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Sample records for genes immune surveillance

  1. Differential association of STK11 and TP53 with KRAS mutation-associated gene expression, proliferation and immune surveillance in lung adenocarcinoma.

    PubMed

    Schabath, M B; Welsh, E A; Fulp, W J; Chen, L; Teer, J K; Thompson, Z J; Engel, B E; Xie, M; Berglund, A E; Creelan, B C; Antonia, S J; Gray, J E; Eschrich, S A; Chen, D-T; Cress, W D; Haura, E B; Beg, A A

    2016-06-16

    While mutations in the KRAS oncogene are among the most prevalent in human cancer, there are few successful treatments to target these tumors. It is also likely that heterogeneity in KRAS-mutant tumor biology significantly contributes to the response to therapy. We hypothesized that the presence of commonly co-occurring mutations in STK11 and TP53 tumor suppressors may represent a significant source of heterogeneity in KRAS-mutant tumors. To address this, we utilized a large cohort of resected tumors from 442 lung adenocarcinoma patients with data including annotation of prevalent driver mutations (KRAS and EGFR) and tumor suppressor mutations (STK11 and TP53), microarray-based gene expression and clinical covariates, including overall survival (OS). Specifically, we determined impact of STK11 and TP53 mutations on a new KRAS mutation-associated gene expression signature as well as previously defined signatures of tumor cell proliferation and immune surveillance responses. Interestingly, STK11, but not TP53 mutations, were associated with highly elevated expression of KRAS mutation-associated genes. Mutations in TP53 and STK11 also impacted tumor biology regardless of KRAS status, with TP53 strongly associated with enhanced proliferation and STK11 with suppression of immune surveillance. These findings illustrate the remarkably distinct ways through which tumor suppressor mutations may contribute to heterogeneity in KRAS-mutant tumor biology. In addition, these studies point to novel associations between gene mutations and immune surveillance that could impact the response to immunotherapy. PMID:26477306

  2. Immune surveillance for ERAAP dysfunction.

    PubMed

    Nagarajan, Niranjana A; Shastri, Nilabh

    2013-09-01

    The ER aminopeptidase associated with antigen processing, ERAAP (or ERAP1), is essential for trimming peptides that are presented by MHC class I molecules. ERAP1 is inhibited by human cytomegalovirus, and ERAP1 polymorphisms are associated with autoimmune diseases. How the immune system detects ERAAP dysfunction, however, is unknown. We have shown previously that ERAAP-deficient cells present an immunogenic pMHC I repertoire, that elicits CD8+ T cell response in WT mice. Additionally, we discovered that the WT CD8+ T cells recognized novel peptides presented by non-classical, or MHC class Ib, molecules on ERAAP-deficient cells. The MHC Ib restricted WT CD8 T cells eliminated ERAAP-deficient cells in vitro and in vivo. We identified the FL9 peptide, presented by Qa-1(b), a MHC class Ib molecule exclusively on ERAAP-deficient cells. Remarkably, T cells specific for the FL9-Qa-1(b) complex were frequent in naïve WT mice, and had an antigen-experienced phenotype. Thus, novel non-classical pQa-1(b) complexes direct cytotoxic T cells to target cells with defective peptide processing in the endoplasmic reticulum. Here, we discuss the implications of our findings, and the possible roles of pMHC Ib-specific T cells in immune surveillance for ERAAP dysfunction. PMID:23433779

  3. Tumor-Associated Glycans and Immune Surveillance

    PubMed Central

    Monzavi-Karbassi, Behjatolah; Pashov, Anastas; Kieber-Emmons, Thomas

    2013-01-01

    Changes in cell surface glycosylation are a hallmark of the transition from normal to inflamed and neoplastic tissue. Tumor-associated carbohydrate antigens (TACAs) challenge our understanding of immune tolerance, while functioning as immune targets that bridge innate immune surveillance and adaptive antitumor immunity in clinical applications. T-cells, being a part of the adaptive immune response, are the most popular component of the immune system considered for targeting tumor cells. However, for TACAs, T-cells take a back seat to antibodies and natural killer cells as first-line innate defense mechanisms. Here, we briefly highlight the rationale associated with the relative importance of the immune surveillance machinery that might be applicable for developing therapeutics. PMID:26343966

  4. Mathematical model of tumor-immune surveillance.

    PubMed

    Mahasa, Khaphetsi Joseph; Ouifki, Rachid; Eladdadi, Amina; Pillis, Lisette de

    2016-09-01

    We present a novel mathematical model involving various immune cell populations and tumor cell populations. The model describes how tumor cells evolve and survive the brief encounter with the immune system mediated by natural killer (NK) cells and the activated CD8(+) cytotoxic T lymphocytes (CTLs). The model is composed of ordinary differential equations describing the interactions between these important immune lymphocytes and various tumor cell populations. Based on up-to-date knowledge of immune evasion and rational considerations, the model is designed to illustrate how tumors evade both arms of host immunity (i.e. innate and adaptive immunity). The model predicts that (a) an influx of an external source of NK cells might play a crucial role in enhancing NK-cell immune surveillance; (b) the host immune system alone is not fully effective against progression of tumor cells; (c) the development of immunoresistance by tumor cells is inevitable in tumor immune surveillance. Our model also supports the importance of infiltrating NK cells in tumor immune surveillance, which can be enhanced by NK cell-based immunotherapeutic approaches. PMID:27317864

  5. Cytokines and immune surveillance in humans

    NASA Technical Reports Server (NTRS)

    Sonnenfeld, Gerald

    1993-01-01

    Evidence from both human and rodent studies has indicated that alterations in immunological parameters occur after space flight. Among the parameters shown, by us and others, to be affected is the production of interferons. Interferons are a family of cytokines that are antiviral and play a major role in regulating immune responses that control resistance to infection. Alterations in interferon and other cytokine production and activity could result in changes in immunity and a possible compromise of host defenses against both opportunistic and external infections. The purpose of the present study is to further explore the effects of space flight on cytokines and cytokine-directed immunological function.

  6. Deubiquitinases: Novel Therapeutic Targets in Immune Surveillance?

    PubMed Central

    2016-01-01

    Inflammation is a protective response of the organism to tissue injury or infection. It occurs when the immune system recognizes Pathogen-Associated Molecular Patterns (PAMPs) or Damage-Associated Molecular Pattern (DAMPs) through the activation of Pattern Recognition Receptors. This initiates a variety of signalling events that conclude in the upregulation of proinflammatory molecules, which initiate an appropriate immune response. This response is tightly regulated since any aberrant activation of immune responses would have severe pathological consequences such as sepsis or chronic inflammatory and autoimmune diseases. Accumulative evidence shows that the ubiquitin system, and in particular ubiquitin-specific isopeptidases also known as deubiquitinases (DUBs), plays crucial roles in the control of these immune pathways. In this review we will give an up-to-date overview on the role of DUBs in the NF-κB pathway and inflammasome activation, two intrinsically related events triggered by activation of the membrane TLRs as well as the cytosolic NOD and NLR receptors. Modulation of DUB activity by small molecules has been proposed as a way to control dysregulation or overactivation of these key players of the inflammatory response. We will also discuss the advances and challenges of a potential use of DUBs as therapeutic targets in inflammatory pathologies. PMID:27597804

  7. Cytokines and immune surveillance in humans

    NASA Technical Reports Server (NTRS)

    Sonnenfeld, Gerald

    1994-01-01

    Evidence from both human and rodent studies has indicated that alterations in immunological parameters occur after space flight. Among the parameters shown, by us and others, to be affected is the production of interferons. Interferons are a family of cytokines that are antiviral and play a major role in regulating immune responses that control resistance to infection. Alterations in interferon and other cytokine production and activity could result in changes in immunity and a possible compromise of host defenses against both opportunistic and external infections. The purpose of the present study is to explore further the effects of space flight on cyotokines and cytokine-directed immunological function. Among the tests carried out are interferon-alpha production, interferon-gamma production, interleukin-1 and -2 production, signal transduction in neutrophils, signal transduction in monocytes, and monocyte phagocytic activity. The experiments will be performed using peripheral blood obtained from human subjects. It is our intent to eventually carry out these experiments using astronauts as subjects to determine the effects of space flight on cytokine production and activity. However, these subjects are not currently available. Until they become available, we will carry out these experiments using subjects maintained in the bed-rest model for microgravity.

  8. Complement - a key system for immune surveillance and homeostasis

    PubMed Central

    Ricklin, Daniel; Hajishengallis, George; Yang, Kun; Lambris, John D.

    2010-01-01

    Nearly a century after the significance of the human complement system was recognized we have come to realize that its versatile functions extend far beyond the elimination of microbes. Indeed, complement acts as a rapid and efficient immune surveillance system that has distinct effects on healthy and altered host cells and foreign intruders. By eliminating cellular debris and infectious microbes, orchestrating immune responses, and sending `danger' signals, complement contributes substantially to homeostasis, but it may also take action against healthy cells if not properly controlled. This review describes our updated view of the function, structure, and dynamics of the complement network, highlights its interconnection with immunity at large and with other endogenous pathways, and illustrates its dual role in homeostasis and disease. PMID:20720586

  9. Immune-surveillance through exhausted effector T-cells.

    PubMed

    Zehn, Dietmar; Utzschneider, Daniel T; Thimme, Robert

    2016-02-01

    Pathogens such as the human immunodeficiency virus (HIV), the hepatitis B and C virus (HBV, HCV) and certain strains of the rodent lymphocytic choriomeningitis virus (LCMV) establish a state of persisting viral replication. This occurs besides strong adoptive immune responses and the induction of large numbers of activated pathogen-specific T-cells. The failure of the immune system to clear these viruses is typically attributed to a loss of effector T-cell function-a phenomenon referred to as T-cell exhaustion. Though largely accepted, this loss of function concept is being more and more challenged by comprehensive clinical and experimental observations which highlight that T-cells in chronic infections are more functional than previously considered. Here, we highlight examples that demonstrate that such T-cells mediate a profound form of immune-surveillance. We also briefly discuss the opportunities and limitations of employing 'exhausted' T-cells for therapeutic purposes. PMID:26826950

  10. Cancer-Associated Immune Resistance and Evasion of Immune Surveillance in Colorectal Cancer.

    PubMed

    Parcesepe, Pietro; Giordano, Guido; Laudanna, Carmelo; Febbraro, Antonio; Pancione, Massimo

    2016-01-01

    Data from molecular profiles of tumors and tumor associated cells provide a model in which cancer cells can acquire the capability of avoiding immune surveillance by expressing an immune-like phenotype. Recent works reveal that expression of immune antigens (PDL1, CD47, CD73, CD14, CD68, MAC387, CD163, DAP12, and CD15) by tumor cells "immune resistance," combined with prometastatic function of nonmalignant infiltrating cells, may represent a strategy to overcome the rate-limiting steps of metastatic cascade through (a) enhanced interactions with protumorigenic myeloid cells and escape from T-dependent immune response mediated by CD8+ and natural killer (NK) cells; (b) production of immune mediators that establish a local and systemic tumor-supportive environment (premetastatic niche); (c) ability to survive either in the peripheral blood as circulating tumor cells (CTCs) or at the metastatic site forming a cooperative prometastatic loop with foreign "myeloid" cells, macrophages, and neutrophils, respectively. The development of cancer-specific "immune resistance" can be orchestrated either by cooperation with tumor microenvironment or by successive rounds of genetic/epigenetic changes. Recognition of the applicability of this model may provide effective therapeutic avenues for complete elimination of immune-resistant metastatic cells and for enhanced antitumor immunity as part of a combinatorial strategy. PMID:27006653

  11. Cancer-Associated Immune Resistance and Evasion of Immune Surveillance in Colorectal Cancer

    PubMed Central

    Laudanna, Carmelo; Febbraro, Antonio

    2016-01-01

    Data from molecular profiles of tumors and tumor associated cells provide a model in which cancer cells can acquire the capability of avoiding immune surveillance by expressing an immune-like phenotype. Recent works reveal that expression of immune antigens (PDL1, CD47, CD73, CD14, CD68, MAC387, CD163, DAP12, and CD15) by tumor cells “immune resistance,” combined with prometastatic function of nonmalignant infiltrating cells, may represent a strategy to overcome the rate-limiting steps of metastatic cascade through (a) enhanced interactions with protumorigenic myeloid cells and escape from T-dependent immune response mediated by CD8+ and natural killer (NK) cells; (b) production of immune mediators that establish a local and systemic tumor-supportive environment (premetastatic niche); (c) ability to survive either in the peripheral blood as circulating tumor cells (CTCs) or at the metastatic site forming a cooperative prometastatic loop with foreign “myeloid” cells, macrophages, and neutrophils, respectively. The development of cancer-specific “immune resistance” can be orchestrated either by cooperation with tumor microenvironment or by successive rounds of genetic/epigenetic changes. Recognition of the applicability of this model may provide effective therapeutic avenues for complete elimination of immune-resistant metastatic cells and for enhanced antitumor immunity as part of a combinatorial strategy. PMID:27006653

  12. Escaping immune surveillance in cancer: is denbinobin the panacea?

    PubMed Central

    Magwere, Tapiwanashe

    2009-01-01

    The bane of anti-cancer therapy is usually the development of resistance to apoptosis in malignant cells. Identification of strategies to re-sensitize cancer cells to apoptosis has now become a top priority in anti-cancer research. Denbinobin is a novel, naturally occurring phenathroquinone isolated from orchids of the genus Dendrobium that has remarkable anti-cancer activities demonstrated both in vitro and in vivo. Recently denbinobin has been shown to diminish the levels of expression of the decoy receptor-3 and also to act synergistically with Fas ligand to induce apoptosis in a pancreatic adenocarcinoma cell line. There is hope that denbinobin could be developed as an adjuvant in combination therapies aimed at killing cancers that rely on decoy receptors to evade the host's immune surveillance. PMID:19664137

  13. Myeloid PTEN deficiency impairs tumor-immune surveillance via immune-checkpoint inhibition.

    PubMed

    Kuttke, M; Sahin, E; Pisoni, J; Percig, S; Vogel, A; Kraemmer, D; Hanzl, L; Brunner, J S; Paar, H; Soukup, K; Halfmann, A; Dohnal, A M; Steiner, C W; Blüml, S; Basilio, J; Hochreiter, B; Salzmann, M; Hoesel, B; Lametschwandtner, G; Eferl, R; Schmid, J A; Schabbauer, G

    2016-07-01

    Tumor-host interaction is determined by constant immune surveillance, characterized by tumor infiltration of myeloid and lymphoid cells. A malfunctioning or diverted immune response promotes tumor growth and metastasis. Recent advances had been made, by treating of certain tumor types, such as melanoma, with T-cell checkpoint inhibitors. This highlights the importance of understanding the molecular mechanisms underlying the crosstalk between tumors and their environment, in particular myeloid and lymphoid cells. Our aim was to study the contribution of the myeloid PI3K/PTEN-signaling pathway in the regulation of tumor-immune surveillance in murine models of cancer. We made use of conditional PTEN-deficient mice, which exhibit sustained activation of the PI3K-signaling axis in a variety of myeloid cell subsets such as macrophages and dendritic cells (DCs). In colitis-associated colon cancer (CAC), mice deficient in myeloid PTEN showed a markedly higher tumor burden and decreased survival. We attributed this observation to the increased presence of immune-modulatory conventional CD8α(+) DCs in the spleen, whereas other relevant myeloid cell subsets were largely unaffected. Notably, we detected enhanced surface expression of PD-L1 and PD-L2 on these DCs. As a consequence, tumoricidal T-cell responses were hampered or redirected. Taken together, our findings indicated an unanticipated role for the PI3K/PTEN-signaling axis in the functional regulation of splenic antigen-presenting cells (APCs). Our data pointed at potential, indirect, tumoricidal effects of subclass-specific PI3K inhibitors, which are currently under clinical investigation for treatment of tumors, via myeloid cell activation. PMID:27622019

  14. Myeloid PTEN deficiency impairs tumor-immune surveillance via immune-checkpoint inhibition

    PubMed Central

    Kuttke, M.; Sahin, E.; Pisoni, J.; Percig, S.; Vogel, A.; Kraemmer, D.; Hanzl, L.; Brunner, J. S.; Paar, H.; Soukup, K.; Halfmann, A.; Dohnal, A. M.; Steiner, C. W.; Blüml, S.; Basilio, J.; Hochreiter, B.; Salzmann, M.; Hoesel, B.; Lametschwandtner, G.; Eferl, R.; Schmid, J. A.; Schabbauer, G.

