrophils.

The Role of Progesterone in the Feto-Maternal Immunological Crosstalk.

PubMed

Szekeres-Bartho, Julia

2018-06-27

This review aims to provide a brief historical overview of the feto-maternal immunological relationship, which profoundly influences the outcome of pregnancy. The initial question posed in the nineteen fifties by Medawar, was based on the assumption that the maternal immune system recognizes the fetus as an allograft. Indeed, based on the association between HLA-matching and spontaneous miscarriage, it became obvious that immunological recognition of pregnancy is required for a successful gestation. The restricted expression of polymorphic HLA antigens on the trophoblast, together with the presence of non-polymorphic MHC products excludes recognition by both T and NK cells of trophoblast presented antigens, however, T cells, which constitute the majority of decidual T cells are likely candidates. Indeed, a high number of activated, progesterone receptor-expressing T cells are present in peripheral blood of healthy pregnant women, and in the presence of progesterone, these cells secrete an immunomodulatory protein called Progesterone-induced Blocking Factor or PIBF. As early as in the peri-implantation period, the embryo communicates with the maternal immune system via PIBF containing extracellular vesicles. PIBF contributes to the dominance of Th2-type reactivity characterising normal pregnancy, by inducing increased production of Th2 cytokines. The high expression of this molecule in the decidua might be one of the reasons for the low cytotoxic activity of decidual NK cells. ©2018The Author(s). Published by S. Karger AG, Basel.

Innate immunological function of TH2 cells in vivo

USDA-ARS?s Scientific Manuscript database

Th2 cells produce IL-13 when stimulated by papain or house dust mites (HDM) and induce eosinophilic inflammation. This innate response of cells of the adaptive immune system is dependent on IL-33-, not T cell receptor-, based stimulation. While type 2 innate lymphoid cells (ILC2s) are the dominant ...

Dendritic Cells Pulsed with Leukemia Cell-Derived Exosomes More Efficiently Induce Antileukemic Immunities

PubMed Central

Wei, Wei; Shen, Chang; Deng, Xiaohui; Chen, Linjun; Ma, Liyuan; Hao, Siguo

2014-01-01

Dendritic cells (DCs) and tumor cell-derived exosomes have been used to develop antitumor vaccines. However, the biological properties and antileukemic effects of leukemia cell-derived exosomes (LEXs) are not well described. In this study, the biological properties and induction of antileukemic immunity of LEXs were investigated using transmission electron microscopy, western blot analysis, cytotoxicity assays, and animal studies. Similar to other tumor cells, leukemia cells release exosomes. Exosomes derived from K562 leukemia cells (LEXK562) are membrane-bound vesicles with diameters of approximately 50–100 μm and harbor adhesion molecules (e.g., intercellular adhesion molecule-1) and immunologically associated molecules (e.g., heat shock protein 70). In cytotoxicity assays and animal studies, LEXs-pulsed DCs induced an antileukemic cytotoxic T-lymphocyte immune response and antileukemic immunity more effectively than did LEXs and non-pulsed DCs (P<0.05). Therefore, LEXs may harbor antigens and immunological molecules associated with leukemia cells. As such, LEX-based vaccines may be a promising strategy for prolonging disease-free survival in patients with leukemia after chemotherapy or hematopoietic stem cell transplantation. PMID:24622345

Association of T and NK Cell Phenotype With the Diagnosis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).

PubMed

Rivas, Jose Luis; Palencia, Teresa; Fernández, Guerau; García, Milagros

2018-01-01

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a pathological condition characterized by incapacitating fatigue and a combination of neurologic, immunologic, and endocrine symptoms. At present its diagnosis is based exclusively on clinical criteria. Several studies have described altered immunologic profiles; therefore, we proposed to further examine the more significant differences, particularly T and NK cell subpopulations that could be conditioned by viral infections, to discern their utility in improving the diagnosis and characterization of the patients. The study included 76 patients that fulfilled the revised Canadian Consensus Criteria (CCC 2010) for ME/CFS and 73 healthy controls, matched for age and gender. Immunophenotyping of different T cell and natural killer cell subpopulations in peripheral blood was determined by flow cytometry. ME/CFS patients showed significantly lower values of T regulatory cells (CD4 + CD25 ++(high) FOXP3 + ) and higher NKT-like cells (CD3 + CD16 +/- CD56 + ) than the healthy individuals. Regarding NK phenotypes, NKG2C was significantly lower and NKCD69 and NKCD56 bright were significantly higher in the patients group. A classification model was generated using the more relevant cell phenotype differences (NKG2C and T regulatory cells) that was able to classify the individuals as ME/CFS patients or healthy in a 70% of cases. The observed differences in some of the subpopulations of T and NK cells between patients and healthy controls could define a distinct immunological profile that can help in the diagnostic process of ME/CFS patients, contribute to the recognition of the disease and to the search of more specific treatments. However, more studies are needed to corroborate these findings and to contribute to establish a consensus in diagnosis.

Association of T and NK Cell Phenotype With the Diagnosis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

PubMed Central

Rivas, Jose Luis; Palencia, Teresa; Fernández, Guerau; García, Milagros

2018-01-01

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a pathological condition characterized by incapacitating fatigue and a combination of neurologic, immunologic, and endocrine symptoms. At present its diagnosis is based exclusively on clinical criteria. Several studies have described altered immunologic profiles; therefore, we proposed to further examine the more significant differences, particularly T and NK cell subpopulations that could be conditioned by viral infections, to discern their utility in improving the diagnosis and characterization of the patients. The study included 76 patients that fulfilled the revised Canadian Consensus Criteria (CCC 2010) for ME/CFS and 73 healthy controls, matched for age and gender. Immunophenotyping of different T cell and natural killer cell subpopulations in peripheral blood was determined by flow cytometry. ME/CFS patients showed significantly lower values of T regulatory cells (CD4+CD25++(high)FOXP3+) and higher NKT-like cells (CD3+CD16+/−CD56+) than the healthy individuals. Regarding NK phenotypes, NKG2C was significantly lower and NKCD69 and NKCD56 bright were significantly higher in the patients group. A classification model was generated using the more relevant cell phenotype differences (NKG2C and T regulatory cells) that was able to classify the individuals as ME/CFS patients or healthy in a 70% of cases. The observed differences in some of the subpopulations of T and NK cells between patients and healthy controls could define a distinct immunological profile that can help in the diagnostic process of ME/CFS patients, contribute to the recognition of the disease and to the search of more specific treatments. However, more studies are needed to corroborate these findings and to contribute to establish a consensus in diagnosis. PMID:29867995

Development of the neonatal B and T cell repertoire in swine: implications for comparative and veterinary immunology.