    2016-01-01

    ABSTRACT Tumor–host interaction is determined by constant immune surveillance, characterized by tumor infiltration of myeloid and lymphoid cells. A malfunctioning or diverted immune response promotes tumor growth and metastasis. Recent advances had been made, by treating of certain tumor types, such as melanoma, with T-cell checkpoint inhibitors. This highlights the importance of understanding the molecular mechanisms underlying the crosstalk between tumors and their environment, in particular myeloid and lymphoid cells. Our aim was to study the contribution of the myeloid PI3K/PTEN-signaling pathway in the regulation of tumor-immune surveillance in murine models of cancer. We made use of conditional PTEN-deficient mice, which exhibit sustained activation of the PI3K-signaling axis in a variety of myeloid cell subsets such as macrophages and dendritic cells (DCs). In colitis-associated colon cancer (CAC), mice deficient in myeloid PTEN showed a markedly higher tumor burden and decreased survival. We attributed this observation to the increased presence of immune-modulatory conventional CD8α+ DCs in the spleen, whereas other relevant myeloid cell subsets were largely unaffected. Notably, we detected enhanced surface expression of PD-L1 and PD-L2 on these DCs. As a consequence, tumoricidal T-cell responses were hampered or redirected. Taken together, our findings indicated an unanticipated role for the PI3K/PTEN-signaling axis in the functional regulation of splenic antigen-presenting cells (APCs). Our data pointed at potential, indirect, tumoricidal effects of subclass-specific PI3K inhibitors, which are currently under clinical investigation for treatment of tumors, via myeloid cell activation. PMID:27622019

  15. A global survey of adverse event following immunization surveillance systems for pregnant women and their infants

    PubMed Central

    Cassidy, Christine; MacDonald, Noni E.; Steenbeek, Audrey; Ortiz, Justin R.; Zuber, Patrick L. F.; Top, Karina A.

    2016-01-01

    ABSTRACT Strengthening antenatal care as a platform for maternal immunization is a priority of the World Health Organization (WHO). Systematic surveillance for adverse events following immunization (AEFI) in pregnancy is needed to identify vaccine safety events. We sought to identify active and passive AEFI surveillance systems for pregnant women and infants. Representatives from all National Pharmacovigilance Centers and a convenience sample of vaccine safety experts were invited to complete a 14-item online survey in English, French or Spanish. The survey captured maternal immunization policies, and active and passive AEFI surveillance systems for pregnant women and infants in respondents' countries. The analysis was descriptive. We received responses from 51/185 (28%) invited persons from 47/148 (32%) countries representing all WHO regions, and low, middle and high-income countries. Thirty countries had national immunization policies targeting pregnant women. Eleven countries had active surveillance systems to detect serious AEFI in pregnant women and/or their infants, including six low and middle-income countries (LMIC). Thirty-nine countries had passive surveillance systems, including 23 LMIC. These active and passive surveillance programs cover approximately 8% and 56% of the worldwide annual birth cohort, respectively. Data from one active and four passive systems have been published. We identified 50 active and passive AEFI surveillance systems for pregnant women and infants, but few have published their findings. AEFI surveillance appears to be feasible in low and high resource settings. Further expansion of AEFI surveillance for pregnant women and sharing of vaccine safety information will provide additional evidence in support of maternal immunization policies. PMID:27159639

  16. Immunity-related genes and gene families in Anopheles gambiae.

    PubMed

    Christophides, George K; Zdobnov, Evgeny; Barillas-Mury, Carolina; Birney, Ewan; Blandin, Stephanie; Blass, Claudia; Brey, Paul T; Collins, Frank H; Danielli, Alberto; Dimopoulos, George; Hetru, Charles; Hoa, Ngo T; Hoffmann, Jules A; Kanzok, Stefan M; Letunic, Ivica; Levashina, Elena A; Loukeris, Thanasis G; Lycett, Gareth; Meister, Stephan; Michel, Kristin; Moita, Luis F; Müller, Hans-Michael; Osta, Mike A; Paskewitz, Susan M; Reichhart, Jean-Marc; Rzhetsky, Andrey; Troxler, Laurent; Vernick, Kenneth D; Vlachou, Dina; Volz, Jennifer; von Mering, Christian; Xu, Jiannong; Zheng, Liangbiao; Bork, Peer; Kafatos, Fotis C

    2002-10-01

    We have identified 242 Anopheles gambiae genes from 18 gene families implicated in innate immunity and have detected marked diversification relative to Drosophila melanogaster. Immune-related gene families involved in recognition, signal modulation, and effector systems show a marked deficit of orthologs and excessive gene expansions, possibly reflecting selection pressures from different pathogens encountered in these insects' very different life-styles. In contrast, the multifunctional Toll signal transduction pathway is substantially conserved, presumably because of counterselection for developmental stability. Representative expression profiles confirm that sequence diversification is accompanied by specific responses to different immune challenges. Alternative RNA splicing may also contribute to expansion of the immune repertoire. PMID:12364793

  17. Targeting Galectin-1 in pancreatic cancer: immune surveillance on guard

    PubMed Central

    Martínez-Bosch, Neus; Navarro, Pilar

    2014-01-01

    The tumor microenviroment and immune barrier are known to modulate malignant disease progression. We have recently identified Galectin-1 as a key player in a novel stromal regulatory reaction driving immune evasion in pancreatic tumors in vivo. These results suggest that Galectin-1 inhibition represents a potential therapeutic strategy for one of the most deadly types of cancer. PMID:25610742

  18. Beneficial Autoimmunity at Body Surfaces – Immune Surveillance and Rapid Type 2 Immunity Regulate Tissue Homeostasis and Cancer

    PubMed Central

    Dalessandri, Tim; Strid, Jessica

    2014-01-01

    Epithelial cells (ECs) line body surface tissues and provide a physicochemical barrier to the external environment. Frequent microbial and non-microbial challenges such as those imposed by mechanical disruption, injury or exposure to noxious environmental substances including chemicals, carcinogens, ultraviolet-irradiation, or toxins cause activation of ECs with release of cytokines and chemokines as well as alterations in the expression of cell-surface ligands. Such display of epithelial stress is rapidly sensed by tissue-resident immunocytes, which can directly interact with self-moieties on ECs and initiate both local and systemic immune responses. ECs are thus key drivers of immune surveillance at body surface tissues. However, ECs have a propensity to drive type 2 immunity (rather than type 1) upon non-invasive challenge or stress – a type of immunity whose regulation and function still remain enigmatic. Here, we review the induction and possible role of type 2 immunity in epithelial tissues and propose that rapid immune surveillance and type 2 immunity are key regulators of tissue homeostasis and carcinogenesis. PMID:25101088

  19. The C. elegans CCAAT-enhancer binding protein gamma is required for surveillance immunity

    PubMed Central

    Reddy, Kirthi C.; Dunbar, Tiffany L.; Nargund, Amrita M.; Haynes, Cole M.; Troemel, Emily R.

    2016-01-01

    Pathogens attack host cells by deploying toxins that perturb core host processes. Recent findings from the nematode C. elegans and other metazoans indicate that surveillance or ‘effector-triggered’ pathways monitor functioning of these core processes and mount protective responses when they are perturbed. Despite a growing number of examples of surveillance immunity, the signaling components remain poorly defined. Here we show that CEBP-2, the C. elegans ortholog of mammalian CCAAT-enhancer binding protein gamma, is a key player in surveillance immunity. We show that CEBP-2 acts together with the bZIP transcription factor ZIP-2 in the protective response to translational block by P. aeruginosa Exotoxin A, as well as to perturbations of other processes. CEBP-2 serves to limit pathogen burden, promote survival upon P. aeruginosa infection, and also promote survival upon Exotoxin A exposure. These findings may have broad implications for the mechanisms by which animals sense pathogenic attack and mount protective responses. PMID:26876169

  20. Immune surveillance and immunotherapy: lessons from carbohydrate mimotopes.

    PubMed

    Pashov, Anastas; Monzavi-Karbassi, Behjatolah; Kieber-Emmons, Thomas

    2009-05-26

    The immune system plays an intricate role in tumorigenesis, therefore cancer immunotherapy borrows concepts both from autoimmunity and vaccinology. Due to tumor-induced immune suppression, the adjuvant setting seems most suitable for immunotherapy, which optimally targets multiple tumor associated antigens after removal of the bulk of the tumor. The responses elicited need not match the intensity of those against pathogens. Retrospective studies suggest that cancer patients' survival correlates with low-titer anti-tumor IgM antibodies. Carbohydrate mimetic peptides (CMPs) prove instrumental as immunogens by boosting similar persistent IgM anti-tumor responses, engaging the innate/adaptive immunity interface and promoting cytotoxic responses and epitope spreading. PMID:19200843

  1. Inflammatory networks and immune surveillance of pancreatic carcinoma

    PubMed Central

    Vonderheide, Robert H.; Bayne, Lauren J.

    2013-01-01

    Cancer-associated inflammation plays an important role in restraining anti-tumor immunity, particularly in pancreatic ductal adenocarcinoma (PDA) for which a massive infiltration of immunosuppressive leukocytes into the tumor stroma is an early and consistent event in oncogenesis. This pathophysiology is in contrast to many other solid tumors for which infiltration of effector T cells is often prominent, associated with improved clinical outcomes, and mechanistically contributes to tumor immunoediting that ultimately can mediate immune escape. In PDA, increasing evidence suggests that the ras oncogene drives an inflammatory program that establishes immune privilege in the tumor microenvironment. Indeed, PDA cells might remain intrinsically sensitive to T cell killing because they have never been exposed to T cell selective pressure in vivo. In support of this hypothesis, recent studies demonstrate that derailing immune suppressive pathways in the PDA microenvironment, such as tumor derived GM-CSF, facilitates T-cell mediated tumor rejection. These findings carry major implications for the development of novel, combination immunotherapies for pancreatic cancer. PMID:23422836

  2. Immune surveillance and response to JC virus infection and PML

    PubMed Central

    Beltrami, Sarah; Gordon, Jennifer

    2014-01-01

    The ubiquitous human polyomavirus JC virus (JCV) is the established etiological agent of the debilitating and often fatal demyelinating disease, progressive multifocal leukoencephalopathy (PML). Most healthy individuals have been infected with JCV and generate an immune response to the virus, yet remain persistently infected at subclinical levels. The onset of PML is rare in the general population, but has become an increasing concern in immunocompromised patients, where reactivation of JCV leads to uncontrolled replication in the CNS. Understanding viral persistence and the normal immune response to JCV provides insight into the circumstances which could lead to viral resurgence. Further, clues on the potential mechanisms of reactivation may be gleaned from the crosstalk among JCV and HIV-1, as well as the impact of monoclonal antibody therapies used for the treatment of autoimmune disorders, including multiple sclerosis, on the development of PML. In this review, we will discuss what is known about viral persistence and the immune response to JCV replication in immunocompromised individuals to elucidate the deficiencies in viral containment that permit viral reactivation and spread. PMID:24297501

  3. Japanese encephalitis surveillance and immunization--Asia and the Western Pacific, 2012.

    PubMed

    2013-08-23

    Japanese encephalitis (JE) virus is a leading cause of encephalitis in Asia, causing an estimated 67,900 JE cases annually. To control JE, the World Health Organization (WHO) recommends that JE vaccine be incorporated into immunization programs in all areas where JE is a public health problem. For many decades, progress mainly occurred in a small number of high-income Asian countries. Recently, prospects for control have improved with better disease burden awareness as a result of increased JE surveillance and wider availability of safe, effective vaccines. This report summarizes the status of JE surveillance and immunization programs in 2012 in Asia and the Western Pacific. Data were obtained from the WHO/United Nations Children's Fund (UNICEF) Joint Reporting Form (JRF), published literature, meeting reports, and websites. In 2012, 18 (75%) of the 24 countries with areas of JE virus transmission risk conducted at least some JE surveillance, and 11 (46%) had a JE immunization program. Further progress toward JE control requires increased awareness of disease burden at the national and regional levels, availability of WHO-prequalified pediatric JE vaccines, and international support for surveillance and vaccine introduction in countries with limited resources. PMID:23965828

  4. Hematological Malignancies Escape from NK Cell Innate Immune Surveillance: Mechanisms and Therapeutic Implications

    PubMed Central

    Farnault, Laure; Sanchez, Carole; Baier, Céline; Le Treut, Thérèse; Costello, Régis T.

    2012-01-01

    Hematological malignancies treatment improved over the last years resulting in increased achievement of complete or partial remission, but unfortunately high relapse rates are still observed. Therefore, sustainment of long-term remission is crucial. Immune system has a key role in tumor surveillance. Natural killer (NK) cells, at the frontier of innate and adaptive immune system, have a central role in tumor cells surveillance as demonstrated in the setting of allogenic stem cell transplantation. Nevertheless, tumor cells develop various mechanisms to escape from NK cells innate immune pressure. Abnormal NK cytolytic functions have been described in nearly all hematological malignancies. We present here various mechanisms involved in the escape of hematological malignancies from NK cells surveillance: NK cells quantitative deficiency and NK cell qualitative deficiency by increased inhibition signaling or decreased activating stimuli. A challenge of immunotherapy is to restore an efficient antitumor response. A combination of classical therapy plus immune modulation strategies will soon become a standard of care for hematological malignancies. PMID:22899948

  5. The innate immune response in the central nervous system and its role in glioma immune surveillance.

    PubMed

    Friese, M A; Steinle, A; Weller, M

    2004-10-01

    The innate immune system encompasses natural killer (NK) cells, macrophages and granulocytes, the complement system and antimicrobial peptides. Recognition pathways of the innate immune system include microbial non-self recognition, missing-self recognition and induced- self recognition. The central nervous system (CNS) participates in responses of the innate immune system. However, immune inhibitory and anti-inflammatory mechanisms physiologically outbalance and counteract immune activity and thereby limit immune-mediated tissue damage in the brain. Human gliomas appear to take advantage of this immunosuppressive milieu. Moreover, glioma cells themselves interfere with anti-tumor immune responses by expressing immune inhibitory cell surface molecules, such as HLA-G, or by releasing soluble immunosuppressants such as transforming growth factor (TGF)-beta. Yet, although glioma cells exhibit all cellular features of malignancy, these tumors very rarely metastasize outside the brain, raising the possibility of immune-mediated control of these cells outside, but not inside, the brain. Accordingly, activating the innate immune system by forcing glioma cells to express danger signals such as NKG2D ligands is a promising strategy of immunotherapy for these tumors. PMID:15585981

  6. Immune surveillance of the central nervous system in multiple sclerosis– Relevance for therapy and experimental models

    PubMed Central

    Hussain, Rehana Z.; Hayardeny, Liat; Cravens, Petra C.; Yarovinsky, Felix; Eagar, Todd N.; Arellano, Benjamine; Deason, Krystin; Castro-Rojas, Cyd; Stüve, Olaf

    2015-01-01

    Treatment of central nervous system (CNS) autoimmune disorders frequently involves the reduction, or depletion of immune-competent cells. Alternatively, immune cells are being sequestered away from the target organ by interfering with their movement from secondary lymphoid organs, or their migration into tissues. These therapeutic strategies have been successful in multiple sclerosis (MS), the most prevalent autoimmune inflammatory disorder of the CNS. However, many of the agents that are currently approved or in clinical development also have severe potential adverse effects that stem from the very mechanisms that mediate their beneficial effects by interfering with CNS immune surveillance. This review will outline the main cellular components of the innate and adaptive immune system that participate in host defense and maintain immune surveillance of the CNS. Their pathogenic role in MS and its animal model experimental autoimmune encephalomyelitis (EAE) is also discussed. Furthermore, an experimental model is introduced that may assist in evaluating the effect of therapeutic interventions on leukocyte homeostasis and function within the CNS. This model or similar models may become a useful tool in the repertoire of pre-clinical tests of pharmacological agents to better explore their potential for adverse events. PMID:25282087

  7. Immune surveillance of mammary tissue by phagocytic cells.

    PubMed

    Paape, M J; Shafer-Weaver, K; Capuco, A V; Van Oostveldt, K; Burvenich, C

    2000-01-01

    The leukocytes in milk consist of lymphocytes, neutrophil polymorphonuclear leukocytes (PMN) and macrophages. Lymphocytes together with antigen-presenting cells function in the generation of an effective immune response. Lymphocytes can be divided into two distinct subsets, T- and B-lymphocytes, that differ in function and protein products. The professional phagocytic cells of the bovine mammary gland are PMN and macrophages. In the normal mammary gland macrophages are the predominate cells which act as sentinels to invading mastitis causing pathogens. Once the invaders are detected, macrophages release chemical messengers called chemoattractants that cause the directed migration of PMN into the infection. Migration of neutrophils into mammary tissue provides the first immunological line of defense against bacteria that penetrate the physical barrier of the teat canal. However, their presence is like a double-edged sword. While the PMN are phagocytosing and destroying the invading pathogens, they inadvertently release chemicals which induces swelling of secretory epithelium cytoplasm, sloughing of secretory cells, and decreased secretory activity. Permanent scarring will result in a loss of milk production. Resident and newly migrated macrophages help reduce the damage to the epithelium by phagocytosing PMN that undergo programmed cell death through a process called apoptosis. Specific ligands on the neutrophil surface are required for directed migration and phagocytosis. In response to infection, freshly migrated leukocytes express greater numbers of cell surface receptors for immunoglobulins and complement and are more phagocytic than their counterparts in blood. However, phagocytic activity rapidly decreases with continued exposure to inhibitory factors such as milk fat globules and casein in mammary secretions. Compensatory hypertrophy in non-mastitic quarters partially compensates for lost milk production in diseased quarters. Advances in molecular biology are

  8. Researchers Find 8 Immune Genes in Aggressive Brain Cancer

    MedlinePlus

    ... news/fullstory_159031.html Researchers Find 8 Immune Genes in Aggressive Brain Cancer Discovery might eventually lead ... 25, 2016 (HealthDay News) -- Researchers have identified immune genes that may affect how long people live after ...