PubMed

Butler, John E; Sinkora, Marek; Wertz, Nancy; Holtmeier, Wolfgang; Lemke, Caitlin D

2006-01-01

Birth in all higher vertebrates is at the center of the critical window of development in which newborns transition from dependence on innate immunity to dependence on their own adaptive immunity, with passive maternal immunity bridging this transition. Therefore we have studied immunological development through fetal and early neonatal life. In swine, B cells appear earlier in fetal development than T cells. B cell development begins in the yolk sac at the 20th day of gestation (DG20), progresses to fetal liver at DG30 and after DG45 continues in bone marrow. The first wave of developing T cells is gammadelta cells expressing a monomorphic Vdelta rearrangement. Thereafter, alphabeta T cells predominate and at birth, at least 19 TRBV subgroups are expressed, 17 of which appear highly homologous with those in humans. In contrast to the T cell repertoire and unlike humans and mice, the porcine pre-immune VH (IGHV-D-J) repertoire is highly restricted, depending primarily on CDR3 for diversity. The V-KAPPA (IGKV-J) repertoire and apparently also the V-LAMBDA (IGLV-J) repertoire, are also restricted. Diversification of the pre-immune B cell repertoire of swine and the ability to respond to both T-dependent and T-independent antigen depends on colonization of the gut after birth in which colonizing bacteria stimulate with Toll-like receptor ligands, especially bacterial DNA. This may explain the link between repertoire diversification and the anatomical location of primary lymphoid tissue like the ileal Peyers patches. Improper development of adaptive immunity can be caused by infectious agents like the porcine reproductive and respiratory syndrome virus that causes immune dysregulation resulting in immunological injury and autoimmunity.

Immune dysregulation in patients with PTEN hamartoma tumor syndrome: Analysis of FOXP3 regulatory T cells.

PubMed

Chen, Hannah H; Händel, Norman; Ngeow, Joanne; Muller, James; Hühn, Michael; Yang, Huei-Ting; Heindl, Mario; Berbers, Roos-Marijn; Hegazy, Ahmed N; Kionke, Janina; Yehia, Lamis; Sack, Ulrich; Bläser, Frank; Rensing-Ehl, Anne; Reifenberger, Julia; Keith, Julia; Travis, Simon; Merkenschlager, Andreas; Kiess, Wieland; Wittekind, Christian; Walker, Lisa; Ehl, Stephan; Aretz, Stefan; Dustin, Michael L; Eng, Charis; Powrie, Fiona; Uhlig, Holm H

2017-02-01

Patients with heterozygous germline mutations in phosphatase and tensin homolog deleted on chromosome 10 (PTEN) experience autoimmunity and lymphoid hyperplasia. Because regulation of the phosphoinositide 3-kinase (PI3K) pathway is critical for maintaining regulatory T (Treg) cell functions, we investigate Treg cells in patients with heterozygous germline PTEN mutations (PTEN hamartoma tumor syndrome [PHTS]). Patients with PHTS were assessed for immunologic conditions, lymphocyte subsets, forkhead box P3 (FOXP3) + Treg cell levels, and phenotype. To determine the functional importance of phosphatases that control the PI3K pathway, we assessed Treg cell induction in vitro, mitochondrial depolarization, and recruitment of PTEN to the immunologic synapse. Autoimmunity and peripheral lymphoid hyperplasia were found in 43% of 79 patients with PHTS. Immune dysregulation in patients with PHTS included lymphopenia, CD4 + T-cell reduction, and changes in T- and B-cell subsets. Although total CD4 + FOXP3 + Treg cell numbers are reduced, frequencies are maintained in the blood and intestine. Despite pathogenic PTEN mutations, the FOXP3 + T cells are phenotypically normal. We show that the phosphatase PH domain leucine-rich repeat protein phosphatase (PHLPP) downstream of PTEN is highly expressed in normal human Treg cells and provides complementary phosphatase activity. PHLPP is indispensable for the differentiation of induced Treg cells in vitro and Treg cell mitochondrial fitness. PTEN and PHLPP form a phosphatase network that is polarized at the immunologic synapse. Heterozygous loss of function of PTEN in human subjects has a significant effect on T- and B-cell immunity. Assembly of the PTEN-PHLPP phosphatase network allows coordinated phosphatase activities at the site of T-cell receptor activation, which is important for limiting PI3K hyperactivation in Treg cells despite PTEN haploinsufficiency. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Induction of long term mucosal immunological memory in humans by an oral inactivated multivalent enterotoxigenic Escherichia coli vaccine.

PubMed

Lundgren, Anna; Jertborn, Marianne; Svennerholm, Ann-Mari

2016-06-08

We have evaluated the capacity of an oral multivalent enterotoxigenic Escherichia coli (ETEC) vaccine (MEV) to induce mucosal immunological memory. MEV consists of four inactivated E. coli strains over-expressing the major colonization factors (CFs) CFA/I, CS3, CS5 and CS6 and the LTB-related toxoid LCTBA. Memory responses were analyzed by comparing the magnitudes and kinetics of intestine-derived antibody-secreting cell responses to a single dose of MEV in three groups of adult Swedish volunteers (n=16-19 subjects per group) in a Phase I trial: non-immunized controls (I) and subjects who in a previous Phase I trial 13-23 months earlier had received two biweekly doses of MEV (II) or MEV+double mutant LT (dmLT) adjuvant (III). Responses against CFs and LTB were analyzed in antibodies in lymphocyte secretions (ALS) of blood mononuclear cells collected before (day 0) and 4/5 and 7 days after immunization. Specific circulating memory B cells present at the time of the single dose vaccination were also studied to determine if such cells may reflect mucosal memory. Considerably higher and significantly more frequent IgA ALS responses against all CFs and LTB were induced by the single vaccine dose in the previously immunized than in non-immunized volunteers. Furthermore, peak IgA ALS responses against all antigens were observed on days 4/5 in most of the previously immunized subjects whereas only a few previously non-vaccinated individuals responded before day 7. Priming with adjuvant did not influence memory responses. Circulating vaccine specific IgA memory B cells were not detected, whereas anti-toxin IgG memory B cells were identified 13-23 months after priming vaccination. We conclude that MEV induces functional mucosal immunological memory which remains at least 1-2 years. Furthermore, our results support that analysis of antibody-secreting cell responses after booster vaccination may be a useful approach to evaluate longstanding mucosal immunological memory in humans. ISRCTN27096290. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

T-Cell Tropism of Simian Varicella Virus during Primary Infection

PubMed Central

Ouwendijk, Werner J. D.; Mahalingam, Ravi; de Swart, Rik L.; Haagmans, Bart L.; van Amerongen, Geert; Getu, Sarah; Gilden, Don; Osterhaus, Albert D. M. E.; Verjans, Georges M. G. M.

2013-01-01

Varicella-zoster virus (VZV) causes varicella, establishes a life-long latent infection of ganglia and reactivates to cause herpes zoster. The cell types that transport VZV from the respiratory tract to skin and ganglia during primary infection are unknown. Clinical, pathological, virological and immunological features of simian varicella virus (SVV) infection of non-human primates parallel those of primary VZV infection in humans. To identify the host cell types involved in virus dissemination and pathology, we infected African green monkeys intratracheally with recombinant SVV expressing enhanced green fluorescent protein (SVV-EGFP) and with wild-type SVV (SVV-wt) as a control. The SVV-infected cell types and virus kinetics were determined by flow cytometry and immunohistochemistry, and virus culture and SVV-specific real-time PCR, respectively. All monkeys developed fever and skin rash. Except for pneumonitis, pathology produced by SVV-EGFP was less compared to SVV-wt. In lungs, SVV infected alveolar myeloid cells and T-cells. During viremia the virus preferentially infected memory T-cells, initially central memory T-cells and subsequently effector memory T-cells. In early non-vesicular stages of varicella, SVV was seen mainly in perivascular skin infiltrates composed of macrophages, dendritic cells, dendrocytes and memory T-cells, implicating hematogenous spread. In ganglia, SVV was found primarily in neurons and occasionally in memory T-cells adjacent to neurons. In conclusion, the data suggest the role of memory T-cells in disseminating SVV to its target organs during primary infection of its natural and immunocompetent host. PMID:23675304

Leukemic blast cell colony formation in semisolid culture with erythropoietin: a case report of acute poorly differentiated erythroid leukemia.

PubMed

Tomonaga, M; Jinnai, I; Tagawa, M; Amenomori, T; Nishino, K; Yao, E; Nonaka, H; Kuriyama, K; Yoshida, Y; Matsuo, T

1987-02-01

The bone marrow of a patient with acute undifferentiated leukemia developed unique colonies after a 14-day culture in erythropoietin (EPO)-containing methylcellulose. The colonies consisted of 20 to 200 nonhemoglobinized large blast cells. Cytogenetic analysis of single colonies revealed hypotetraploid karyotypes with several marker chromosomes that were identical to those found in directly sampled bone marrow. The concurrently formed erythroid bursts showed only normal karyotypes. No leukemic colony formation was observed in other culture systems with either colony-stimulating activity (CSA) or phytohemagglutinin-stimulated leukocyte-conditioned medium (PHA-LCM). The leukemic colonies exhibited a complete EPO-dose dependency similar to that of the patient's normal BFU-E. Although cytochemical and immunologic marker studies of the bone marrow cells failed to clarify the cell lineage of the leukemic cells with extraordinarily large cell size, ultrastructural study revealed erythroid differentiation such as siderosome formation in the cytoplasm and ferritin particles in the rhophecytosis invaginations. These findings indicate that the patient had poorly differentiated erythroid leukemia and that some of the clonogenic cells might respond to EPO in vitro. Corresponding to this biological feature, the leukemic cells were markedly decreased in number in response to repeated RBC transfusions, and partial remission was obtained. These observations suggest that erythroid leukemia distinct from erythroleukemia (M6) with a myeloblastic component, can develop as a minor entity of human acute leukemia.

Long-term immunologically competent human peripheral lymphoid tissue cultures in a 3D bioreactor

PubMed Central

Kuzin, Igor; Sun, Hongliang; Moshkani, Safiekhatoon; Feng, Changyong; Mantalaris, Athanasios; Wu, JH David; Bottaro, Andrea

2011-01-01

Peripheral lymphoid organs (PLOs), the primary sites of development of adaptive immune responses, display a complex structural organization reflecting separation of cellular subsets (e.g. T and B lymphocytes) and functional compartments which is critical for immune function. The generation of in vitro culture systems capable of recapitulating salient features of PLOs for experimental, biotechnological and clinical applications would be highly desirable, but has been hampered so far by the complexity of these systems. We have previously developed a three-dimensional bioreactor system for long-term, functional culture of human bone marrow cells on macroporous microspheres in a packed-bed bioreactor with frequent medium change. Here we adapt the same system for culture of human primary cells from PLOs (tonsil) in the absence of specific exogenous growth factors or activators. Cells in this system displayed higher viability over several weeks, and maintain population diversity and cell surface markers largely comparable to primary cells. Light microscopy showed cells organizing in large diverse clusters within the scaffold pores and presence of B cell-enriched areas. Strikingly, these cultures generated a significant number of antibody-producing B cells when challenged with a panel of diverse antigens, as expected from a lymphoid tissue. Thus the three-dimensional tonsil bioreactor culture system may serve as a useful model of PLOs by recapitulating their structural organization and function ex vivo. PMID:21309085

Long-term immunologically competent human peripheral lymphoid tissue cultures in a 3D bioreactor.

PubMed

Kuzin, Igor; Sun, Hongliang; Moshkani, Safiekhatoon; Feng, Changyong; Mantalaris, Athanasios; Wu, J H David; Bottaro, Andrea

2011-06-01

Peripheral lymphoid organs (PLOs), the primary sites of development of adaptive immune responses, display a complex structural organization reflecting separation of cellular subsets (e.g., T and B lymphocytes) and functional compartments which is critical for immune function. The generation of in vitro culture systems capable of recapitulating salient features of PLOs for experimental, biotechnological, and clinical applications would be highly desirable, but has been hampered so far by the complexity of these systems. We have previously developed a three-dimensional bioreactor system for long-term, functional culture of human bone marrow cells on macroporous microspheres in a packed-bed bioreactor with frequent medium change. Here we adapt the same system for culture of human primary cells from PLOs (tonsil) in the absence of specific exogenous growth factors or activators. Cells in this system displayed higher viability over several weeks, and maintain population diversity and cell surface markers largely comparable to primary cells. Light microscopy showed cells organizing in large diverse clusters within the scaffold pores and presence of B cell-enriched areas. Strikingly, these cultures generated a significant number of antibody-producing B cells when challenged with a panel of diverse antigens, as expected from a lymphoid tissue. Thus the three-dimensional tonsil bioreactor culture system may serve as a useful model of PLOs by recapitulating their structural organization and function ex vivo. Copyright © 2011 Wiley Periodicals, Inc.

Anti-ATLA (antibody to adult T-cell leukemia-lymphoma virus-associated antigen)-negative adult T-cell leukemia-lymphoma.

PubMed

Shimoyama, M; Minato, K; Tobinai, K; Nagai, M; Setoya, T; Watanabe, S; Hoshino, H; Miwa, M; Nagoshi, H; Ichiki, N; Fukushima, N; Sugiura, K; Funaki, N

1983-01-01

Five cases of adult T-cell leukemia-lymphoma (ATL) having typical clinicohematologic and morphologic features but negative for anti-ATLA [antibody to ATL virus (ATLV)-associated antigen (ATLA)] are presented. Some differences in immunologic, epidemiologic, and serologic data between anti-ATLA-positive and -negative ATLs are also described. Expression of ATLA in early primary cultured leukemic cells was found to be negative in three patients tested (Cases 1, 2 and 4), however, a long-term cultured cell line, ATL-6A, derived from peripheral blood leukemia cells from Case 1, was found to express ATLA. Mother of Case 1 and a daughter of Case 2 were anti-ATLA negative. These results indicate that ATLV was involved in certain anti-ATLA-negative ATL patients, at least in Case 1, and that the patient had no detectable immune response against ATLV and ATLA. However, in other cases in which no ATLA reactivity of serum and no ATLA expression in cultured leukemic cells were observed, another possibility such as activation of an unknown cellular oncogene specific for ATL without ATLV involvement may be considered. In order to prove these possibilities definitely, it is necessary to elucidate whether or not proviral DNA of ATLV is integrated into chromosomal DNA of ATL cells and to find a cellular oncogene specific for ATL in the future.