  9. Immune Surveillance Against a Solid Tumor Fails because of Immunological Ignorance

    NASA Astrophysics Data System (ADS)

    Ochsenbein, Adrian F.; Klenerman, Paul; Karrer, Urs; Ludewig, Burkhard; Pericin, Marcus; Hengartner, Hans; Zinkernagel, Rolf M.

    1999-03-01

    Many peripheral solid tumors such as sarcomas and carcinomas express tumor-specific antigens that can serve as targets for immune effector T cells. Nevertheless, overall immune surveillance against such tumors seems relatively inefficient. We studied immune surveillance against a s.c. sarcoma expressing a characterized viral tumor antigen. Surprisingly, the tumor cells were capable of inducing a protective cytotoxic T cell response if transferred as a single-cell suspension. However, if they were transplanted as small tumor pieces, tumors readily grew. Tumor growth correlated strictly with (i) failure of tumor cells to reach the draining lymph nodes and (ii) absence of primed cytotoxic T cells. Cytotoxic T cells were not tolerant or deleted because a tumor antigen-specific cytotoxic T cell response was readily induced in lymphoid tissue by immunization with virus or with tumor cells even in the presence of large tumors. Established tumors were rejected by vaccine-induced effector T cells if effector T cells were maintained by prolonged or repetitive vaccination, but not by single-dose vaccination. Thus, in addition to several other tumor-promoting parameters, some antigenic peripheral sarcomas--and probably carcinomas--may grow not because they anergize or tolerize tumor-specific T cells, but because such tumors are immunologically dealt with as if they were in a so-called immunologically privileged site and are ignored for too long.

  10. Immune responses in multiple myeloma: role of the natural immune surveillance and potential of immunotherapies.

    PubMed

    Guillerey, Camille; Nakamura, Kyohei; Vuckovic, Slavica; Hill, Geoffrey R; Smyth, Mark J

    2016-04-01

    Multiple myeloma (MM) is a tumor of terminally differentiated B cells that arises in the bone marrow. Immune interactions appear as key determinants of MM progression. While myeloid cells foster myeloma-promoting inflammation, Natural Killer cells and T lymphocytes mediate protective anti-myeloma responses. The profound immune deregulation occurring in MM patients may be involved in the transition from a premalignant to a malignant stage of the disease. In the last decades, the advent of stem cell transplantation and new therapeutic agents including proteasome inhibitors and immunoregulatory drugs has dramatically improved patient outcomes, suggesting potentially key roles for innate and adaptive immunity in disease control. Nevertheless, MM remains largely incurable for the vast majority of patients. A better understanding of the complex interplay between myeloma cells and their immune environment should pave the way for designing better immunotherapies with the potential of very long term disease control. Here, we review the immunological microenvironment in myeloma. We discuss the role of naturally arising anti-myeloma immune responses and their potential corruption in MM patients. Finally, we detail the numerous promising immune-targeting strategies approved or in clinical trials for the treatment of MM. PMID:26801219

  11. Active chinese mistletoe lectin-55 enhances colon cancer surveillance through regulating innate and adaptive immune responses

    PubMed Central

    Ma, Yan-Hui; Cheng, Wei-Zhi; Gong, Fang; Ma, An-Lun; Yu, Qi-Wen; Zhang, Ji-Ying; Hu, Chao-Ying; Chen, Xue-Hua; Zhang, Dong-Qing

    2008-01-01

    AIM: To investigate the potential role of Active Chinese mistletoe lectin-55 (ACML-55) in tumor immune surveillance. METHODS: In this study, an experimental model was established by hypodermic inoculating the colon cancer cell line CT26 (5 × 105 cells) into BALB/c mice. The experimental treatment was orally administered with ACML-55 or PBS, followed by the inoculation of colon cancer cell line CT26. Intracellular cytokine staining was used to detect IFN-γ production by tumor antigen specific CD8+ T cells. FACS analysis was employed to profile composition and activation of CD4+, CD8+, γδ T and NK cells. RESULTS: Our results showed, compared to PBS treated mice, ACML-55 treatment significantly delayed colon cancer development in colon cancer -bearing Balb/c mice in vivo. Treatment with ACML-55 enhanced both Ag specific activation and proliferation of CD4+ and CD8+ T cells, and increased the number of tumor Ag specific CD8+ T cells. It was more important to increase the frequency of tumor Ag specific IFN-γ producing-CD8+ T cells. Interestingly, ACML-55 treatment also showed increased cell number of NK, and γδT cells, indicating the role of ACML-55 in activation of innate lymphocytes. CONCLUSION: Our results demonstrate that ACML-55 therapy can enhance function in immune surveillance in colon cancer-bearing mice through regulating both innate and adaptive immune responses. PMID:18785279

  12. Gene gun immunization to combat malaria.

    PubMed

    Bergmann-Leitner, Elke S; Leitner, Wolfgang W

    2013-01-01

    DNA immunization by gene gun against a variety of infectious diseases has yielded promising results in animal models. Skin-based DNA vaccination against these diseases is not only an attractive option for the clinic but can aid in the discovery and optimization of vaccine candidates. Vaccination against the protozoan parasite Plasmodium presents unique challenges: (a) most parasite-associated antigens are stage-specific; (b) antibodies capable of neutralizing the parasite during the probing of the mosquitoes have to be available at high titers in order to prevent infection of the liver; (c) immunity to liver-stage infection needs to be absolute in order to prevent subsequent blood-stage parasitemia. Gene gun vaccination has successfully been used to prevent the infection of mice with the rodent malaria strain P. berghei and has been employed in a macaque model of human P. falciparum. DNA plasmid delivery by gene gun offers the opportunity to economically and efficiently test novel malaria vaccine candidates and vaccination strategies, which include the evaluation of novel molecular adjuvant strategies. Here we describe the procedures involved in making and delivering a pre-clinical malaria DNA vaccine by gene gun as well as the correct approach for the in vivo evaluation of the vaccine. Furthermore, we discuss various approaches that either have already been tested or could be employed to improve DNA vaccines against malaria. PMID:23104349

  13. Routine surveillance of adverse events following immunization as an important tool to monitor vaccine safety.

    PubMed

    Alicino, Cristiano; Merlano, Caterina; Zappettini, Simona; Schiaffino, Sergio; Della Luna, Giovanni; Accardo, Cristina; Gasparini, Roberto; Durando, Paolo; Icardi, Giancarlo

    2015-01-01

    Post licensure surveillance of adverse events following immunization (AEFI) is a fundamental activity to improve safety and maintain public confidence in vaccines.   Since 2011, the Liguria Region has been involved in the inter-regional project of post-marketing surveillance of AEFI, coordinated by the Italian Medicine Agency and the Veneto region. The main objectives of the project are: (1) to coordinate the surveillance activities in the 8 Italian Regions included in the project; (2) to encourage the signal of AEFI by healthcare workers and patients; (3) to organize education activities addressed to health care workers, and, finally; (4) to establish vaccination counseling services in each Region. In particular, the Ligurian multidisciplinary team, composed by physicians expert in the field of vaccination and pharmacists, is involved in the causality assessment between vaccines and all adverse events signaled within the Liguria Region and in the analysis of all adverse events signaled in Italy as possibly related to influenza vaccines. During 2013, the team has organized 4 courses, addressed to healthcare personnel of vaccination outpatient clinics, focused on European and Italian legislation on pharmaco-vigilance and vaccine-vigilance and aimed at promoting signal of AEFI. Since October 2013, the Liguria Region has been participating to the inter-regional project of active surveillance of adverse events aimed at promoting the signal of AEFI by parents of vaccinated infants. After two years of implementation of the project both the number of reported AEFI and the reporting rate per 100 000 administered doses of vaccine increased. The activities need to be consolidated in the next years in order to guarantee high standard of vaccine safety, maintain the confidence in current immunization programs and reach optimal vaccination coverage rate. PMID:25483520

  14. Nowhere to hide: unconventional translation yields cryptic peptides for immune surveillance.

    PubMed

    Starck, Shelley R; Shastri, Nilabh

    2016-07-01

    Effective immune surveillance by CD8(+) cytotoxic T cells of intracellular microbes and cancer depends on the antigen presentation pathway. This pathway produces an optimal peptide repertoire for presentation by major histocompatibility (MHC) class I molecules (pMHCs I) on the cell surface. We have known for years that the pMHC I repertoire is a reflection of the intracellular protein pool. However, many studies have revealed that pMHCs I present peptides not only from precursors encoded in open-reading frames of mRNA transcripts but also cryptic peptides encoded in apparently 'untranslated' regions. These sources vastly increase the availability of peptides for presentation and immune evasion. Here, we review studies on the composition of the cryptic pMHC I repertoire, the immunological significance of these pMHC I, and the novel translational mechanisms that generate cryptic peptides from unusual sources. PMID:27319338

  15. Delay-induced state transition and resonance in periodically driven tumor model with immune surveillance

    NASA Astrophysics Data System (ADS)

    Yang, Tao; Han, Qinglin; Zeng, Chunhua; Wang, Hua; Fu, Yunchang; Zhang, Chun

    2014-06-01

    The phenomenon of stochastic resonance (SR) in a tumor growth model under the presence of immune surveillance is investigated. Time delay and cross-correlation between multiplicative and additive noises are considered in the system. The signal-to-noise ratio (SNR) is calculated when periodic signal is introduced multiplicatively. Our results show that: (i) the time delay can accelerate the transition from the state of stable tumor to that of extinction, however the correlation between two noises can accelerate the transition from the state of extinction to that of stable tumor; (ii) the time delay and correlation between two noises can lead to a transition between SR and double SR in the curve of SNR as a function of additive noise intensity, however for the curve of SNR as a function of multiplicative noise intensity, the time delay can cause the SR phenomenon to disappear, and the cross-correlation between two noises can lead to a transition from SR to stochastic reverse-resonance. Finally, we compare the SR phenomenon for the multiplicative periodic signal with that for additive periodic signal in the tumor growth model with immune surveillance.

  16. Microbial sensing by goblet cells controls immune surveillance of luminal antigens in the colon.

    PubMed

    Knoop, K A; McDonald, K G; McCrate, S; McDole, J R; Newberry, R D

    2015-01-01

    The delivery of luminal substances across the intestinal epithelium to the immune system is a critical event in immune surveillance, resulting in tolerance to dietary antigens and immunity to pathogens. How this process is regulated is largely unknown. Recently goblet cell-associated antigen passages (GAPs) were identified as a pathway delivering luminal antigens to underlying lamina propria (LP) dendritic cells in the steady state. Here, we demonstrate that goblet cells (GCs) form GAPs in response to acetylcholine (ACh) acting on muscarinic ACh receptor 4. GAP formation in the small intestine was regulated at the level of ACh production, as GCs rapidly formed GAPs in response to ACh analogs. In contrast, colonic GAP formation was regulated at the level of GC responsiveness to ACh. Myd88-dependent microbial sensing by colonic GCs inhibited the ability of colonic GCs to respond to Ach to form GAPs and deliver luminal antigens to colonic LP-antigen-presenting cells (APCs). Disruption of GC microbial sensing in the setting of an intact gut microbiota opened colonic GAPs, and resulted in recruitment of neutrophils and APCs and production of inflammatory cytokines. Thus GC intrinsic sensing of the microbiota has a critical role regulating the exposure of the colonic immune system to luminal substances. PMID:25005358

  17. Innate Immune Gene Polymorphisms in Tuberculosis

    PubMed Central

    Sadee, Wolfgang

    2012-01-01

    Tuberculosis (TB) is a leading cause worldwide of human mortality attributable to a single infectious agent. Recent studies targeting candidate genes and “case-control” association have revealed numerous polymorphisms implicated in host susceptibility to TB. Here, we review current progress in the understanding of causative polymorphisms in host innate immune genes associated with TB pathogenesis. We discuss genes encoding several types of proteins: macrophage receptors, such as the mannose receptor (MR, CD206), dendritic cell-specific ICAM-3-grabbing nonintegrin (DC-SIGN, CD209), Dectin-1, Toll-like receptors (TLRs), complement receptor 3 (CR3, CD11b/CD18), nucleotide oligomerization domain 1 (NOD1) and NOD2, CD14, P2X7, and the vitamin D nuclear receptor (VDR); soluble C-type lectins, such as surfactant protein-A (SP-A), SP-D, and mannose-binding lectin (MBL); phagocyte cytokines, such as tumor necrosis factor (TNF), interleukin-1β (IL-1β), IL-6, IL-10, IL-12, and IL-18; chemokines, such as IL-8, monocyte chemoattractant protein 1 (MCP-1), RANTES, and CXCL10; and other important innate immune molecules, such as inducible nitric oxide synthase (iNOS) and solute carrier protein 11A1 (SLC11A1). Polymorphisms in these genes have been variably associated with susceptibility to TB among different populations. This apparent variability is probably accounted for by evolutionary selection pressure as a result of long-term host-pathogen interactions in certain regions or populations and, in part, by lack of proper study design and limited knowledge of molecular and functional effects of the implicated genetic variants. Finally, we discuss genomic technologies that hold promise for resolving questions regarding the evolutionary paths of the human genome, functional effects of polymorphisms, and corollary impacts of adaptation on human health, ultimately leading to novel approaches to controlling TB. PMID:22825450

  18. Has innate immunity evolved through different routes?

    NASA Astrophysics Data System (ADS)

    Parrinello, Nicolò

    2010-03-01

    Invertebrate self/non-self recognition, defense responses, mating and development share innate immune surveillance and functions challenged by competition and linked to fitness. Independent evolutionary branches of immune responses may use conserved gene traits. On the other hand immunity genes may be conserved due to their role in development. Finally, upregulation of innate immunity genes during ascidian metamorphosis supports the danger hypothesis.

  19. Inactivation of conserved genes induces microbial aversion, drug detoxification, and innate immunity in C.elegans

    PubMed Central

    Melo, Justine A.; Ruvkun, Gary

    2012-01-01

    Summary The nematode C. elegans consumes benign bacteria such as E. coli and is repelled by pathogens and toxins. Here we show that RNAi and toxin-mediated disruption of core cellular activities, including translation, respiration, and protein turnover, stimulates behavioral avoidance of attractive E. coli. RNAi of such essential processes also induces expression of detoxification and innate immune response genes in the absence of toxins or pathogens. Disruption of core processes in non-neuronal tissues can stimulate aversion behavior, revealing a neuroendocrine axis of control. Microbial avoidance requires serotonergic and Jnk kinase signaling. We propose that surveillance pathways oversee critical cellular activities to detect pathogens, many of which deploy toxins and virulence factors to disrupt these same host pathways. Variation in cellular surveillance and endocrine pathways controlling behavior, detoxification and immunity selected by past toxin or microbial interactions could underlie aberrant responses to foods, medicines, and microbes. PMID:22500807

  20. Positive and negative influence of the matrix architecture on antitumor immune surveillance.

    PubMed

    Peranzoni, Elisa; Rivas-Caicedo, Ana; Bougherara, Houcine; Salmon, Hélène; Donnadieu, Emmanuel

    2013-12-01

    The migration of T cells and access to tumor antigens is of utmost importance for the induction of protective anti-tumor immunity. Once having entered a malignant site, T cells encounter a complex environment composed of non-tumor cells along with the extracellular matrix (ECM). It is now well accepted that a deregulated ECM favors tumor progression and metastasis. Recent progress in imaging technologies has also highlighted the impact of the matrix architecture found in solid tumor on immune cells and especially T cells. In this review, we argue that the ability of T cells to mount an antitumor response is dependent on the matrix structure, more precisely on the balance between pro-migratory reticular fiber networks and unfavorable migration zones composed of dense and aligned ECM structures. Thus, the matrix architecture, that has long been considered to merely provide the structural framework of connective tissues, can play a key role in facilitating or suppressing the antitumor immune surveillance. A new challenge in cancer therapy will be to develop approaches aimed at altering the architecture of the tumor stroma, rendering it more permissive to antitumor T cells. PMID:23649148

  1. A Skin-selective Homing Mechanism for Human Immune Surveillance T Cells

    PubMed Central

    Schaerli, Patrick; Ebert, Lisa; Willimann, Katharina; Blaser, Andrea; Roos, Regula Stuber; Loetscher, Pius; Moser, Bernhard

    2004-01-01

    Effective immune surveillance is essential for maintaining protection and homeostasis of peripheral tissues. However, mechanisms controlling memory T cell migration to peripheral tissues such as the skin are poorly understood. Here, we show that the majority of human T cells in healthy skin express the chemokine receptor CCR8 and respond to its selective ligand I-309/CCL1. These CCR8+ T cells are absent in small intestine and colon tissue, and are extremely rare in peripheral blood, suggesting healthy skin as their physiological target site. Cutaneous CCR8+ T cells are preactivated and secrete proinflammatory cytokines such as tumor necrosis factor–α and interferon-γ, but lack markers of cytolytic T cells. Secretion of interleukin (IL)-4, IL-10, and transforming growth factor–β was low to undetectable, arguing against a strict association of CCR8 expression with either T helper cell 2 or regulatory T cell subsets. Potential precursors of skin surveillance T cells in peripheral blood may correspond to the minor subset of CCR8+CD25− T cells. Importantly, CCL1 is constitutively expressed at strategic cutaneous locations, including dermal microvessels and epidermal antigen-presenting cells. For the first time, these findings define a chemokine system for homeostatic T cell traffic in normal human skin. PMID:15123746