Cytoskeletal stabilization of inhibitory interactions in immunologic synapses of mature human dendritic cells with natural killer cells

PubMed Central

Barreira da Silva, Rosa; Graf, Claudine

2011-01-01

Human mature dendritic cells (DCs) can efficiently stimulate natural killer (NK)–cell responses without being targeted by their cytotoxicity. To understand this important regulatory crosstalk, we characterized the development of the immunologic synapse between mature DCs and resting NK cells. Conjugates between these 2 innate leukocyte populations formed rapidly, persisted for prolonged time periods and matured with DC-derived f-actin polymerization at the synapse. Polarization of IL-12 and IL-12R to the synapse coincided with f-actin polymerization, while other activating and inhibitory molecules were enriched at the interface between DCs and NK cells earlier. Functional assays revealed that inhibition of f-actin polymerization in mature synapses led to an increase of IFN-γ secretion and cytotoxicity by NK cells. This elevated NK-cell reactivity resulted from decreased inhibitory signaling in the absence of MHC class I polarization at the interface, which was observed on inhibition of f-actin polymerization in DCs. Thus, inhibitory signaling is stabilized by f-actin at the synapse between mature DCs and resting NK cells. PMID:21917751

ImmuneQuest: Assessment of a Video Game as a Supplement to an Undergraduate Immunology Course.

PubMed

Raimondi, Stacey L

2016-05-01

The study of immunology, particularly in this day and age, is an integral aspect of the training of future biologists, especially health professionals. Unfortunately, many students lose interest in or lack true comprehension of immunology due to the jargon of the field, preventing them from gaining a true conceptual understanding that is essential to all biological learning. To that end, a new video game, ImmuneQuest, has been developed that allows undergraduate students to "be" cells in the immune system, finding and attacking pathogens, while answering questions to earn additional abilities. The ultimate goal of ImmuneQuest is to allow students to understand how the major cells in the immune system work together to fight disease, rather than focusing on them as separate entities as is more commonly done in lecture material. This work provides the first assessment of ImmuneQuest in an upper-level immunology course. Students had significant gains in learning of information presented in ImmuneQuest compared with information discussed in lecture only. Furthermore, while students found the game "frustrating" at times, they agreed that the game aided their learning and recommended it for future courses. Taken together, these results suggest that ImmuneQuest appears to be a useful tool to supplement lecture material and increase student learning and comprehension.

Spontaneous onset and transplant models of the Vk*MYC mouse show immunological sequelae comparable to human multiple myeloma.

PubMed

Cooke, Rachel E; Gherardin, Nicholas A; Harrison, Simon J; Quach, Hang; Godfrey, Dale I; Prince, Miles; Koldej, Rachel; Ritchie, David S

2016-09-06

The Vk*MYC transgenic and transplant mouse models of multiple myeloma (MM) are well established as a research tool for anti-myeloma drug discovery. However, little is known of the immune response in these models. Understanding the immunological relevance of these models is of increasing importance as immunotherapeutic drugs are developed against MM. We set out to examine how cellular immunity is affected in Vk*MYC mouse models and compare that to the immunology of patients with newly diagnosed and relapsed/refractory MM. We found that there were significant immunological responses in mice developing either spontaneous (transgenic) or transplanted MM as a consequence of the degree of tumor burden. Particularly striking were the profound B cell lymphopenia and the expansion of CD8(+) effector memory T cells within the lymphocyte population that progressively developed with advancing disease burden, mirroring changes seen in human MM. High disease burden was also associated with increased inflammatory cytokine production by T lymphocytes, which is more fitting with relapsed/refractory MM in humans. These findings have important implications for the application of this mouse model in the development of MM immunotherapies. Trial registration LitVacc ANZCTR trial ID ACTRN12613000344796; RevLite ANZCTR trial ID NCT00482261.

[Immunotherapy in epithelial ovarian carcinoma: hope and reality].

PubMed

Lavoué, V; Foucher, F; Henno, S; Bauville, E; Catros, V; Cabillic, F; Levêque, J

2014-03-01

Epithelial ovarian carcinoma (EOC) has a worst prognosis with little progress in terms of survival for the last two decades. Immunology received little interest in EOC in the past, but now appears very important in the natural history of this cancer. This review is an EOC immunology state of art and focuses on the place of immunotherapy in future. A systematic review of published studies was performed. Medline baseline interrogation was performed with the following keywords: "Ovarian carinoma, immunotherapy, T-lymphocyte, regulator T-lymphocyte, dendritic cells, macrophage, antigen, chemotherapy, surgery, clinical trials". Identified publications (English or French) were assessed for the understanding of EOC immunology and the place of conventional treatment and immunotherapy strategy. Intratumoral infiltration by immune cells is a strong prognotic factor in EOC. Surgery and chemotherapy in EOC decrease imunosuppression in patients. The antitumoral immunity is a part of the therapeutic action of surgery and chemotherapy. Until now, immunotherapy gave some disappointing results, but the new drugs that target the tolerogenic tumoral microenvironnement rise and give a new hope in the treatment of cancer. Immunology controls the EOC natural history. The modulation of immunosuppressive microenvironment associated with the stimulation of antitumoral immunity could be the next revolution in the treatment of cancer. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Immunology of Gut Mucosal Vaccines

PubMed Central

Pasetti, Marcela F.; Simon, Jakub K.; Sztein, Marcelo B.; Levine, Myron M.

2011-01-01

Summary Understanding the mechanisms underlying the induction of immunity in the gastrointestinal mucosa following oral immunization and the cross-talk between mucosal and systemic immunity should expedite the development of vaccines to diminish the global burden caused by enteric pathogens. Identifying an immunological correlate of protection in the course of field trials of efficacy, animal models (when available), or human challenge studies is also invaluable. In industrialized country populations, live attenuated vaccines (e.g. polio, typhoid, and rotavirus) mimic natural infection and generate robust protective immune responses. In contrast, a major challenge is to understand and overcome the barriers responsible for the diminished immunogenicity and efficacy of the same enteric vaccines in underprivileged populations in developing countries. Success in developing vaccines against some enteric pathogens has heretofore been elusive (e.g. Shigella). Different types of oral vaccines can selectively or inclusively elicit mucosal secretory immunoglobulin A and serum immunoglobulin G antibodies and a variety of cell-mediated immune responses. Areas of research that require acceleration include interaction between the gut innate immune system and the stimulation of adaptive immunity, development of safe yet effective mucosal adjuvants, better understanding of homing to the mucosa of immunologically relevant cells, and elicitation of mucosal immunologic memory. This review dissects the immune responses elicited in humans by enteric vaccines. PMID:21198669

Immunology in the Clinic Review Series; focus on allergies: immunotherapy for food allergy

PubMed Central

Mousallem, T; Burks, A W

2012-01-01

OTHER THEMES PUBLISHED IN THIS IMMUNOLOGY IN THE CLINIC REVIEW SERIES Metabolic Diseases, Host Responses, Cancer, Autoinflammatory Diseases, Type 1 diabetes and viruses. There is no approved therapy for food allergy. The current standard of care is elimination of the triggering food from the diet and accessibility to epinephrine. Immunotherapy is a promising treatment approach. While desensitization to most foods seems feasible, it remains unclear if a permanent state of tolerance is achievable. The research team at Duke is pioneering immunotherapy for food allergies. Work here has evolved over time from small open-label pilot studies to larger randomized designs. Our data show that immunological changes associated with immunotherapy include reduction in mast cell reactivity, decreased basophil responses, decreased specific-immunoglobulin (Ig)E, increased IgG4 and induction of regulatory T cells. Immunotherapy has generated much excitement in the food allergy community; however, further studies are needed before it is ready for clinical use. PMID:22132881

Integration of lyoplate based flow cytometry and computational analysis for standardized immunological biomarker discovery.

PubMed

Villanova, Federica; Di Meglio, Paola; Inokuma, Margaret; Aghaeepour, Nima; Perucha, Esperanza; Mollon, Jennifer; Nomura, Laurel; Hernandez-Fuentes, Maria; Cope, Andrew; Prevost, A Toby; Heck, Susanne; Maino, Vernon; Lord, Graham; Brinkman, Ryan R; Nestle, Frank O

2013-01-01

Discovery of novel immune biomarkers for monitoring of disease prognosis and response to therapy in immune-mediated inflammatory diseases is an important unmet clinical need. Here, we establish a novel framework for immunological biomarker discovery, comparing a conventional (liquid) flow cytometry platform (CFP) and a unique lyoplate-based flow cytometry platform (LFP) in combination with advanced computational data analysis. We demonstrate that LFP had higher sensitivity compared to CFP, with increased detection of cytokines (IFN-γ and IL-10) and activation markers (Foxp3 and CD25). Fluorescent intensity of cells stained with lyophilized antibodies was increased compared to cells stained with liquid antibodies. LFP, using a plate loader, allowed medium-throughput processing of samples with comparable intra- and inter-assay variability between platforms. Automated computational analysis identified novel immunophenotypes that were not detected with manual analysis. Our results establish a new flow cytometry platform for standardized and rapid immunological biomarker discovery with wide application to immune-mediated diseases.

Integration of Lyoplate Based Flow Cytometry and Computational Analysis for Standardized Immunological Biomarker Discovery

PubMed Central

Villanova, Federica; Di Meglio, Paola; Inokuma, Margaret; Aghaeepour, Nima; Perucha, Esperanza; Mollon, Jennifer; Nomura, Laurel; Hernandez-Fuentes, Maria; Cope, Andrew; Prevost, A. Toby; Heck, Susanne; Maino, Vernon; Lord, Graham; Brinkman, Ryan R.; Nestle, Frank O.

2013-01-01

Discovery of novel immune biomarkers for monitoring of disease prognosis and response to therapy in immune-mediated inflammatory diseases is an important unmet clinical need. Here, we establish a novel framework for immunological biomarker discovery, comparing a conventional (liquid) flow cytometry platform (CFP) and a unique lyoplate-based flow cytometry platform (LFP) in combination with advanced computational data analysis. We demonstrate that LFP had higher sensitivity compared to CFP, with increased detection of cytokines (IFN-γ and IL-10) and activation markers (Foxp3 and CD25). Fluorescent intensity of cells stained with lyophilized antibodies was increased compared to cells stained with liquid antibodies. LFP, using a plate loader, allowed medium-throughput processing of samples with comparable intra- and inter-assay variability between platforms. Automated computational analysis identified novel immunophenotypes that were not detected with manual analysis. Our results establish a new flow cytometry platform for standardized and rapid immunological biomarker discovery with wide application to immune-mediated diseases. PMID:23843942

Compendium of Immune Signatures Identifies Conserved and Species-Specific Biology in Response to Inflammation.

PubMed

Godec, Jernej; Tan, Yan; Liberzon, Arthur; Tamayo, Pablo; Bhattacharya, Sanchita; Butte, Atul J; Mesirov, Jill P; Haining, W Nicholas

2016-01-19

Gene-expression profiling has become a mainstay in immunology, but subtle changes in gene networks related to biological processes are hard to discern when comparing various datasets. For instance, conservation of the transcriptional response to sepsis in mouse models and human disease remains controversial. To improve transcriptional analysis in immunology, we created ImmuneSigDB: a manually annotated compendium of ∼5,000 gene-sets from diverse cell states, experimental manipulations, and genetic perturbations in immunology. Analysis using ImmuneSigDB identified signatures induced in activated myeloid cells and differentiating lymphocytes that were highly conserved between humans and mice. Sepsis triggered conserved patterns of gene expression in humans and mouse models. However, we also identified species-specific biological processes in the sepsis transcriptional response: although both species upregulated phagocytosis-related genes, a mitosis signature was specific to humans. ImmuneSigDB enables granular analysis of transcriptomic data to improve biological understanding of immune processes of the human and mouse immune systems. Copyright © 2016 Elsevier Inc. All rights reserved.

Immunologic status and virologic outcomes in repeat pregnancies to HIV-positive women not on antiretroviral therapy at conception: a case for lifelong antiretroviral therapy?

PubMed Central

French, Clare E.; Thorne, Claire; Tariq, Shema; Cortina-Borja, Mario; Tookey, Pat A.

2014-01-01

During their second pregnancy with diagnosed HIV (n = 1177), two-fifths of women in the UK/Ireland not on antiretroviral therapy (ART) at conception had an immunological indication for treatment (CD4+ <350 cells/μl), of whom nearly half had CD4+ at least 350 cells/μl in their previous pregnancy. Those initiating ART during pregnancy had a 4.3-fold increased odds of detectable viral load at delivery compared with those conceiving on treatment, suggesting that continuation of ART after pregnancy may be beneficial for many women. PMID:24685820

Advances in basic and clinical immunology in 2006.

PubMed

Chinen, Javier; Shearer, William T

2007-08-01

This article reviews the progress in the field of basic and clinical immunology in 2006, focusing on the articles published in the Journal. The role of Toll-like receptors in the immune response was explored in detail in several articles. The knowledge gained in these investigations is being used to develop strategies that enhance the immunogenicity of vaccines to prevent infectious diseases and to have an immunomodulatory effect on allergic diseases. Other components of the innate immunity reported on were the recognition of allergens with lipid-derived motifs by CD1d-restricted T cells and the role of dendritic cells in the development of an allergic response. More than 120 primary immunodeficiencies were defined at a molecular level, and biological agents such as TNF-alpha antagonists and IFN-alpha were shown to have therapeutic use. New anti-HIV drugs that block cell entry were proven to be effective, thus offering alternative therapies to respond to the development of multidrug-resistant HIV strains. The modern understanding of immunologic concepts is helping to elucidate the mechanisms of defense against viruses, bacteria, and parasites; as a result, strategies to improve management and prevention continue to emerge.