  2. Drug induced immune haemolytic anaemia in the Berlin Case-Control Surveillance Study.

    PubMed

    Garbe, Edeltraut; Andersohn, Frank; Bronder, Elisabeth; Klimpel, Andreas; Thomae, Michael; Schrezenmeier, Hubert; Hildebrandt, Martin; Späth-Schwalbe, Ernst; Grüneisen, Andreas; Mayer, Beate; Salama, Abdulgabar; Kurtal, Hanife

    2011-09-01

    Drug-induced immune haemolytic anaemia is a rare but serious condition. This study investigated the possibility of drug aetiology of immune haemolytic anaemia (IHA) in 134 patients with new onset of IHA who were identified in the Berlin Case-Control Surveillance Study between 2000 and 2009. Single drugs related to IHA in three or more patients and assessed more than once as a certain or probable cause of IHA in a standardized causality assessment included diclofenac, fludarabine, oxaliplatin, ceftriaxone and piperacillin. In a case-control study including all 124 IHA cases developed in outpatient care and 731 controls, significantly increased odds ratios (OR) were observed for beta-lactam antibiotics (OR=8·8; 95% confidence interval [CI] 3·2-25·2), cotrimoxazole (OR=6·5; CI 1·1-37·9), ciprofloxacin (OR=6·9, CI 1·3-38·5), fludarabine (OR=22·2; CI: 2·8-454·5) and lorazepam (OR=5·3; CI: 1·2-21·2). Excluding new onset cases with a chronic IHA disease course, an increased risk became also apparent for diclofenac with an OR of 3·1 (CI 1·3-7·0). This is the first case-control study investigating drugs as risk factors for IHA. It corroborates an increased risk for several drugs that have been implicated as a cause of IHA in the standardized causality assessment of individual cases. PMID:21749359

  3. Age-related changes in natural killer cell repertoires: impact on NK cell function and immune surveillance.

    PubMed

    Manser, Angela R; Uhrberg, Markus

    2016-04-01

    A key feature of human natural killer (NK) cells, which enables efficient recognition of infected and malignant target cells, is the expression of HLA class I-specific receptors of the KIR and NKG2 gene families. Cell-to-cell variability in receptor expression leads to the formation of complex NK cell repertoires. As outlined here, NK cells go through major changes from newborns to adults characterized by downregulation of the inhibitory NKG2A receptor and concomitant upregulation of KIR family members. This process is completed in young adults, and in the majority of individuals, KIR/NKG2A repertoires remain remarkably stable until old age. Nonetheless, age-related factors have the potential to majorly influence the complexity of NK cell repertoires: Firstly infection with HCMV is associated with major clonal expansions of terminally differentiated NKG2C- and KIR-expressing NK cells in certain individuals. Secondly, ineffective hematopoiesis can lead to immature and less diversified NK cell repertoires as observed in myelodysplastic syndrome (MDS), a malignant disease of the elderly. Thus, whereas in the majority of elderly the NK cell compartment appears to be highly stable in terms of function and phenotype, in a minority of subjects a breakdown of NK cell repertoire diversity is observed that might influence immune surveillance and healthy aging. PMID:26288343

  4. Researchers Find 8 Immune Genes in Aggressive Brain Cancer

    MedlinePlus

    ... 159031.html Researchers Find 8 Immune Genes in Aggressive Brain Cancer Discovery might eventually lead to better ... tissue samples from 170 people with a less aggressive type of brain tumor. This led to the ...

  5. Genotype and gene expression associations with immune function in Drosophila.

    PubMed

    Sackton, Timothy B; Lazzaro, Brian P; Clark, Andrew G

    2010-01-01

    It is now well established that natural populations of Drosophila melanogaster harbor substantial genetic variation associated with physiological measures of immune function. In no case, however, have intermediate measures of immune function, such as transcriptional activity of immune-related genes, been tested as mediators of phenotypic variation in immunity. In this study, we measured bacterial load sustained after infection of D. melanogaster with Serratia marcescens, Providencia rettgeri, Enterococcus faecalis, and Lactococcus lactis in a panel of 94 third-chromosome substitution lines. We also measured transcriptional levels of 329 immune-related genes eight hours after infection with E. faecalis and S. marcescens in lines from the phenotypic tails of the test panel. We genotyped the substitution lines at 137 polymorphic markers distributed across 25 genes in order to test for statistical associations among genotype, bacterial load, and transcriptional dynamics. We find that genetic polymorphisms in the pathogen recognition genes (and particularly in PGRP-LC, GNBP1, and GNBP2) are most significantly associated with variation in bacterial load. We also find that overall transcriptional induction of effector proteins is a significant predictor of bacterial load after infection with E. faecalis, and that a marker upstream of the recognition gene PGRP-SD is statistically associated with variation in both bacterial load and transcriptional induction of effector proteins. These results show that polymorphism in genes near the top of the immune system signaling cascade can have a disproportionate effect on organismal phenotype due to the amplification of minor effects through the cascade. PMID:20066029

  6. Tumoral NKG2D alters cell cycle of acute myeloid leukemic cells and reduces NK cell-mediated immune surveillance.

    PubMed

    Tang, Mingying; Acheampong, Desmond Omane; Wang, Youfu; Xie, Wei; Wang, Min; Zhang, Juan

    2016-06-01

    The stimulatory natural killer group 2 member D (NKG2D) lymphocyte receptor, initially discovered and expressed mostly on natural killer (NK) cells, T cells and natural killer T cells, can promote tumor immune surveillance. However, with increasing tumor grade, tumors themselves express NKG2D to self-stimulate oncogenic pathways. To confirm that cancer cells themselves express NKG2D, we have now investigated the role of the tumoral NKG2D in NK cell-mediated immune surveillance. Both anti-NKG2D and shRNA to that down-regulated tumoral NKG2D increased the number of cells in G1 phase and S phase, increased the expression of cyclin E-CDK2 and decreased P21. In addition, CD107a, IFN-γ and TNF-α increased when the cells were treated with anti-NKG2D which suggests that blocking tumoral NKG2D could augment tumor surveillance of NK cells. Altogether, tumoral NKG2D stimulates cell propagation and immune escape in acute myeloid leukemia cells. PMID:26740330

  7. Inherited variation in immune genes and pathways and glioblastoma risk

    PubMed Central

    Schwartzbaum, Judith A.; Xiao, Yuanyuan; Liu, Yanhong; Tsavachidis, Spyros; Berger, Mitchel S.; Bondy, Melissa L.; Chang, Jeffrey S.; Chang, Susan M.; Decker, Paul A.; Ding, Bo; Hepworth, Sarah J.; Houlston, Richard S.; Hosking, Fay J.; Jenkins, Robert B.; Kosel, Matthew L.; McCoy, Lucie S.; McKinney, Patricia A.; Muir, Kenneth; Patoka, Joe S.; Prados, Michael; Rice, Terri; Robertson, Lindsay B.; Schoemaker, Minouk J.; Shete, Sanjay; Swerdlow, Anthony J.; Wiemels, Joe L.; Wiencke, John K.; Yang, Ping; Wrensch, Margaret R.

    2010-01-01

    To determine whether inherited variations in immune function single-nucleotide polymorphisms (SNPs), genes or pathways affect glioblastoma risk, we analyzed data from recent genome-wide association studies in conjunction with predefined immune function genes and pathways. Gene and pathway analyses were conducted on two independent data sets using 6629 SNPs in 911 genes on 17 immune pathways from 525 glioblastoma cases and 602 controls from the University of California, San Francisco (UCSF) and a subset of 6029 SNPs in 893 genes from 531 cases and 1782 controls from MD Anderson (MDA). To further assess consistency of SNP-level associations, we also compared data from the UK (266 cases and 2482 controls) and the Mayo Clinic (114 cases and 111 controls). Although three correlated epidermal growth factor receptor (EGFR) SNPs were consistently associated with glioblastoma in all four data sets (Mantel–Haenzel P values = 1 × 10−5 to 4 × 10−3), independent replication is required as genome-wide significance was not attained. In gene-level analyses, eight immune function genes were significantly (minP < 0.05) associated with glioblastoma; the IL-2RA (CD25) cytokine gene had the smallest minP values in both UCSF (minP = 0.01) and MDA (minP = 0.001) data sets. The IL-2RA receptor is found on the surface of regulatory T cells potentially contributing to immunosuppression characteristic of the glioblastoma microenvironment. In pathway correlation analyses, cytokine signaling and adhesion–extravasation–migration pathways showed similar associations with glioblastoma risk in both MDA and UCSF data sets. Our findings represent the first systematic description of immune genes and pathways that characterize glioblastoma risk. PMID:20668009

  8. Inherited variation in immune genes and pathways and glioblastoma risk.

    PubMed

    Schwartzbaum, Judith A; Xiao, Yuanyuan; Liu, Yanhong; Tsavachidis, Spyros; Berger, Mitchel S; Bondy, Melissa L; Chang, Jeffrey S; Chang, Susan M; Decker, Paul A; Ding, Bo; Hepworth, Sarah J; Houlston, Richard S; Hosking, Fay J; Jenkins, Robert B; Kosel, Matthew L; McCoy, Lucie S; McKinney, Patricia A; Muir, Kenneth; Patoka, Joe S; Prados, Michael; Rice, Terri; Robertson, Lindsay B; Schoemaker, Minouk J; Shete, Sanjay; Swerdlow, Anthony J; Wiemels, Joe L; Wiencke, John K; Yang, Ping; Wrensch, Margaret R

    2010-10-01

    To determine whether inherited variations in immune function single-nucleotide polymorphisms (SNPs), genes or pathways affect glioblastoma risk, we analyzed data from recent genome-wide association studies in conjunction with predefined immune function genes and pathways. Gene and pathway analyses were conducted on two independent data sets using 6629 SNPs in 911 genes on 17 immune pathways from 525 glioblastoma cases and 602 controls from the University of California, San Francisco (UCSF) and a subset of 6029 SNPs in 893 genes from 531 cases and 1782 controls from MD Anderson (MDA). To further assess consistency of SNP-level associations, we also compared data from the UK (266 cases and 2482 controls) and the Mayo Clinic (114 cases and 111 controls). Although three correlated epidermal growth factor receptor (EGFR) SNPs were consistently associated with glioblastoma in all four data sets (Mantel-Haenzel P values = 1 × 10⁻⁵ to 4 × 10⁻³), independent replication is required as genome-wide significance was not attained. In gene-level analyses, eight immune function genes were significantly (minP < 0.05) associated with glioblastoma; the IL-2RA (CD25) cytokine gene had the smallest minP values in both UCSF (minP = 0.01) and MDA (minP = 0.001) data sets. The IL-2RA receptor is found on the surface of regulatory T cells potentially contributing to immunosuppression characteristic of the glioblastoma microenvironment. In pathway correlation analyses, cytokine signaling and adhesion-extravasation-migration pathways showed similar associations with glioblastoma risk in both MDA and UCSF data sets. Our findings represent the first systematic description of immune genes and pathways that characterize glioblastoma risk. PMID:20668009

  9. Genetics of gene expression in immunity to infection

    PubMed Central

    Fairfax, Benjamin P; Knight, Julian C

    2015-01-01

    Mapping gene expression as a quantitative trait (eQTL mapping) can reveal local and distant associations with functionally important genetic variation informative for disease. Recent studies are reviewed which have demonstrated that this approach is particularly informative when applied to diverse immune cell populations and situations relevant to infection and immunity. Context-specific eQTL have now been characterised following endotoxin activation, induction with interferons, mycobacteria, and influenza, together with genetic determinants of response to vaccination. The application of genetical genomic approaches offers new opportunities to advance our understanding of gene–environment interactions and fundamental processes in innate and adaptive immunity. PMID:25078545

  10. Population Genetics of Anopheles coluzzii Immune Pathways and Genes

    PubMed Central

    Rottschaefer, Susan M.; Crawford, Jacob E.; Riehle, Michelle M.; Guelbeogo, Wamdaogo M.; Gneme, Awa; Sagnon, N’Fale; Vernick, Kenneth D.; Lazzaro, Brian P.

    2014-01-01

    Natural selection is expected to drive adaptive evolution in genes involved in host–pathogen interactions. In this study, we use molecular population genetic analyses to understand how natural selection operates on the immune system of Anopheles coluzzii (formerly A. gambiae “M form”). We analyzed patterns of intraspecific and interspecific genetic variation in 20 immune-related genes and 17 nonimmune genes from a wild population of A. coluzzii and asked if patterns of genetic variation in the immune genes are consistent with pathogen-driven selection shaping the evolution of defense. We found evidence of a balanced polymorphism in CTLMA2, which encodes a C-type lectin involved in regulation of the melanization response. The two CTLMA2 haplotypes, which are distinguished by fixed amino acid differences near the predicted peptide cleavage site, are also segregating in the sister species A. gambiae (“S form”) and A. arabiensis. Comparison of the two haplotypes between species indicates that they were not shared among the species through introgression, but rather that they arose before the species divergence and have been adaptively maintained as a balanced polymorphism in all three species. We additionally found that STAT-B, a retroduplicate of STAT-A, shows strong evidence of adaptive evolution that is consistent with neofunctionalization after duplication. In contrast to the striking patterns of adaptive evolution observed in these Anopheles-specific immune genes, we found no evidence of adaptive evolution in the Toll and Imd innate immune pathways that are orthologously conserved throughout insects. Genes encoding the Imd pathway exhibit high rates of amino acid divergence between Anopheles species but also display elevated amino acid diversity that is consistent with relaxed purifying selection. These results indicate that adaptive coevolution between A. coluzzii and its pathogens is more likely to involve novel or lineage-specific molecular mechanisms

  11. big bang gene modulates gut immune tolerance in Drosophila.

    PubMed

    Bonnay, François; Cohen-Berros, Eva; Hoffmann, Martine; Kim, Sabrina Y; Boulianne, Gabrielle L; Hoffmann, Jules A; Matt, Nicolas; Reichhart, Jean-Marc

    2013-02-19

    Chronic inflammation of the intestine is detrimental to mammals. Similarly, constant activation of the immune response in the gut by the endogenous flora is suspected to be harmful to Drosophila. Therefore, the innate immune response in the gut of Drosophila melanogaster is tightly balanced to simultaneously prevent infections by pathogenic microorganisms and tolerate the endogenous flora. Here we describe the role of the big bang (bbg) gene, encoding multiple membrane-associated PDZ (PSD-95, Discs-large, ZO-1) domain-containing protein isoforms, in the modulation of the gut immune response. We show that in the adult Drosophila midgut, BBG is present at the level of the septate junctions, on the apical side of the enterocytes. In the absence of BBG, these junctions become loose, enabling the intestinal flora to trigger a constitutive activation of the anterior midgut immune response. This chronic epithelial inflammation leads to a reduced lifespan of bbg mutant flies. Clearing the commensal flora by antibiotics prevents the abnormal activation of the gut immune response and restores a normal lifespan. We now provide genetic evidence that Drosophila septate junctions are part of the gut immune barrier, a function that is evolutionarily conserved in mammals. Collectively, our data suggest that septate junctions are required to maintain the subtle balance between immune tolerance and immune response in the Drosophila gut, which represents a powerful model to study inflammatory bowel diseases. PMID:23378635

  12. The heterogeneous immune microenvironment in breast cancer is affected by hypoxia-related genes.

    PubMed

    Duechler, Markus; Peczek, Lukasz; Zuk, Karolina; Zalesna, Izabela; Jeziorski, Arkadiusz; Czyz, Malgorzata

    2014-02-01

    The immune system constitutes an important first-line defence against malignant transformation. However, cancer mediated immunosuppression inactivates the mechanisms of host immune surveillance. Cancer cells shut down anti-cancer immunity through direct cell-cell interactions with leukocytes and through soluble factors, establishing an immunosuppressive environment for unimpeded cancer growth. The composition of the immunosuppressive microenvironment in breast tumours is not well documented. To address this question, selected immunosuppressive factors were analyzed in tumour specimens from 33 breast cancer patients after surgery. The mRNA expression of selected genes was quantified in fresh tumour samples. Tumour infiltrating leukocytes were characterized by flow cytometry to identify regulatory T cells, myeloid derived suppressor cells, and type 2 macrophages. Statistical analysis revealed several interesting correlations between the studied parameters and clinical features. Overall, a surprisingly high degree of heterogeneity in the composition of the immunosuppressive environment was found across all breast cancer samples which adds to the complexity of this disease. The influence of the hypoxia inducible factors (HIFs) on the immune microenvironment was also addressed. The level of HIFs correlated with hormone receptor status and the expression of several immunosuppressive molecules. Targeting HIFs might not only sensitize breast tumours for radiation and chemotherapies but also interfere with cancer immunosuppression. PMID:24091277

  13. The Challenge for Gene Therapy: Innate Immune Response to Adenoviruses

    PubMed Central

    Thaci, Bart; Ulasov, Ilya V.; Wainwright, Derek A.; Lesniak, Maciej S.