Role of T cell TGF beta signaling in intestinal cytokine responses and helminthic immune modulation

USDA-ARS?s Scientific Manuscript database

Colonization with helminthic parasites down-regulates inflammation in murine colitis and improves activity scores in human inflammatory bowel disease. Helminths induce mucosal regulatory T cells, which are important for intestinal immunologic homeostasis. Regulatory T cell function involves cytoki...

The Yin and Yang of Innate Lymphoid Cells in Cancer.

PubMed

Carrega, Paolo; Campana, Stefania; Bonaccorsi, Irene; Ferlazzo, Guido

2016-11-01

The recent appreciation of novel subsets of innate lymphoid cells (ILCs) as important regulators of tissue homeostasis, inflammation and repair, raise questions regarding the presence and role of these cells in cancer tissues. In addition to natural killer and fetal lymphoid tissue inducer (LTi) cells, the ILC family comprises non-cytolytic, cytokine-producing cells that are classified into ILC1, ILC2 and ILC3 based on phenotypic and functional characteristics. Differently from natural killer cells, which are the prototypical members of ILC1 and whose role in tumors is better established, the involvement of other ILC subsets in cancer progression or resistance is still fuzzy and in several instances controversial, since current studies indicate both context-dependent beneficial or pathogenic effects. Here, we review the current knowledge regarding the involvement of these novel ILC subsets in the context of tumor immunology, highlighting how ILC subsets might behave either as friends or foes. Copyright © 2016 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.

Immune Regulatory Properties of CD117pos Amniotic Fluid Stem Cells Vary According to Gestational Age

PubMed Central

Di Trapani, Mariano; Bassi, Giulio; Fontana, Emanuela; Giacomello, Luca; Pozzobon, Michela; Guillot, Pascale V.; De Coppi, Paolo

2015-01-01

Amniotic Fluid Stem (AFS) cells are broadly multipotent fetal stem cells derived from the positive selection and ex vivo expansion of amniotic fluid CD117/c-kitpos cells. Considering the differentiation potential in vitro toward cell lineages belonging to the three germ layers, AFS cells have raised great interest as a new therapeutic tool, but their immune properties still need to be assessed. We analyzed the in vitro immunological properties of AFS cells from different gestational age in coculture with T, B, and natural killer (NK) cells. Nonactivated (resting) first trimester-AFS cells showed lower expression of HLA class-I molecules and NK-activating ligands than second and third trimester-AFS cells, whose features were associated with lower sensitivity to NK cell-mediated lysis. Nevertheless, inflammatory priming with interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α) enhanced resistance of all AFS cell types to NK cytotoxicity. AFS cells modulated lymphocyte proliferation in a different manner according to gestational age: first trimester-AFS cells significantly inhibited T and NK cell proliferation, while second and third trimester-AFS cells were less efficient. In addition, only inflammatory-primed second trimester-AFS cells could suppress B cell proliferation, which was not affected by the first and third trimester-AFS cells. Indolamine 2,3 dioxygenase pathway was significantly involved only in T cell suppression mediated by second and third trimester-AFS cells. Overall, this study shows a number of significant quantitative differences among AFS cells of different gestational age that have to be considered in view of their clinical application. PMID:25072397

Ginsenoside Rh2 enhances the antitumor immunological response of a melanoma mice model.

PubMed

Wang, Meng; Yan, Shi-Ju; Zhang, Hong-Tao; Li, Nan; Liu, Tao; Zhang, Ying-Long; Li, Xiao-Xiang; Ma, Qiong; Qiu, Xiu-Chun; Fan, Qing-Yu; Ma, Bao-An

2017-02-01

The treatment of malignant tumors following surgery is important in preventing relapse. Among all the post-surgery treatments, immunomodulators have demonstrated satisfactory effects on preventing recurrence according to recent studies. Ginsenoside is a compound isolated from panax ginseng, which is a famous traditional Chinese medicine. Ginsenoside aids in killing tumor cells through numerous processes, including the antitumor processes of ginsenoside Rh2 and Rg1, and also affects the inflammatory processes of the immune system. However, the role that ginsenoside serves in antitumor immunological activity remains to be elucidated. Therefore, the present study aimed to analyze the effect of ginsenoside Rh2 on the antitumor immunological response. With a melanoma mice model, ginsenoside Rh2 was demonstrated to inhibit tumor growth and improved the survival time of the mice. Ginsenoside Rh2 enhanced T-lymphocyte infiltration in the tumor and triggered cytotoxicity in spleen lymphocytes. In addition, the immunological response triggered by ginsenoside Rh2 could be transferred to other mice. In conclusion, the present study provides evidence that ginsenoside Rh2 treatment enhanced the antitumor immunological response, which may be a potential therapy for melanoma.

Immune checkpoint inhibitors for non-small-cell lung cancer: does that represent a 'new frontier'?

PubMed

Pilotto, Sara; Kinspergher, Stefania; Peretti, Umberto; Calio, Anna; Carbognin, Luisa; Ferrara, Roberto; Brunelli, Matteo; Chilosi, Marco; Tortora, Giampaolo; Bria, Emilio

2015-01-01

Advances in the interpretation and understanding of cancer behaviour, particularly of its ability to evade the host immunosurveillance, deregulating the balance between inhibitory and stimulatory factors, led to the development of an innovative category of immunotherapeutic agents, currently under investigation. Although the disappointing data deriving from the employment of vaccines in non-small cell lung cancer (NSCLC), more promising results have been obtained in the early phase trials with immune checkpoint inhibitors, such as cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), programmed cell death protein-1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors. This review delineates the main features of the available immunotherapeutic agents, focusing the discussion on immune checkpoint inhibitors, those that have already demonstrated a relevant clinical activity (such as Ipilimumab and Nivolumab) and those molecules still in early development phase. Moreover, we underline the possible emerging issues deriving from the progressive diffusion of Immuno-Oncology into the standard clinical practice. The careful and accurate identification and management of immune-related toxicities, the validation of more reliable immune response criteria and the increasing research of potential predictive biomarkers are key points of discussion. The perspective is that immunotherapy might represent an effective 'magic bullet', able to change the treatment paradigm of NSCLC, particularly of those subgroups featured by a heavily mutant cancer (squamous histology and smokers), where the immunologic agents contribute in cancer development and progression seems to be strong and, concurrently, the efficacy of standard therapies particularly limited.

Pediatric hyperimmunoglobulin E syndrome

PubMed Central

Fan, Huifeng; Huang, Li; Yang, Diyuan; Lin, Yunting; Lu, Gen; Xie, Yaping; Yu, Jialu; Zhang, Dongwei

2018-01-01

Abstract Hyperimmunoglobulin E syndromes (HIES) are rare primary immunodeficiency diseases characterized by markedly elevated serum immunoglobulin (Ig) E, recurrent pneumonia, and chronic eczema. To date, information about pediatric HIES is limited. We aimed to evaluate the spectrum of clinical and immunological features in pediatric patients with HIES in China. We retrospectively reviewed the cases of 4 pediatric patients with HIES followed at the Guangzhou Women and Children's Medical Center from May 2013 to September 2017. We analyzed clinical presentation, laboratory data, immunological evaluations, imagenological characteristics, treatment, response to therapy, genetic and bronchoalveolar lavage fluid (BALF) findings, and prognosis. The common clinical features of the patients were recurrent respiratory and mucocutaneous infections and eczematoid skin lesions. In 3 of 4 patients, BALF and transbronchial lung biopsy (TBLB) demonstrated fungal pneumonia with organisms including invasive Aspergillus and Penicillium marneffei. Elevated serum IgG and IgM were detected in 3 and 2 cases, respectively, while CD4+ T and CD19+ B cells were slightly reduced in only 1 patient. Nitroblue tetrazolium tests (NBTs) were normal in all patients, and reduced natural killer cell counts were identified in 3 patients. A novel missense mutation in exon 17 (c.1593A>T, p.K531N) was identified in the signal transducer and activator of transcription 3 (STAT3) gene that has not been reported previously. One patient had 3 homozygous nonsynonymous variations of the complement receptor 2 (CR2) gene distributed in exons 10 (c.1916G>A, p.S639N) and 11 (c.1987T>C, p.S663P and c.2012G>A, p.R671H) with high frequency. This case series suggests that fungi are important respiratory pathogens in children with HIES and should be considered in cases of pneumonia in this population. The NIH scoring system does not allow diagnostic certainty, particularly in infants, because some of the common manifestations of HIES may not develop until the patient matures. Pulmonary complications must be identified in the early stage of the disease to treat them effectively. In addition, we report a mutation in STAT3 that has not been identified previously. PMID:29620631

Paradoxical arthritis occurring during anti-TNF in patients with inflammatory bowel disease: histological and immunological features of a complex synovitis.

PubMed

Alivernini, Stefano; Pugliese, Daniela; Tolusso, Barbara; Bui, Laura; Petricca, Luca; Guidi, Luisa; Mirone, Luisa; Rapaccini, Gian Ludovico; Federico, Francesco; Ferraccioli, Gianfranco; Armuzzi, Alessandro; Gremese, Elisa

2018-01-01

Paradoxical arthritis under tumour necrosis factor inhibitor (TNF-i) for inflammatory bowel disease (IBD) has been described. This study aims to evaluate the histological features of paired synovial tissue (ST) and colonic mucosa (CM) tissue in patients with IBD developing paradoxical arthritis under TNF-i. Patients with IBD without history of coexisting joint involvement who developed arthritis under TNF-i were enrolled. Each patient underwent ST biopsy and ileocolonoscopy with CM biopsies. ST and CM paired samples were stained through immunohistochemistry (IHC) for CD68, CD21, CD20, CD3 and CD117. Clinical and immunological parameters (anticitrullinated peptides antibodies (ACPA)-immunoglobulin (Ig)M/IgA rheumatoid factor (RF)) were collected. Psoriatic arthritis (PsA) and ACPA/IgM-RF/IgA-RF negative rheumatoid arthritis (RA) were enrolled as comparison. 10 patients with IBD (age 46.0±9.7 years, 13.2±9.9 years of disease duration, 2.5±1.6 years of TNF-i exposure, six with Crohn's disease and four with ulcerative colitis, respectively) were studied. At ST level, IHC revealed that patients with IBD with paradoxical arthritis showed more similar histological findings in terms of synovial CD68 + , CD21 + , CD20 + , CD3 + and CD117 + cells compared with PsA than ACPA/IgM-RF/IgA-RF negative RA. Analysing the CM specimens, patients with IBD showed the presence of CD68 + , CD3 + , CD117 + and CD20 + cells in 100%, 70%, 60% and 50% of cases, respectively, despite endoscopic remission. Finally, addition of conventional disease-modifying antirheumatic drugs and switch to ustekinumab were more effective than swapping into different TNF-i in patients with IBD with paradoxical arthritis. Patients with IBD may develop histologically proven synovitis during TNF-i, comparable to PsA. The inhibition of inflammatory pathways alternative to TNF (IL12/1L23) may be an effective therapeutic option for severe paradoxical articular manifestations.

Paradoxical arthritis occurring during anti-TNF in patients with inflammatory bowel disease: histological and immunological features of a complex synovitis

PubMed Central

Alivernini, Stefano; Pugliese, Daniela; Tolusso, Barbara; Bui, Laura; Petricca, Luca; Guidi, Luisa; Mirone, Luisa; Rapaccini, Gian Ludovico; Federico, Francesco; Ferraccioli, Gianfranco; Armuzzi, Alessandro; Gremese, Elisa

2018-01-01

Objective Paradoxical arthritis under tumour necrosis factor inhibitor (TNF-i) for inflammatory bowel disease (IBD) has been described. This study aims to evaluate the histological features of paired synovial tissue (ST) and colonic mucosa (CM) tissue in patients with IBD developing paradoxical arthritis under TNF-i. Methods Patients with IBD without history of coexisting joint involvement who developed arthritis under TNF-i were enrolled. Each patient underwent ST biopsy and ileocolonoscopy with CM biopsies. ST and CM paired samples were stained through immunohistochemistry (IHC) for CD68, CD21, CD20, CD3 and CD117. Clinical and immunological parameters (anticitrullinated peptides antibodies (ACPA)-immunoglobulin (Ig)M/IgA rheumatoid factor (RF)) were collected. Psoriatic arthritis (PsA) and ACPA/IgM-RF/IgA-RF negative rheumatoid arthritis (RA) were enrolled as comparison. Results 10 patients with IBD (age 46.0±9.7 years, 13.2±9.9 years of disease duration, 2.5±1.6 years of TNF-i exposure, six with Crohn’s disease and four with ulcerative colitis, respectively) were studied. At ST level, IHC revealed that patients with IBD with paradoxical arthritis showed more similar histological findings in terms of synovial CD68+, CD21+, CD20+, CD3+ and CD117+ cells compared with PsA than ACPA/IgM-RF/IgA-RF negative RA. Analysing the CM specimens, patients with IBD showed the presence of CD68+, CD3+, CD117+ and CD20+ cells in 100%, 70%, 60% and 50% of cases, respectively, despite endoscopic remission. Finally, addition of conventional disease-modifying antirheumatic drugs and switch to ustekinumab were more effective than swapping into different TNF-i in patients with IBD with paradoxical arthritis. Conclusion Patients with IBD may develop histologically proven synovitis during TNF-i, comparable to PsA. The inhibition of inflammatory pathways alternative to TNF (IL12/1L23) may be an effective therapeutic option for severe paradoxical articular manifestations. PMID:29657833

The immunological response of HIV-positive patients initiating HAART at the Komfo Anokye Teaching Hospital, Kumasi, Ghana.