    2011-01-01

    Adenoviruses are the most commonly used vectors for gene therapy. Despite the promising safety profile demonstrated in clinical trials, the efficacy of using adenoviruses for gene therapy is poor. A major hurdle to adenoviral-mediated gene therapy is the innate immune system. Cell-mediated recognition of viruses via capsid components or nucleic acids has received significant attention, principally thought to be regulated by the toll-like receptors (TLRs). Antiviral innate immune responses are initiated by the infected cell, which activates the interferon (IFN) response to block viral replication, while simultaneously releasing chemokines to attract neutrophils, mononuclear- and natural killer-cells. While the IFN and cellular recruitment pathways are activated and regulated independently of each other, both are required to overcome immune escape mechanisms by adenoviruses. Recent work has shown that the generation of adenoviral vectors lacking specific transcriptionally-active regions decreases immune system activation and increases the chance for immune escape. In this review, we elucidate how adenoviral vector modifications alter the IFN and innate inflammatory pathway response and propose future targets with clinically-translational relevance. PMID:21399236

  14. Immune Surveillance and Therapy of Lymphomas Driven by Epstein-Barr -Virus Protein LMP1 in a Mouse Model

    PubMed Central

    Zhang, Baochun; Kracker, Sven; Yasuda, Tomoharu; Casola, Stefano; Vanneman, Matthew; Hömig-Hölzel, Cornelia; Wang, Zhe; Derudder, Emmanuel; Li, Shuang; Chakraborty, Tirtha; Cotter, Shane E.; Koyama, Shohei; Currie, Treeve; Freeman, Gordon J.; Kutok, Jeffery L.; Rodig, Scott J.; Dranoff, Glenn; Rajewsky, Klaus

    2012-01-01

    SUMMARY B cells infected by Epstein-Barr-Virus (EBV), a transforming virus endemic in humans, are rapidly cleared by the immune system, but some cells harboring the virus persist for life. Under conditions of immunosuppression EBV can spread from these cells and cause life threatening pathologies. We have generated mice expressing the transforming EBV latent membrane protein 1 (LMP1), mimicking a constitutively active CD40 coreceptor, specifically in B cells. Like human EBV infected cells, LMP1+ B cells were efficiently eliminated by T cells, and breaking immune surveillance resulted in rapid, fatal lymphoproliferation and lymphomagenesis. The lymphoma cells expressed ligands for a natural killer (NK) cell receptor, NKG2D, and could be targeted by an NKG2D-Fc fusion protein. These experiments indicate a central role for LMP1 in the surveillance and transformation of EBV infected B cells in vivo, establish a pre-clinical model for B cell lymphomagenesis in immunosuppressed patients, and validate a novel therapeutic approach. PMID:22341446

  15. The evolution of secondary organization in immune system gene libraries

    SciTech Connect

    Hightower, R.; Forrest, S.; Perelson, A.S.

    1993-02-01

    A binary model of the immune system is used to study the effects of evolution on the genetic encoding for antibody molecules. We report experiments which show that the evolution of immune system genes, simulated by the genetic algorithm, can induce a high degree of genetic organization even though that organization is not explicitly required by the fitness function. This secondary organization is related to the true fitness of an individual, in contrast to the sampled fitness which is the explicit fitness measure used to drive the process of evolution.

  16. The evolution of secondary organization in immune system gene libraries

    SciTech Connect

    Hightower, R.; Forrest, S. . Dept. of Computer Science); Perelson, A.S. )

    1993-01-01

    A binary model of the immune system is used to study the effects of evolution on the genetic encoding for antibody molecules. We report experiments which show that the evolution of immune system genes, simulated by the genetic algorithm, can induce a high degree of genetic organization even though that organization is not explicitly required by the fitness function. This secondary organization is related to the true fitness of an individual, in contrast to the sampled fitness which is the explicit fitness measure used to drive the process of evolution.

  17. Human genes in TB infection: their role in immune response.

    PubMed

    Lykouras, D; Sampsonas, F; Kaparianos, A; Karkoulias, K; Tsoukalas, G; Spiropoulos, K

    2008-03-01

    Tuberculosis (TB) caused by the human pathogen Mycobacterium tuberculosis, is the leading cause of morbidity and mortality caused by infectious agents worldwide. Recently, there has been an ongoing concern about the clarification of the role of specific human genes and their polymorphisms involved in TB infection. In the vast majority of individuals, innate immune pathways and T-helper 1 (Th1) cell mediated immunity are activated resulting in the lysis of the bacterium. Firstly, PTPN22 R620W polymorphism is involved in the response to cases of infection. The Arg753Gln polymorphism in TLR-2 leads to a weaker response against the M. tuberculosis. The gene of the vitamin D receptor (VDR) has a few polymorphisms (BsmI, ApaI, Taq1, FokI) whose mixed genotypes alter the immune response. Solute carrier family 11 member (SLC11A1) is a proton/divalent cation antiporter that is more familiar by its former name NRAMP1 (natural resistance associated macrophage protein 1) and can affect M. tuberculosis growth. Polymorphisms of cytokines such as IL-10, IL-6, IFN-g, TNF-a, TGF-b1 can affect the immune response in various ways. Finally, a major role is played by M. tuberculosis antigens and the Ras-associated small GTP-ase 33A. As far as we know this is the first review that collates all these polymorphisms in order to give a comprehensive image of the field, which is currently evolving. PMID:18507196

  18. Gaucher disease gene GBA functions in immune regulation

    PubMed Central

    Liu, Jun; Halene, Stephanie; Yang, Mei; Iqbal, Jameel; Yang, Ruhua; Mehal, Wajahat Z.; Chuang, Wei-Lien; Jain, Dhanpat; Yuen, Tony; Sun, Li; Zaidi, Mone; Mistry, Pramod K.

    2012-01-01

    Inherited deficiency of acid β-glucosidase (GCase) due to biallelic mutations in the GBA (glucosidase, β, acid) gene causes the classic manifestations of Gaucher disease (GD) involving the viscera, the skeleton, and the lungs. Clinical observations point to immune defects in GD beyond the accumulation of activated macrophages engorged with lysosomal glucosylceramide. Here, we show a plethora of immune cell aberrations in mice in which the GBA gene is deleted conditionally in hematopoietic stem cells (HSCs). The thymus exhibited the earliest and most striking alterations reminiscent of impaired T-cell maturation, aberrant B-cell recruitment, enhanced antigen presentation, and impaired egress of mature thymocytes. These changes correlated strongly with disease severity. In contrast to the profound defects in the thymus, there were only limited cellular defects in peripheral lymphoid organs, mainly restricted to mice with severe disease. The cellular changes in GCase deficiency were accompanied by elevated T-helper (Th)1 and Th2 cytokines that also tracked with disease severity. Finally, the proliferation of GCase-deficient HSCs was inhibited significantly by both GL1 and Lyso-GL1, suggesting that the “supply” of early thymic progenitors from bone marrow may, in fact, be reduced in GBA deficiency. The results not only point to a fundamental role for GBA in immune regulation but also suggest that GBA mutations in GD may cause widespread immune dysregulation through the accumulation of substrates. PMID:22665763

  19. Identifying genes that mediate anthracyline toxicity in immune cells

    PubMed Central

    Frick, Amber; Suzuki, Oscar T.; Benton, Cristina; Parks, Bethany; Fedoriw, Yuri; Richards, Kristy L.; Thomas, Russell S.; Wiltshire, Tim

    2015-01-01

    The role of the immune system in response to chemotherapeutic agents remains elusive. The interpatient variability observed in immune and chemotherapeutic cytotoxic responses is likely, at least in part, due to complex genetic differences. Through the use of a panel of genetically diverse mouse inbred strains, we developed a drug screening platform aimed at identifying genes underlying these chemotherapeutic cytotoxic effects on immune cells. Using genome-wide association studies (GWAS), we identified four genome-wide significant quantitative trait loci (QTL) that contributed to the sensitivity of doxorubicin and idarubicin in immune cells. Of particular interest, a locus on chromosome 16 was significantly associated with cell viability following idarubicin administration (p = 5.01 × 10−8). Within this QTL lies App, which encodes amyloid beta precursor protein. Comparison of dose-response curves verified that T-cells in App knockout mice were more sensitive to idarubicin than those of C57BL/6J control mice (p < 0.05). In conclusion, the cellular screening approach coupled with GWAS led to the identification and subsequent validation of a gene involved in T-cell viability after idarubicin treatment. Previous studies have suggested a role for App in in vitro and in vivo cytotoxicity to anticancer agents; the overexpression of App enhances resistance, while the knockdown of this gene is deleterious to cell viability. Further investigations should include performing mechanistic studies, validating additional genes from the GWAS, including Ppfia1 and Ppfibp1, and ultimately translating the findings to in vivo and human studies. PMID:25926793

  20. Mmi1 RNA surveillance machinery directs RNAi complex RITS to specific meiotic genes in fission yeast

    PubMed Central

    Hiriart, Edwige; Vavasseur, Aurélia; Touat-Todeschini, Leila; Yamashita, Akira; Gilquin, Benoit; Lambert, Emeline; Perot, Jonathan; Shichino, Yuichi; Nazaret, Nicolas; Boyault, Cyril; Lachuer, Joel; Perazza, Daniel; Yamamoto, Masayuki; Verdel, André

    2012-01-01

    RNA interference (RNAi) silences gene expression by acting both at the transcriptional and post-transcriptional levels in a broad range of eukaryotes. In the fission yeast Schizosaccharomyces pombe the RNA-Induced Transcriptional Silencing (RITS) RNAi complex mediates heterochromatin formation at non-coding and repetitive DNA. However, the targeting and role of RITS at other genomic regions, including protein-coding genes, remain unknown. Here we show that RITS localizes to specific meiotic genes and mRNAs. Remarkably, RITS is guided to these meiotic targets by the RNA-binding protein Mmi1 and its associated RNA surveillance machinery that together degrade selective meiotic mRNAs during vegetative growth. Upon sexual differentiation, RITS localization to the meiotic genes and mRNAs is lost. Large-scale identification of Mmi1 RNA targets reveals that RITS subunit Chp1 associates with the vast majority of them. In addition, loss of RNAi affects the effective repression of sexual differentiation mediated by the Mmi1 RNA surveillance machinery. These findings uncover a new mechanism for recruiting RNAi to specific meiotic genes and suggest that RNAi participates in the control of sexual differentiation in fission yeast. PMID:22522705

  1. Plasmodium falciparum var gene expression is modified by host immunity

    PubMed Central

    Warimwe, George M.; Keane, Thomas M.; Fegan, Gregory; Musyoki, Jennifer N.; Newton, Charles R. J. C.; Pain, Arnab; Berriman, Matthew; Marsh, Kevin; Bull, Peter C.

    2009-01-01

    Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) is a potentially important family of immune targets, which play a central role in the host–parasite interaction by binding to various host molecules. They are encoded by a diverse family of genes called var, of which there are ≈60 copies in each parasite genome. In sub-Saharan Africa, although P. falciparum infection occurs throughout life, severe malarial disease tends to occur only in childhood. This could potentially be explained if (i) PfEMP1 variants differ in their capacity to support pathogenesis of severe malaria and (ii) this capacity is linked to the likelihood of each molecule being recognized and cleared by naturally acquired antibodies. Here, in a study of 217 Kenyan children with malaria, we show that expression of a group of var genes “cys2,” containing a distinct pattern of cysteine residues, is associated with low host immunity. Expression of cys2 genes was associated with parasites from young children, those with severe malaria, and those with a poorly developed antibody response to parasite-infected erythrocyte surface antigens. Cys-2 var genes form a minor component of all genomic var repertoires analyzed to date. Therefore, the results are compatible with the hypothesis that the genomic var gene repertoire is organized such that PfEMP1 molecules that confer the most virulence to the parasite tend also to be those that are most susceptible to the development of host immunity. This may help the parasite to adapt effectively to the development of host antibodies through modification of the host–parasite relationship. PMID:20018734

  2. Effect of Recombination in the Evolutionary Dynamics of HIV under the Surveillance of Immune System

    NASA Astrophysics Data System (ADS)

    Peng, Weiqun; Yang, Wenjing; Wang, Guanyu

    2009-03-01

    Human immunodeficiency virus (HIV) is a retrovirus that causes acquired immunodeficiency syndrome (AIDS), which has become one of the most destructive pandemics in history. The fact that HIV virus evolves very fast plays a central role in AIDS immunopathogenesis and the difficulty we face in finding a cure or a vaccine for AIDS. A distinguishing feature of HIV is its high frequency of recombination. The effect of recombination in the HIV evolution is not clear. We establish a mathematical model of the evolutionary dynamics. This model incorporates both point mutation and recombination for genetic diversity, and employs a fitness function developed by Wang and Deem (PRL 97, 188106, 2006) that accounts for the effect of immune system. Using this model, we explore the role of recombination in the battle between the virus population and the immune system, with a special focus on the condition under which recombination helps the virus population to escape from the immune system.

  3. Role of Trypanosoma cruzi Trans-sialidase on the Escape from Host Immune Surveillance

    PubMed Central

    Nardy, Ana F. F. R.; Freire-de-Lima, Celio G.; Pérez, Ana R.; Morrot, Alexandre

    2016-01-01

    Chagas disease is caused by the flagellate protozoan Trypanosoma cruzi, affecting millions of people throughout Latin America. The parasite dampens host immune response causing modifications in diverse lymphoid compartments, including the thymus. T. cruzi trans-sialidase (TS) seems to play a fundamental role in such immunopathological events. This unusual enzyme catalyses the transference of sialic acid molecules from host glycoconjugates to acceptor molecules placed on the parasite surface. TS activity mediates several biological effects leading to the subversion of host immune system, hence favoring both parasite survival and the establishment of chronic infection. This review summarizes current findings on the roles of TS in the immune response during T. cruzi infection. PMID:27047464

  4. Transferred interbacterial antagonism genes augment eukaryotic innate immune function

    PubMed Central

    Chou, Seemay; Daugherty, Matthew D.; Peterson, S. Brook; Biboy, Jacob; Yang, Youyun; Jutras, Brandon L.; Fritz-Laylin, Lillian K.; Ferrin, Michael A.; Harding, Brittany N.; Jacobs-Wagner, Christine; Yang, X. Frank; Vollmer, Waldemar; Malik, Harmit S.

    2015-01-01

    Horizontal gene transfer (HGT) allows organisms to rapidly acquire adaptive traits1. Though documented instances of HGT from bacteria to eukaryotes remain rare, bacteria represent a rich source of new functions potentially available for co-option2. One benefit that genes of bacterial origin could provide to eukaryotes is the capacity to produce anti-bacterials, which have evolved in prokaryotes as the result of eons of interbacterial competition. The type VI secretion amidase effector (Tae) proteins are potent bacteriocidal enzymes that degrade the cell wall when delivered into competing bacterial cells by the type VI secretion system (T6SS)3. Here we show that tae genes have been transferred to eukaryotes on at least six occasions, and that the resulting domesticated amidase effector (dae) genes have been preserved for hundreds of millions of years via purifying selection. We show that the dae genes acquired eukaryotic secretion signals, are expressed within recipient organisms, and encode active antibacterial toxins that possess substrate specificity matching extant Tae proteins of the same lineage. Finally, we show that a dae gene in the deer tick Ixodes scapularis limits proliferation of Borrelia burgdorferi, the etiologic agent of Lyme disease. Our work demonstrates that a family of horizontally acquired toxins honed to mediate interbacterial antagonism confers previously undescribed antibacterial capacity to eukaryotes. We speculate that the selective pressure imposed by competition between bacteria has produced a reservoir of genes encoding diverse antimicrobial functions that are tailored for facile co-option by eukaryotic innate immune systems. PMID:25470067

  5. Gene Expression by PBMC in Primary Sclerosing Cholangitis: Evidence for Dysregulation of Immune Mediated Genes

    PubMed Central

    Aoki, Christopher A.; Dawson, Kevin; Kenny, Thomas P.; Gershwin, M. Eric; Bowlus, Christopher L.

    2006-01-01

    Primary sclerosing cholangitis (PSC) is a chronic disease of the bile ducts characterized by an inflammatory infiltrate and obliterative fibrosis. The precise role of the immune system in the pathogenesis of PSC remains unknown. We used RNA microarray analysis to identify immune-related genes and pathways that are differentially expressed in PSC. Messenger RNA (mRNA) from peripheral blood mononuclear cells (PBMC) was isolated from both patients with PSC and age and sex matched healthy controls. Samples from 5 PSC patients and 5 controls were analyzed by microarray and based upon rigorous statistical analysis of the data, relevant genes were chosen for confirmation by RT-PCR in 10 PSC patients and 10 controls. Using unsupervised hierarchical clustering, gene expression in PSC was statistically different from our control population. Interestingly, genes within the IL-2 receptor beta, IL-6 and MAP Kinase pathways were found to be differently expressed in patients with PSC compared to controls. Further, individual genes, TNF-α induced protein 6 (TNFaip6) and membrane-spanning 4-domains, subfamily A (ms4a) were found to be upregulated in PSC while similar to Mothers against decapentaplegic homolog 5 (SMAD 5) was downregulated. In conclusion, several immune-related pathways and genes were differentially expressed in PSC compared to control patients, giving further evidence that this disease is systemic and immune-mediated. PMID:17162367

  6. Among-lake reciprocal transplants induce convergent expression of immune genes in threespine stickleback.

    PubMed

    Stutz, William E; Schmerer, Matthew; Coates, Jessica L; Bolnick, Daniel I

    2015-09-01

    Geographic variation in parasite communities can drive evolutionary divergence in host immune genes. However, biotic and abiotic environmental variation can also induce plastic differences in immune function among populations. At present, there is little information concerning the relative magnitudes of heritable vs. induced immune divergence in natural populations. We examined immune gene expression profiles of threespine stickleback (Gasterosteus aculeatus) from six lakes on Vancouver Island, British Columbia. Parasite community composition differs between lake types (large or small, containing limnetic- or benthic-like stickleback) and between watersheds. We observed corresponding differences in immune gene expression profiles among wild-caught stickleback, using a set of seven immune genes representing distinct branches of the immune system. To evaluate the role of environmental effects on this differentiation, we experimentally transplanted wild-caught fish into cages in their native lake, or into a nearby foreign lake. Transplanted individuals' immune gene expression converged on patterns typical of their destination lake, deviating from their native expression profile. Transplant individuals' source population had a much smaller effect, suggesting relatively weak genetic underpinning of population differences in immunity, as viewed through gene expression. This strong environmental regulation of immune gene expression provides a counterpoint to the large emerging literature documenting microevolution and genetic diversification of immune function. Our findings illustrate the value of studying immunity in natural environmental settings where the immune system has evolved and actively functions. PMID:26118468

  7. Gene Gun-Mediated DNA Immunization Primes Development of Mucosal Immunity against Bovine Herpesvirus 1 in Cattle†

    PubMed Central

    Loehr, B. I.; Willson, P.; Babiuk, L. A.; van Drunen Littel-van den Hurk, S.

    2000-01-01

    Vaccination by a mucosal route is an excellent approach to the control of mucosally acquired infections. Several reports on rodents suggest that DNA vaccines can be used to achieve mucosal immunity when applied to mucosal tissues. However, with the exception of one study with pigs and another with horses, there is no information on mucosal DNA immunization of the natural host. In this study, the potential of inducing mucosal immunity in cattle by immunization with a DNA vaccine was demonstrated. Cattle were immunized with a plasmid encoding bovine herpesvirus 1 (BHV-1) glycoprotein B, which was delivered with a gene gun either intradermally or intravulvomucosally. Intravulvomucosal DNA immunization induced strong cellular immune responses and primed humoral immune responses. This was evident after BHV-1 challenge when high levels of both immunoglobulin G (IgG) and IgA were detected. Intradermal delivery resulted in lower levels of immunity than mucosal immunization. To determine whether the differences between the immune responses induced by intravulvomucosal and intradermal immunizations might be due to the efficacy of antigen presentation, the distributions of antigen and Langerhans cells in the skin and mucosa were compared. After intravulvomucosal delivery, antigen was expressed early and throughout the mucosa, but after intradermal administration, antigen expression occurred later and superficially in the skin. Furthermore, Langerhans cells were widely distributed in the mucosal epithelium but found primarily in the basal layers of the epidermis of the skin. Collectively, these observations may account for the stronger immune response induced by mucosal administration. PMID:10846091

  8. Diversification of innate immune genes: lessons from the purple sea urchin.

    PubMed

    Smith, L Courtney

    2010-01-01

    Pathogen diversification can alter infection virulence, which in turn drives the evolution of host immune diversification, resulting in countermeasures for survival in this arms race. Somatic recombination of the immunoglobulin gene family members is a very effective mechanism to diversify antibodies and T-cell receptors that function in the adaptive immune system. Although mechanisms to diversify innate immune genes are not clearly understood, a seemingly unlikely source for insight into innate immune diversification may be derived from the purple sea urchin, which has recently had its genome sequenced and annotated. Although there are many differences, some characteristics of the sea urchin make for a useful tool to understand the human immune system. The sea urchin is phylogenetically related to humans although, as a group, sea urchins are evolutionarily much older than mammals. Humans require both adaptive and innate immune responses to survive immune challenges, whereas sea urchins only require innate immune functions. Genes that function in immunity tend to be members of families, and the sea urchin has several innate immune gene families. One of these is the Sp185/333 gene family with about 50 clustered members that encode a diverse array of putative immune response proteins. Understanding gene diversification in the Sp185/333 family in the sea urchin may illuminate new mechanisms of diversification that could apply to gene families that function in innate immunity in humans, such as the killer immunoglobulin-like receptor genes. PMID:20354110

  9. Calcitonin Gene-Related Peptide: Key Regulator of Cutaneous Immunity

    PubMed Central

    Granstein, Richard D.; Wagner, John A.; Stohl, Lori L.; Ding, Wanhong

    2014-01-01

    Calcitonin gene-related peptide (CGRP) has been viewed as a neuropeptide and vasodilator. However, CGRP is more appropriately thought of as a pleiotropic signaling molecule. Indeed, CGRP has key regulatory functions on immune and inflammatory processes within the skin. CGRP-containing nerves are intimately associated with epidermal LCs and CGRP has profound regulatory effects on Langerhans cell antigen-presenting capability. When LCs are exposed to CGRP in vitro, their ability to present antigen for in vivo priming of naïve mice or elicitation of delayed-type hypersensitivity is inhibited in at least some situations. Administration of CGRP intradermally inhibits acquisition of immunity to Th1-dominant haptens applied to the injected site while augmenting immunity to Th2-dominant haptens, although the cellular targets of activity in these experiments remains unclear. Although CGRP can be a pro-inflammatory agent, several studies have demonstrated that administration of CGRP can inhibit the elicitation of inflammation by inflammatory stimuli in vivo. In this regard, CGRP inhibits the release of certain chemokines by stimulated endothelial cells. This is likely to be physiologically relevant since cutaneous blood vessels are innervated by sensory nerves. Exciting new studies suggest a significant role for CGRP in the pathogenesis of psoriasis and, most strikingly, that CGRP inhibit the ability of LCs to transmit the human immunodeficiency virus 1 to T lymphocytes. A more complete understanding of the role of CGRP in the skin immune system may lead to new and novel approaches for the therapy of immune mediated skin disorders. PMID:25534428

  10. Gene Expression Control by Glucocorticoid Receptors during Innate Immune Responses

    PubMed Central

    Xavier, Andre Machado; Anunciato, Aparecida Kataryna Olimpio; Rosenstock, Tatiana Rosado; Glezer, Isaias

    2016-01-01

    Glucocorticoids (GCs) are potent anti-inflammatory compounds that have been extensively used in clinical practice for several decades. GC’s effects on inflammation are generally mediated through GC receptors (GRs). Signal transduction through these nuclear receptors leads to dramatic changes in gene expression programs in different cell types, typically due to GR binding to DNA or to transcription modulators. During the last decade, the view of GCs as exclusive anti-inflammatory molecules has been challenged. GR negative interference in pro-inflammatory gene expression was a landmark in terms of molecular mechanisms that suppress immune activity. In fact, GR can induce varied inhibitory molecules, including a negative regulator of Toll-like receptors pathway, or subject key transcription factors, such as NF-κB and AP-1, to a repressor mechanism. In contrast, the expression of some acute-phase proteins and other players of innate immunity generally requires GR signaling. Consequently, GRs must operate context-dependent inhibitory, permissive, or stimulatory effects on host defense signaling triggered by pathogens or tissue damage. This review aims to disclose how contradictory or comparable effects on inflammatory gene expression can depend on pharmacological approach (including selective GC receptor modulators; SEGRMs), cell culture, animal treatment, or transgenic strategies used as models. Although the current view of GR-signaling integrated many advances in the field, some answers to important questions remain elusive. PMID:27148162

  11. Gene Expression Control by Glucocorticoid Receptors during Innate Immune Responses.

    PubMed

    Xavier, Andre Machado; Anunciato, Aparecida Kataryna Olimpio; Rosenstock, Tatiana Rosado; Glezer, Isaias

    2016-01-01

    Glucocorticoids (GCs) are potent anti-inflammatory compounds that have been extensively used in clinical practice for several decades. GC's effects on inflammation are generally mediated through GC receptors (GRs). Signal transduction through these nuclear receptors leads to dramatic changes in gene expression programs in different cell types, typically due to GR binding to DNA or to transcription modulators. During the last decade, the view of GCs as exclusive anti-inflammatory molecules has been challenged. GR negative interference in pro-inflammatory gene expression was a landmark in terms of molecular mechanisms that suppress immune activity. In fact, GR can induce varied inhibitory molecules, including a negative regulator of Toll-like receptors pathway, or subject key transcription factors, such as NF-κB and AP-1, to a repressor mechanism. In contrast, the expression of some acute-phase proteins and other players of innate immunity generally requires GR signaling. Consequently, GRs must operate context-dependent inhibitory, permissive, or stimulatory effects on host defense signaling triggered by pathogens or tissue damage. This review aims to disclose how contradictory or comparable effects on inflammatory gene expression can depend on pharmacological approach (including selective GC receptor modulators; SEGRMs), cell culture, animal treatment, or transgenic strategies used as models. Although the current view of GR-signaling integrated many advances in the field, some answers to important questions remain elusive. PMID:27148162

  12. Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production.

    PubMed

    Michelucci, Alessandro; Cordes, Thekla; Ghelfi, Jenny; Pailot, Arnaud; Reiling, Norbert; Goldmann, Oliver; Binz, Tina; Wegner, André; Tallam, Aravind; Rausell, Antonio; Buttini, Manuel; Linster, Carole L; Medina, Eva; Balling, Rudi; Hiller, Karsten

    2013-05-01

    Immunoresponsive gene 1 (Irg1) is highly expressed in mammalian macrophages during inflammation, but its biological function has not yet been elucidated. Here, we identify Irg1 as the gene coding for an enzyme producing itaconic acid (also known as methylenesuccinic acid) through the decarboxylation of cis-aconitate, a tricarboxylic acid cycle intermediate. Using a gain-and-loss-of-function approach in both mouse and human immune cells, we found Irg1 expression levels correlating with the amounts of itaconic acid, a metabolite previously proposed to have an antimicrobial effect. We purified IRG1 protein and identified its cis-aconitate decarboxylating activity in an enzymatic assay. Itaconic acid is an organic compound that inhibits isocitrate lyase, the key enzyme of the glyoxylate shunt, a pathway essential for bacterial growth under specific conditions. Here we show that itaconic acid inhibits the growth of bacteria expressing isocitrate lyase, such as Salmonella enterica and Mycobacterium tuberculosis. Furthermore, Irg1 gene silencing in macrophages resulted in significantly decreased intracellular itaconic acid levels as well as significantly reduced antimicrobial activity during bacterial infections. Taken together, our results demonstrate that IRG1 links cellular metabolism with immune defense by catalyzing itaconic acid production. PMID:23610393

  13. Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production

    PubMed Central

    Michelucci, Alessandro; Cordes, Thekla; Ghelfi, Jenny; Pailot, Arnaud; Reiling, Norbert; Goldmann, Oliver; Binz, Tina; Wegner, André; Tallam, Aravind; Rausell, Antonio; Buttini, Manuel; Linster, Carole L.; Medina, Eva; Balling, Rudi; Hiller, Karsten

    2013-01-01

    Immunoresponsive gene 1 (Irg1) is highly expressed in mammalian macrophages during inflammation, but its biological function has not yet been elucidated. Here, we identify Irg1 as the gene coding for an enzyme producing itaconic acid (also known as methylenesuccinic acid) through the decarboxylation of cis-aconitate, a tricarboxylic acid cycle intermediate. Using a gain-and-loss-of-function approach in both mouse and human immune cells, we found Irg1 expression levels correlating with the amounts of itaconic acid, a metabolite previously proposed to have an antimicrobial effect. We purified IRG1 protein and identified its cis-aconitate decarboxylating activity in an enzymatic assay. Itaconic acid is an organic compound that inhibits isocitrate lyase, the key enzyme of the glyoxylate shunt, a pathway essential for bacterial growth under specific conditions. Here we show that itaconic acid inhibits the growth of bacteria expressing isocitrate lyase, such as Salmonella enterica and Mycobacterium tuberculosis. Furthermore, Irg1 gene silencing in macrophages resulted in significantly decreased intracellular itaconic acid levels as well as significantly reduced antimicrobial activity during bacterial infections. Taken together, our results demonstrate that IRG1 links cellular metabolism with immune defense by catalyzing itaconic acid production. PMID:23610393

  14. Gene Risk Factors for Age-Related Brain Disorders May Affect Immune System Function

    MedlinePlus

    ... for age-related brain disorders may affect immune system function June 17, 2014 Scientists have discovered gene ... factors for age-related neurological disorders to immune system functions, such as inflammation, offers new insights into ...

  15. Royal Decree: Gene Expression in Trans-Generationally Immune Primed Bumblebee Workers Mimics a Primary Immune Response.

    PubMed

    Barribeau, Seth M; Schmid-Hempel, Paul; Sadd, Ben M

    2016-01-01

    Invertebrates lack the cellular and physiological machinery of the adaptive immune system, but show specificity in their immune response and immune priming. Functionally, immune priming is comparable to immune memory in vertebrates. Individuals that have survived exposure to a given parasite are better protected against subsequent exposures. Protection may be cross-reactive, but demonstrations of persistent and specific protection in invertebrates are increasing. This immune priming can cross generations ("trans-generational" immune priming), preparing offspring for the prevailing parasite environment. While these phenomena gain increasing support, the mechanistic foundations underlying such immune priming, both within and across generations, remain largely unknown. Using a transcriptomic approach, we show that exposing bumblebee queens with an injection of heat-killed bacteria, known to induce trans-generational immune priming, alters daughter (worker) gene expression. Daughters, even when unexposed themselves, constitutively express a core set of the genes induced upon direct bacterial exposure, including high expression of antimicrobial peptides, a beta-glucan receptor protein implicated in bacterial recognition and the induction of the toll signaling pathway, and slit-3 which is important in honeybee immunity. Maternal exposure results in a distinct upregulation of their daughters' immune system, with a signature overlapping with the induced individual response to a direct exposure. This will mediate mother-offspring protection, but also associated costs related to reconfiguration of constitutive immune expression. Moreover, identification of conserved immune pathways in memory-like responses has important implications for our understanding of the innate immune system, including the innate components in vertebrates, which share many of these pathways. PMID:27442590

  16. Royal Decree: Gene Expression in Trans-Generationally Immune Primed Bumblebee Workers Mimics a Primary Immune Response

    PubMed Central

    Schmid-Hempel, Paul; Sadd, Ben M.

    2016-01-01

    Invertebrates lack the cellular and physiological machinery of the adaptive immune system, but show specificity in their immune response and immune priming. Functionally, immune priming is comparable to immune memory in vertebrates. Individuals that have survived exposure to a given parasite are better protected against subsequent exposures. Protection may be cross-reactive, but demonstrations of persistent and specific protection in invertebrates are increasing. This immune priming can cross generations ("trans-generational" immune priming), preparing offspring for the prevailing parasite environment. While these phenomena gain increasing support, the mechanistic foundations underlying such immune priming, both within and across generations, remain largely unknown. Using a transcriptomic approach, we show that exposing bumblebee queens with an injection of heat-killed bacteria, known to induce trans-generational immune priming, alters daughter (worker) gene expression. Daughters, even when unexposed themselves, constitutively express a core set of the genes induced upon direct bacterial exposure, including high expression of antimicrobial peptides, a beta-glucan receptor protein implicated in bacterial recognition and the induction of the toll signaling pathway, and slit-3 which is important in honeybee immunity. Maternal exposure results in a distinct upregulation of their daughters’ immune system, with a signature overlapping with the induced individual response to a direct exposure. This will mediate mother-offspring protection, but also associated costs related to reconfiguration of constitutive immune expression. Moreover, identification of conserved immune pathways in memory-like responses has important implications for our understanding of the innate immune system, including the innate components in vertebrates, which share many of these pathways. PMID:27442590

  17. Depressed immune surveillance against cancer: role of deficient T cell: extracellular matrix interactions.

    PubMed

    Górski, A; Castronovo, V; Stepień-Sopniewska, B; Grieb, P; Ryba, M; Mrowiec, T; Korczak-Kowalska, G; Wierzbicki, P; Matysiak, W; Dybowska, B

    1994-07-01

    Although T cells infiltrate malignant tumors, the local immune response is usually inefficient and tumors escape destruction. While extracellular matrix proteins strongly costimulate T cell responses in normal individuals, our studies indicate that peripheral blood T cells from cancer patients and tumor infiltrating cells respond poorly or are resistant to stimulative signals mediated by collagen I and IV and fibronectin. Moreover, the adhesive properties of cancer T cells are markedly depressed. Those functional deficiencies are paralleled by variable deficits in integrin and non-integrin T cell receptors for extracellular matrix. Immunotherapy with BCG causes a dramatic but transient increase in T cell: ECM interactions. PMID:7827959

  18. Autochthonous primary and metastatic melanomas in Hgf-Cdk4 R24C mice evade T-cell-mediated immune surveillance.

    PubMed

    Landsberg, Jennifer; Gaffal, Evelyn; Cron, Mira; Kohlmeyer, Judith; Renn, Marcel; Tüting, Thomas

    2010-10-01

    Genetically engineered mouse models offer new opportunities to investigate the role of cell-mediated immunity in the natural progression of melanoma in an immunocompetent host. Here we report that Hgf-Cdk4(R24C) mice spontaneously develop a spectrum of primary melanomas with high penetrance during their first year of life. Malignant transformation proceeds in a stepwise manner from multiple melanocytic nevi to single nodular melanomas and disseminated metastases in most mice. Migrating melanoma cells invade the draining lymph nodes without activating the immune system. Autochthonous primary tumors are destroyed following experimental introduction of immune surveillance using an adoptive lymphocyte transfer approach. However, some tumor cells are able to survive, evade immune cell control, and recur both locally and systemically. Immune tolerance in recurring tumors may be supported by immunosuppressive Gr1(+) myeloid cells. Taken together, our results demonstrate that primary and metastatic melanomas developing spontaneously in Hgf-Cdk4(R24C) mice effectively evade cellular immune surveillance. PMID:20649939

  19. How is the effectiveness of immune surveillance impacted by the spatial distribution of spreading infections?

    PubMed Central

    Kadolsky, Ulrich D.; Yates, Andrew J.