PubMed

Annison, L; Dompreh, A; Adu-Sarkodie, Y

2013-12-01

The study sought to document the experience of immunological improvement among Ghanaian PLHIV on HAART comparing different categories of patients. Serology Unit, Komfo Anokye Teaching Hospital, Kumasi, Ghana. The study comprised a convenient sample of 303 treatment naïve HIV patients due to start HAART. Questionnaires were used to collect patient demographic and clinical data. Four CD4 counts were measured at six-monthly intervals to determine rates of CD4 change. These were pre-therapy, 1(st) post-therapy, 2(nd) post-therapy, and 3(rd) post-therapy counts. The rates of CD4 change among the different categories of patients were also compared. At baseline, women had higher CD4 count (mean of 77.4 cells/μl), and mean age of participants was 40 years. The CD4 count increased from a mean baseline of 70.2 cells/μl to 229.2, 270.0, and 297.6 cells/μl at 6, 12, and 18 months of treatment respectively (P < 0.0001 at each time point). There were no gender (P=0.46) and age (P=0.96) differences in treatment response. There was no difference (P=0.18) in treatment response comparing those with CD4 <250 cells/μl and those whose CD4 count was between 250 and 350 cells/μl at baseline although patients with baseline CD4 count <250 cells/μl showed larger increases after 12 months of treatment. Out of 282 patients with pre-therapy CD4 count ≤250 cells/μl, 241 (85.5%) and 41 (14.5%) were adherents and nonadherents respectively. Mean rate of increase was 15.2 and 8.4 cells/μl/month in adherent and non-adherent patients respectively (p=0.2). The study suggests that a sustained CD4 increase could be achieved in adherent patients commencing therapy with baseline CD4 count ≤250 cells/μl, and that these patients have greater ability for immunological recovery during 12 months of treatment The study, therefore, concludes that significant immunological improvement is possible among Ghanaian PLHIV on HAART as long as a high level of treatment adherence is observed.

Neuropathologic features in the hippocampus and cerebellum of three older men with fragile X syndrome

PubMed Central

2011-01-01

Background Fragile X syndrome (FXS) is the most common inherited form of intellectual disability, and is the most common single-gene disorder known to be associated with autism. Despite recent advances in functional neuroimaging and our understanding of the molecular pathogenesis, only limited neuropathologic information on FXS is available. Methods Neuropathologic examinations were performed on post-mortem brain tissue from three older men (aged 57, 64 and 78 years) who had received a clinical or genetic diagnosis of FXS. In each case, physical and cognitive features were typical of FXS, and one man was also diagnosed with autism. Guided by reports of clinical and neuroimaging abnormalities of the limbic system and cerebellum of individuals with FXS, the current analysis focused on neuropathologic features present in the hippocampus and the cerebellar vermis. Results Histologic and immunologic staining revealed abnormalities in both the hippocampus and cerebellar vermis. Focal thickening of hippocampal CA1 and irregularities in the appearance of the dentate gyrus were identified. All lobules of the cerebellar vermis and the lateral cortex of the posterior lobe of the cerebellum had decreased numbers of Purkinje cells, which were occasionally misplaced, and often lacked proper orientation. There were mild, albeit excessive, undulations of the internal granular cell layer, with patchy foliar white matter axonal and astrocytic abnormalities. Quantitative analysis documented panfoliar atrophy of both the anterior and posterior lobes of the vermis, with preferential atrophy of the posterior lobule (VI to VII) compared with age-matched normal controls. Conclusions Significant morphologic changes in the hippocampus and cerebellum in three adult men with FXS were identified. This pattern of pathologic features supports the idea that primary defects in neuronal migration, neurogenesis and aging may underlie the neuropathology reported in FXS. PMID:21303513

Fatal neonatal-onset mitochondrial respiratory chain disease with T cell immunodeficiency.

PubMed

Reichenbach, Janine; Schubert, Ralf; Horvàth, Rita; Petersen, Jens; Fütterer, Nancy; Malle, Elisabeth; Stumpf, Andreas; Gebhardt, Boris R; Koehl, Ulrike; Schraven, Burkhart; Zielen, Stefan

2006-09-01

We present the clinical and laboratory features of a boy with a new syndrome of mitochondrial depletion syndrome and T cell immunodeficiency. The child suffered from severe recurrent infectious diseases, anemia, and thrombocytopenia. Clinically, he presented with severe psychomotor retardation, axial hypotonia, and a disturbed pain perception leading to debilitating biting of the thumb, lower lip, and tongue. Brain imaging showed hypoplasia of corpus callosum and an impaired myelinization of the temporo-occipital region with consecutive supratentorial hydrocephalus. Histologic examination of a skeletal muscle biopsy was normal. Biochemical investigation showed combined deficiency of respiratory chain complexes II+III and IV. MtDNA depletion was found by real-time PCR. No pathogenic mutations were identified in the TK2, SUCLA2, DGUOK, and ECGF1 genes. A heterozygous missense mutation was found in POLG1. The pathogenic relevance of this mutation is unclear. Interestingly, a lack of CD8(+) T lymphocytes as well as NK cells was also observed. The percentage of CD45RO-expressing cells was decreased in activated CD8(+) T lymphocytes. Activation of T lymphocytes via IL-2 was diminished. The occurrence of the immunologic deficiency in our patient with mtDNA depletion is a rare finding, implying that cells of the immune system might also be affected by mitochondrial disease.

Direct Detection of T- and B-Memory Lymphocytes by ImmunoSpot® Assays Reveals HCMV Exposure that Serum Antibodies Fail to Identify.

PubMed

Terlutter, Fredrik; Caspell, Richard; Nowacki, Tobias M; Lehmann, Alexander; Li, Ruliang; Zhang, Ting; Przybyla, Anna; Kuerten, Stefanie; Lehmann, Paul V

2018-05-19

It is essential to identify donors who have not been infected with human cytomegalovirus (HCMV) in order to avoid transmission of HCMV to recipients of blood transfusions or organ transplants. In the present study, we tested the reliability of seronegativity as an indicator for the lack of HCMV exposure in healthy human blood donors. Eighty-two HCMV seronegative individuals were identified, and their peripheral blood mononuclear cells (PBMC) were tested in ImmunoSpot® assays for the presence of HCMV-specific T- and B-memory lymphocytes. Eighty-two percent (67 of 82) of these HCMV seronegative individuals featured at least one memory cell that was lineage specific for HCMV, with the majority of these subjects possessing CD4+ and CD8+ T cells, as well as B cells, providing three independent lines of evidence for having developed immunity to HCMV. Only 15 of these 82 donors (18%) showed neither T- nor B-cell memory to HCMV, consistent with immunological naïveté to the virus. The data suggest that measurements of serum antibodies frequently fail to reveal HCMV exposure in humans, which may be better identified by direct detection of HCMV-specific memory lymphocytes.

Immunology: Is Actin at the Lytic Synapse a Friend or a Foe?

PubMed

Hammer, John A

2018-02-19

Cytotoxic T cells and natural killer cells defend us against disease by secreting lytic granules. Whether actin facilitates or thwarts lytic granule secretion has been an open question. Recent results now indicate that the answer depends on the maturation stage of the immune cell-target cell contact. Published by Elsevier Ltd.