    2015-01-01

    What effect does the spatial distribution of infected cells have on the efficiency of their removal by immune cells, such as cytotoxic T lymphocytes (CTL)? If infected cells spread in clusters, CTL may initially be slow to locate them but subsequently kill more rapidly than in diffuse infections. We address this question using stochastic, spatially explicit models of CTL interacting with different patterns of infection. Rather than the effector : target ratio, we show that the relevant quantity is the ratio of a CTL's expected time to locate its next target (search time) to the average time it spends conjugated with a target that it is killing (handling time). For inefficient (slow) CTL, when the search time is always limiting, the critical density of CTL (that required to control 50% of infections, C*) is independent of the spatial distribution and derives from simple mass-action kinetics. For more efficient CTL such that handling time becomes limiting, mass-action underestimates C*, and the more clustered an infection the greater is C*. If CTL migrate chemotactically towards targets the converse holds—C* falls, and clustered infections are controlled most efficiently. Real infections are likely to spread patchily; this combined with even weak chemotaxis means that sterilizing immunity may be achieved with substantially lower numbers of CTL than standard models predict. PMID:26150655

  20. The multifaceted role of autophagy in tumor evasion from immune surveillance

    PubMed Central

    Janji, Bassam; Viry, Elodie; Moussay, Etienne; Paggetti, Jérôme; Arakelian, Tsolère; Mgrditchian, Takouhie; Messai, Yosra; Noman, Muhammad Zaeem; Van Moer, Kris; Hasmim, Meriem; Mami-Chouaib, Fathia; Berchem, Guy; Chouaib, Salem

    2016-01-01

    While autophagy is constitutively executed at basal level in all cells, it is activated in cancer cells in response to various microenvironmental stresses including hypoxia. It is now well established that autophagy can act both as tumor suppressor or tumor promoter. In this regard, several reports indicate that the tumor suppressor function of autophagy is associated with its ability to scavenge damaged oxidative organelles, thereby preventing the accumulation of toxic oxygen radicals and limiting the genome instability. Paradoxically, in developed tumors, autophagy can promote the survival of cancer cells and therefore operates as a cell resistance mechanism. The consensus appears to be that autophagy has a dual role in suppressing tumor initiation and in promoting the survival of established tumors. This has inspired significant interest in applying anti-autophagy therapies as an entirely new approach to cancer treatment. While much remains to be learned about the regulation and context-dependent biological role of autophagy, it is now well established that modulation of this process could be an attractive approach for the development of novel anticancer therapeutic strategies. In this review, we will summarize recent reports describing how tumor cells, by activating autophagy, manage to resist the immune cell attack. Data described in this review strongly argue that targeting autophagy may represent a conceptual realm for new immunotherapeutic strategies aiming to block the immune escape and therefore providing rational approach to future tumor immunotherapy design. PMID:26910842

  1. The Nuclear Orphan Receptor NR2F6 Is a Central Checkpoint for Cancer Immune Surveillance

    PubMed Central

    Hermann-Kleiter, Natascha; Klepsch, Victoria; Wallner, Stephanie; Siegmund, Kerstin; Klepsch, Sebastian; Tuzlak, Selma; Villunger, Andreas; Kaminski, Sandra; Pfeifhofer-Obermair, Christa; Gruber, Thomas; Wolf, Dominik; Baier, Gottfried

    2015-01-01

    Summary Nuclear receptor subfamily 2, group F, member 6 (NR2F6) is an orphan member of the nuclear receptor superfamily. Here, we show that genetic ablation of Nr2f6 significantly improves survival in the murine transgenic TRAMP prostate cancer model. Furthermore, Nr2f6−/− mice spontaneously reject implanted tumors and develop host-protective immunological memory against tumor rechallenge. This is paralleled by increased frequencies of both CD4+ and CD8+ T cells and higher expression levels of interleukin 2 and interferon γ at the tumor site. Mechanistically, CD4+ and CD8+ T cell-intrinsic NR2F6 acts as a direct repressor of the NFAT/AP-1 complex on both the interleukin 2 and the interferon γ cytokine promoters, attenuating their transcriptional thresholds. Adoptive transfer of Nr2f6-deficient T cells into tumor-bearing immunocompetent mice is sufficient to delay tumor outgrowth. Altogether, this defines NR2F6 as an intracellular immune checkpoint in effector T cells, governing the amplitude of anti-cancer immunity. PMID:26387951

  2. The Nuclear Orphan Receptor NR2F6 Is a Central Checkpoint for Cancer Immune Surveillance.

    PubMed

    Hermann-Kleiter, Natascha; Klepsch, Victoria; Wallner, Stephanie; Siegmund, Kerstin; Klepsch, Sebastian; Tuzlak, Selma; Villunger, Andreas; Kaminski, Sandra; Pfeifhofer-Obermair, Christa; Gruber, Thomas; Wolf, Dominik; Baier, Gottfried

    2015-09-29

    Nuclear receptor subfamily 2, group F, member 6 (NR2F6) is an orphan member of the nuclear receptor superfamily. Here, we show that genetic ablation of Nr2f6 significantly improves survival in the murine transgenic TRAMP prostate cancer model. Furthermore, Nr2f6(-/-) mice spontaneously reject implanted tumors and develop host-protective immunological memory against tumor rechallenge. This is paralleled by increased frequencies of both CD4(+) and CD8(+) T cells and higher expression levels of interleukin 2 and interferon γ at the tumor site. Mechanistically, CD4(+) and CD8(+) T cell-intrinsic NR2F6 acts as a direct repressor of the NFAT/AP-1 complex on both the interleukin 2 and the interferon γ cytokine promoters, attenuating their transcriptional thresholds. Adoptive transfer of Nr2f6-deficient T cells into tumor-bearing immunocompetent mice is sufficient to delay tumor outgrowth. Altogether, this defines NR2F6 as an intracellular immune checkpoint in effector T cells, governing the amplitude of anti-cancer immunity. PMID:26387951

  3. Passive Immunization against HIV/AIDS by Antibody Gene Transfer

    PubMed Central

    Yang, Lili; Wang, Pin

    2014-01-01

    Despite tremendous efforts over the course of many years, the quest for an effective HIV vaccine by the classical method of active immunization remains largely elusive. However, two recent studies in mice and macaques have now demonstrated a new strategy designated as Vectored ImmunoProphylaxis (VIP), which involves passive immunization by viral vector-mediated delivery of genes encoding broadly neutralizing antibodies (bnAbs) for in vivo expression. Robust protection against virus infection was observed in preclinical settings when animals were given VIP to express monoclonal neutralizing antibodies. This unorthodox approach raises new promise for combating the ongoing global HIV pandemic. In this article, we survey the status of antibody gene transfer, review the revolutionary progress on isolation of extremely bnAbs, detail VIP experiments against HIV and its related virus conduced in humanized mice and macaque monkeys, and discuss the pros and cons of VIP and its opportunities and challenges towards clinical applications to control HIV/AIDS endemics. PMID:24473340

  4. Flg22-Triggered Immunity Negatively Regulates Key BR Biosynthetic Genes

    PubMed Central

    Jiménez-Góngora, Tamara; Kim, Seong-Ki; Lozano-Durán, Rosa; Zipfel, Cyril

    2015-01-01

    In plants, activation of growth and activation of immunity are opposing processes that define a trade-off. In the past few years, the growth-promoting hormones brassinosteroids (BR) have emerged as negative regulators of pathogen-associated molecular pattern (PAMP)-triggered immunity (PTI), promoting growth at the expense of defense. The crosstalk between BR and PTI signaling was described as negative and unidirectional, since activation of PTI does not affect several analyzed steps in the BR signaling pathway. In this work, we describe that activation of PTI by the bacterial PAMP flg22 results in the reduced expression of BR biosynthetic genes. This effect does not require BR perception or signaling, and occurs within 15 min of flg22 treatment. Since the described PTI-induced repression of gene expression may result in a reduction in BR biosynthesis, the crosstalk between PTI and BR could actually be negative and bidirectional, a possibility that should be taken into account when considering the interaction between these two pathways. PMID:26617621

  5. Passive immunization against HIV/AIDS by antibody gene transfer.

    PubMed

    Yang, Lili; Wang, Pin

    2014-02-01

    Despite tremendous efforts over the course of many years, the quest for an effective HIV vaccine by the classical method of active immunization remains largely elusive. However, two recent studies in mice and macaques have now demonstrated a new strategy designated as Vectored ImmunoProphylaxis (VIP), which involves passive immunization by viral vector-mediated delivery of genes encoding broadly neutralizing antibodies (bnAbs) for in vivo expression. Robust protection against virus infection was observed in preclinical settings when animals were given VIP to express monoclonal neutralizing antibodies. This unorthodox approach raises new promise for combating the ongoing global HIV pandemic. In this article, we survey the status of antibody gene transfer, review the revolutionary progress on isolation of extremely bnAbs, detail VIP experiments against HIV and its related virus conduced in humanized mice and macaque monkeys, and discuss the pros and cons of VIP and its opportunities and challenges towards clinical applications to control HIV/AIDS endemics. PMID:24473340

  6. Integrated immunogenomics in the chicken: Deciphering the immune response to identify disease resistance genes

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Resistance to infection takes place at many levels, and involves both non-specific and specific immune mechanisms. The chicken has a different repertoire of immune genes, molecules, cells and organs compared to mammals. To understand the role of any disease resistance gene(s), it is therefore impo...

  7. Characterization of rainbow trout (Oncorhynchus mykiss) spleen transcriptome and identification of immune-related genes

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Resistance against specific diseases is affecting profitability in fish production systems including rainbow trout. Limited information is known about functions and mechanisms of the immune gene pathways in teleosts. Immunogenomics are powerful tools to determine immune-related genes/gene pathways a...

  8. Gene Therapy for the Treatment of Primary Immune Deficiencies.

    PubMed

    Kuo, Caroline Y; Kohn, Donald B

    2016-05-01

    The use of gene therapy in the treatment of primary immune deficiencies (PID) has advanced significantly in the last decade. Clinical trials for X-linked severe combined immunodeficiency, adenosine deaminase deficiency (ADA), chronic granulomatous disease, and Wiskott-Aldrich syndrome have demonstrated that gene transfer into hematopoietic stem cells and autologous transplant can result in clinical improvement and is curative for many patients. Unfortunately, early clinical trials were complicated by vector-related insertional mutagenic events for several diseases with the exception of ADA-deficiency SCID. These results prompted the current wave of clinical trials for primary immunodeficiency using alternative retro- or lenti-viral vector constructs that are self-inactivating, and they have shown clinical efficacy without leukemic events thus far. The field of gene therapy continues to progress, with improvements in viral vector profiles, stem cell culturing techniques, and site-specific genome editing platforms. The future of gene therapy is promising, and we are quickly moving towards a time when it will be a standard cellular therapy for many forms of PID. PMID:27056559

  9. PD-L1 expression in metastatic neuroblastoma as an additional mechanism for limiting immune surveillance

    PubMed Central

    Dondero, Alessandra; Pastorino, Fabio; Della Chiesa, Mariella; Corrias, Maria Valeria; Morandi, Fabio; Pistoia, Vito; Olive, Daniel; Bellora, Francesca; Locatelli, Franco; Castellano, Aurora; Moretta, Lorenzo; Moretta, Alessandro; Bottino, Cristina; Castriconi, Roberta

    2016-01-01

    ABSTRACT The prognosis of high-risk neuroblastoma (NB) remains poor, although immunotherapies with anti-GD2 antibodies have been reported to provide some benefit. Immunotherapies can be associated with an IFNγ storm that induces in tumor cells the “adaptive immune resistance” characterized by the de-novo expression of Programmed Death Ligands (PD-Ls). Tumor cells can also constitutively express PD-Ls in response to oncogenic signaling. Here, we analyze the constitutive and the inducible surface expression of PD-Ls in NB cells. We show that virtually all HLA class Ipos NB cell lines constitutively express PD-L1, whereas PD-L2 is rarely detected. IFNγ upregulates or induces PD-L1 both in NB cell lines in vitro and in NB engrafted nude/nude mice. Importantly, after IFNγ stimulation PD-L1 can be acquired by NB cell lines, as well as by metastatic neuroblasts isolated from bone marrow aspirates of high-risk NB patients, characterized by different MYCN amplification status. Interestingly, in one patient NB cells were poorly responsive to IFNγ stimulation, pointing out that responsiveness to IFNγ might represent a further element of heterogeneity in metastatic neuroblasts. Finally, we document the presence of lymphocytes expressing the PD-1 receptor in NB-infiltrated bone marrow of patients. PD-1pos cells are mainly represented by αβ T cells, but also include small populations of γδ T cells and NK cells. Moreover, PD-1pos T cells have a higher expression of activation markers. Overall, our data show that a PD-L1-mediated immune resistance mechanism occurs in metastatic neuroblasts and provide a biological rationale for blocking the PD-1/PD-Ls axis in future combined immunotherapeutic approaches. PMID:26942080

  10. Copy number polymorphisms are not a common feature of innate immune genes.

    PubMed

    Linzmeier, Rose M; Ganz, Tomas

    2006-07-01

    Extensive copy number polymorphism was recently reported for innate immunity-related alpha-defensin genes DEFA1 and DEFA3 and beta-defensin genes DEFB4, DEFB103, and DEFB104. To establish whether such polymorphisms are a common feature of innate immune genes we used quantitative real-time PCR to determine the copy numbers of seven genes whose products have important innate immune functions. The genes encoding lysozyme, lactoferrin, cathelicidin antimicrobial peptide (hCAP18/LL-37), cathepsin G, bactericidal/permeability-increasing protein, azurocidin (CAP37/heparin-binding protein), and neutrophil elastase were each found to be single copy per haploid genome. These findings, along with the recent observation that defensin genes DEFA4, DEFA5, DEFA6, and DEFB1 are single copy, suggest that copy number polymorphisms are not a common feature of the innate immune genome but are restricted to a small subset of innate immunity-related genes. PMID:16617005

  11. The identification of immune genes in the milk transcriptome of the Tasmanian devil (Sarcophilus harrisii)

    PubMed Central

    Hewavisenti, Rehana V.; Morris, Katrina M.; O’Meally, Denis; Cheng, Yuanyuan; Papenfuss, Anthony T.

    2016-01-01

    Tasmanian devil (Sarcophilus harrisii) pouch young, like other marsupials, are born underdeveloped and immunologically naïve, and are unable to mount an adaptive immune response. The mother’s milk provides nutrients for growth and development as well as providing passive immunity. To better understand immune response in this endangered species, we set out to characterise the genes involved in passive immunity by sequencing and annotating the transcriptome of a devil milk sample collected during mid-lactation. At mid-lactation we expect the young to have heightened immune responses, as they have emerged from the pouch, encountering new pathogens. A total of 233,660 transcripts were identified, including approximately 17,827 unique protein-coding genes and 846 immune genes. The most highly expressed transcripts were dominated by milk protein genes such as those encoding early lactation protein, late lactation proteins, α-lactalbumin, α-casein and β-casein. There were numerous highly expressed immune genes including lysozyme, whey acidic protein, ferritin and major histocompatibility complex I and II. Genes encoding immunoglobulins, antimicrobial peptides, chemokines and immune cell receptors were also identified. The array of immune genes identified in this study reflects the importance of the milk in providing immune protection to Tasmanian devil young and provides the first insight into Tasmanian devil milk. PMID:26793426

  12. The identification of immune genes in the milk transcriptome of the Tasmanian devil (Sarcophilus harrisii).

    PubMed

    Hewavisenti, Rehana V; Morris, Katrina M; O'Meally, Denis; Cheng, Yuanyuan; Papenfuss, Anthony T; Belov, Katherine

    2016-01-01

    Tasmanian devil (Sarcophilus harrisii) pouch young, like other marsupials, are born underdeveloped and immunologically naïve, and are unable to mount an adaptive immune response. The mother's milk provides nutrients for growth and development as well as providing passive immunity. To better understand immune response in this endangered species, we set out to characterise the genes involved in passive immunity by sequencing and annotating the transcriptome of a devil milk sample collected during mid-lactation. At mid-lactation we expect the young to have heightened immune responses, as they have emerged from the pouch, encountering new pathogens. A total of 233,660 transcripts were identified, including approximately 17,827 unique protein-coding genes and 846 immune genes. The most highly expressed transcripts were dominated by milk protein genes such as those encoding early lactation protein, late lactation proteins, α-lactalbumin, α-casein and β-casein. There were numerous highly expressed immune genes including lysozyme, whey acidic protein, ferritin and major histocompatibility complex I and II. Genes encoding immunoglobulins, antimicrobial peptides, chemokines and immune cell receptors were also identified. The array of immune genes identified in this study reflects the importance of the milk in providing immune protection to Tasmanian devil young and provides the first insight into Tasmanian devil milk. PMID:26793426

  13. Contrasting patterns of selection and drift between two categories of immune genes in prairie-chickens.

    PubMed

    Bateson, Zachary W; Whittingham, Linda A; Johnson, Jeff A; Dunn, Peter O

    2015-12-01

    Immune-receptor genes of the adaptive immune system, such as the major histocompatibility complex (MHC), are involved in recognizing specific pathogens and are known to have high rates of adaptive evolution, presumably as a consequence of rapid co-evolution between hosts and pathogens. In contrast, many 'mediating' genes of the immune system do not interact directly with specific pathogens and are involved in signalling (e.g. cytokines) or controlling immune cell growth. As a consequence, we might expect stronger selection at immune-receptor than mediating genes, but these two types of genes have not been compared directly in wild populations. Here, we tested the hypothesis that selection differs between MHC (class I and II) and mediating genes by comparing levels of population differentiation across the range of greater prairie-chickens (Tympanuchus cupido). As predicted, there was stronger population differentiation and isolation by distance at immune receptor (MHC) than at either mediating genes or neutral microsatellites, suggesting a stronger role of local adaptation at the MHC. In contrast, mediating genes displayed weaker differentiation between populations than neutral microsatellites, consistent with selection favouring similar alleles across populations for mediating genes. In addition to selection, drift also had a stronger effect on immune receptor (MHC) than mediating genes as indicated by the stronger decline of MHC variation in relation to population size. This is the first study in the wild to show that the effects of selection and drift on immune genes vary across populations depending on their functional role. PMID:26547898

  14. Identification of pleiotropic genes and gene sets underlying growth and immunity traits: a case study on Meishan pigs.

    PubMed

    Zhang, Z; Wang, Z; Yang, Y; Zhao, J; Chen, Q; Liao, R; Chen, Z; Zhang, X; Xue, M; Yang, H; Zheng, Y; Wang, Q; Pan, Y

    2016-04-01

    Both growth and immune capacity are important traits in animal breeding. The animal quantitative trait loci (QTL) database is a valuable resource and can be used for interpreting the genetic mechanisms that underlie growth and immune traits. However, QTL intervals often involve too many candidate genes to find the true causal genes. Therefore, the aim of this study was to provide an effective annotation pipeline that can make full use of the information of Gene Ontology terms annotation, linkage gene blocks and pathways to further identify pleiotropic genes and gene sets in the overlapping intervals of growth-related and immunity-related QTLs. In total, 55 non-redundant QTL overlapping intervals were identified, 1893 growth-related genes and 713 immunity-related genes were further classified into overlapping intervals and 405 pleiotropic genes shared by the two gene sets were determined. In addition, 19 pleiotropic gene linkage blocks and 67 pathways related to immunity and growth traits were discovered. A total of 343 growth-related genes and 144 immunity-related genes involved in pleiotropic pathways were also identified, respectively. We also sequenced and genotyped 284 individuals from Chinese Meishan pigs and European pigs and mapped the single nucleotide polymorphisms (SNPs) to the pleiotropic genes and gene sets that we identified. A total of 971 high-confidence SNPs were mapped to the pleiotropic genes and gene sets that we identified, and among them 743 SNPs were statistically significant in allele frequency between Meishan and European pigs. This study explores the relationship between growth and immunity traits from the view of QTL overlapping intervals and can be generalized to explore the relationships between other traits. PMID:26689779

  15. Emerging roles of interferon-stimulated genes in the innate immune response to hepatitis C virus infection.

    PubMed

    Wong, Mun-Teng; Chen, Steve S-L

    2016-01-01

    Infection with hepatitis C virus (HCV), a major viral cause of chronic liver disease, frequently progresses to steatosis and cirrhosis, which can lead to hepatocellular carcinoma. HCV infection strongly induces host responses, such as the activation of the unfolded protein response, autophagy and the innate immune response. Upon HCV infection, the host induces the interferon (IFN)-mediated frontline defense to limit virus replication. Conversely, HCV employs diverse strategies to escape host innate immune surveillance. Type I IFN elicits its antiviral actions by inducing a wide array of IFN-stimulated genes (ISGs). Nevertheless, the mechanisms by which these ISGs participate in IFN-mediated anti-HCV actions remain largely unknown. In this review, we first outline the signaling pathways known to be involved in the production of type I IFN and ISGs and the tactics that HCV uses to subvert innate immunity. Then, we summarize the effector mechanisms of scaffold ISGs known to modulate IFN function in HCV replication. We also highlight the potential functions of emerging ISGs, which were identified from genome-wide siRNA screens, in HCV replication. Finally, we discuss the functions of several cellular determinants critical for regulating host immunity in HCV replication. This review will provide a basis for understanding the complexity and functionality of the pleiotropic IFN system in HCV infection. Elucidation of the specificity and the mode of action of these emerging ISGs will also help to identify novel cellular targets against which effective HCV therapeutics can be developed. PMID:25544499

  16. Molecular surveillance for carbapenemase genes in carbapenem-resistant Pseudomonas aeruginosa in Australian patients with cystic fibrosis.

    PubMed

    Tai, Anna S; Kidd, Timothy J; Whiley, David M; Ramsay, Kay A; Buckley, Cameron; Bell, Scott C

    2015-02-01

    The aim of this study was to assess the prevalence of acquired carbapenemase genes amongst carbapenem non-susceptible Pseudomonas aeruginosa isolates in Australian patients with cystic fibrosis (CF). Cross-sectional molecular surveillance for acquired carbapenemase genes was performed on CF P. aeruginosa isolates from two isolate banks comprising: (i) 662 carbapenem resistant P. aeruginosa isolates from 227 patients attending 10 geographically diverse Australian CF centres (2007-2009), and (ii) 519 P. aeruginosa isolates from a cohort of 173 adult patients attending one Queensland CF clinic in 2011. All 1189 P. aeruginosa isolates were tested by polymerase chain reaction (PCR) protocols targeting ten common carbapenemase genes, as well the Class 1 integron intI1 gene and the aadB aminoglycoside resistance gene. No carbapenemase genes were identified among all isolates tested. The intI1 and aadB genes were frequently detected and were significantly associated with the AUST-02 strain (OR 24.6, 95% CI 9.3-65.6; p < 0.0001) predominantly from Queensland patients. Despite the high prevalence of carbapenem resistance in P. aeruginosa in Australian patients with CF, no acquired carbapenemase genes were detected in the study, suggesting chromosomal mutations remain the key resistance mechanism in CF isolates. Systematic surveillance for carbapenemase-producing P. aeruginosa in CF by molecular surveillance is ongoing. PMID:25551306

  17. PCR-based detection of gene transfer vectors: application to gene doping surveillance.

    PubMed

    Perez, Irene C; Le Guiner, Caroline; Ni, Weiyi; Lyles, Jennifer; Moullier, Philippe; Snyder, Richard O

    2013-12-01

    Athletes who illicitly use drugs to enhance their athletic performance are at risk of being banned from sports competitions. Consequently, some athletes may seek new doping methods that they expect to be capable of circumventing detection. With advances in gene transfer vector design and therapeutic gene transfer, and demonstrations of safety and therapeutic benefit in humans, there is an increased probability of the pursuit of gene doping by athletes. In anticipation of the potential for gene doping, assays have been established to directly detect complementary DNA of genes that are top candidates for use in doping, as well as vector control elements. The development of molecular assays that are capable of exposing gene doping in sports can serve as a deterrent and may also identify athletes who have illicitly used gene transfer for performance enhancement. PCR-based methods to detect foreign DNA with high reliability, sensitivity, and specificity include TaqMan real-time PCR, nested PCR, and internal threshold control PCR. PMID:23912835

  18. The broken "Off" switch in cancer signaling: PP2A as a regulator of tumorigenesis, drug resistance, and immune surveillance.

    PubMed

    Ruvolo, Peter P

    2016-12-01

    Aberrant activation of signal transduction pathways can transform a normal cell to a malignant one and can impart survival properties that render cancer cells resistant to therapy. A diverse set of cascades have been implicated in various cancers including those mediated by serine/threonine kinases such RAS, PI3K/AKT, and PKC. Signal transduction is a dynamic process involving both "On" and "Off" switches. Activating mutations of RAS or PI3K can be viewed as the switch being stuck in the "On" position resulting in continued signaling by a survival and/or proliferation pathway. On the other hand, inactivation of protein phosphatases such as the PP2A family can be seen as the defective "Off" switch that similarly can activate these pathways. A problem for therapeutic targeting of PP2A is that the enzyme is a hetero-trimer and thus drug targeting involves complex structures. More importantly, since PP2A isoforms generally act as tumor suppressors one would want to activate these enzymes rather than suppress them. The elucidation of the role of cellular inhibitors like SET and CIP2A in cancer suggests that targeting these proteins can have therapeutic efficacy by mechanisms involving PP2A activation. Furthermore, drugs such as FTY-720 can activate PP2A isoforms directly. This review will cover the current state of knowledge of PP2A role as a tumor suppressor in cancer cells and as a mediator of processes that can impact drug resistance and immune surveillance. PMID:27556014

  19. Genome-wide analysis of immune system genes by expressed sequence Tag profiling.

    PubMed

    Giallourakis, Cosmas C; Benita, Yair; Molinie, Benoit; Cao, Zhifang; Despo, Orion; Pratt, Henry E; Zukerberg, Lawrence R; Daly, Mark J; Rioux, John D; Xavier, Ramnik J

    2013-06-01

    Profiling studies of mRNA and microRNA, particularly microarray-based studies, have been extensively used to create compendia of genes that are preferentially expressed in the immune system. In some instances, functional studies have been subsequently pursued. Recent efforts such as the Encyclopedia of DNA Elements have demonstrated the benefit of coupling RNA sequencing analysis with information from expressed sequence tags (ESTs) for transcriptomic analysis. However, the full characterization and identification of transcripts that function as modulators of human immune responses remains incomplete. In this study, we demonstrate that an integrated analysis of human ESTs provides a robust platform to identify the immune transcriptome. Beyond recovering a reference set of immune-enriched genes and providing large-scale cross-validation of previous microarray studies, we discovered hundreds of novel genes preferentially expressed in the immune system, including noncoding RNAs. As a result, we have established the Immunogene database, representing an integrated EST road map of gene expression in human immune cells, which can be used to further investigate the function of coding and noncoding genes in the immune system. Using this approach, we have uncovered a unique metabolic gene signature of human macrophages and identified PRDM15 as a novel overexpressed gene in human lymphomas. Thus, we demonstrate the utility of EST profiling as a basis for further deconstruction of physiologic and pathologic immune processes. PMID:23616578

  20. Identification and evolution of an NFAT gene involving Branchiostoma belcheri innate immunity.

    PubMed

    Song, Xiaojun; Hu, Jing; Jin, Ping; Chen, Liming; Ma, Fei

    2013-10-01

    The Nuclear Factor of Activated T cells (NFAT) plays an important role in innate and adaptive immunity, but no NFAT genes have yet been identified in amphioxus species. Here we identified and characterized an NFAT-like gene from Branchiostoma belcheri, and also studied extensively the evolutionary history of NFAT family genes. We found that the amphioxus genome contains an AmphiNFAT gene encoding an NFAT homolog. The AmphiNFAT gene was found to be involved in the innate immune response to LPS stimulation in B. belcheri and was ubiquitously and differentially expressed in all investigated tissues. The NFAT family genes were present in a common ancestor with cnidaria, and NFAT1-4 paralogs were lost early in Branchiostoma and Strongylocentrotus genomes. We discovered that NFAT family genes underwent strong purifying selection. Taken together, our findings provide an insight into the innate immune response of amphioxus and the evolution of the NFAT gene family. PMID:23657135

  1. Genome-Wide RNAi Screens in C. elegans to Identify Genes Influencing Lifespan and Innate Immunity.

    PubMed

    Sinha, Amit; Rae, Robbie

    2016-01-01

    RNA interference is a rapid, inexpensive, and highly effective tool used to inhibit gene function. In C. elegans, whole genome screens have been used to identify genes involved with numerous traits including aging and innate immunity. RNAi in C. elegans can be carried out via feeding, soaking, or injection. Here we outline protocols used to maintain, grow, and carry out RNAi via feeding in C. elegans and determine whether the inhibited genes are essential for lifespan or innate immunity. PMID:27581293

  2. Massive expansion and functional divergence of innate immune genes in a protostome

    PubMed Central

    Zhang, Linlin; Li, Li; Guo, Ximing; Litman, Gary W.; Dishaw, Larry J.; Zhang, Guofan

    2015-01-01

    The molecules that mediate innate immunity are encoded by relatively few genes and exhibit broad specificity. Detailed annotation of the Pacific oyster (Crassostrea gigas) genome, a protostome invertebrate, reveals large-scale duplication and divergence of multigene families encoding molecules that effect innate immunity. Transcriptome analyses indicate dynamic and orchestrated specific expression of numerous innate immune genes in response to experimental challenge with pathogens, including bacteria, and a pathogenic virus. Variable expression of individual members of the multigene families encoding these genes also occurs during different types of abiotic stress (environmentally-equivalent conditions of temperature, salinity and desiccation). Multiple families of immune genes are responsive in concert to certain biotic and abiotic challenges. Individual members of expanded families of immune genes are differentially expressed under both biotic challenge and abiotic stress conditions. Members of the same families of innate immune molecules also are transcribed in developmental stage- and tissue-specific manners. An integrated, highly complex innate immune system that exhibits remarkable discriminatory properties and responses to different pathogens as well as environmental stress has arisen through the adaptive recruitment of tandem duplicated genes. The co-adaptive evolution of stress and innate immune responses appears to have an ancient origin in phylogeny. PMID:25732911

  3. Comparative tissue expression of American lobster (Homarus americanus) immune genes during bacterial and scuticociliate challenge.

    PubMed

    Clark, K Fraser; Acorn, Adam R; Wang, Haili; Greenwood, Spencer J

    2015-12-01

    The American lobster (Homarus americanus) fishery is the most economically significant fishery in Canada; although comparatively little is known about the lobsters' response to pathogenic challenge. This is the first study to investigate the expression of immune genes in tissues outside of the lobster hepatopancreas in response to challenges by the Gram-positive bacteria, Aerococcus viridans var. homari or the scuticociliate parasite, Anophryoides haemophila. The hepatopancreas has been regarded as the major humoral immune organ in crustaceans, but the contribution of other organs and tissues to the molecular immune response has largely been overlooked. This study used RT-qPCR to monitor the gene expression of several immune genes including three anti-lipopolysaccharide isoforms (ALF) Homame ALF-B1, Homame ALF-C1 and ALFHa-1, acute phase serum amyloid protein A (SAA), as well as thioredoxin and hexokinase, in antennal gland and gill tissues. Our findings indicate that the gene expression of the SAA and all ALF isoforms in the antennal gland and gill tissues increased in response to pathogenic challenge. However, there was differential expression of individual ALF isoforms that were dependent on both the tissue, and the pathogen used in the challenge. The gene expression changes of several immune genes were found to be higher in the antennal gland than have been previously reported for the hepatopancreas. This study demonstrates that increased immune gene expression from the gill and antennal gland over the course of pathogen induced disease contributes to the immune response of H. americanus. PMID:26551049

  4. Innate immunity gene polymorphisms and the risk of colorectal neoplasia.

    PubMed

    Chang, Cindy M; Chia, Victoria M; Gunter, Marc J; Zanetti, Krista A; Ryan, Bríd M; Goodman, Julie E; Harris, Curtis C; Weissfeld, Joel; Huang, Wen-Yi; Chanock, Stephen; Yeager, Meredith; Hayes, Richard B; Berndt, Sonja I

    2013-11-01

    Inherited variation in genes that regulate innate immunity and inflammation may contribute to colorectal neoplasia risk. To evaluate this association, we conducted a nested case-control study of 451 colorectal cancer cases, 694 colorectal advanced adenoma cases and 696 controls of European descent within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. A total of 935 tag single-nucleotide polymorphisms (SNPs) in 98 genes were evaluated. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association with colorectal neoplasia. Sixteen SNPs were associated with colorectal neoplasia risk at P < 0.01, but after adjustment for multiple testing, only rs2838732 (ITGB2) remained suggestively associated with colorectal neoplasia (OR(per T allele) = 0.68, 95% CI: 0.57-0.83, P = 7.7 × 10(-5), adjusted P = 0.07). ITGB2 codes for the CD18 protein in the integrin beta chain family. The ITGB2 association was stronger for colorectal cancer (OR(per T allele) = 0.41, 95% CI: 0.30-0.55, P = 2.4 × 10(-) (9)) than for adenoma (OR(per T allele) = 0.84, 95%CI: 0.69-1.03, P = 0.08), but it did not replicate in the validation study. The ITGB2 rs2838732 association was significantly modified by smoking status (P value for interaction = 0.003). Among never and former smokers, it was inversely associated with colorectal neoplasia (OR(per T allele) = 0.5, 95% CI: 0.37-0.69 and OR(per T allele) = 0.72, 95% CI: 0.54-0.95, respectively), but no association was seen among current smokers. Other notable findings were observed for SNPs in BPI/LBP and MYD88. Although the results need to be replicated, our findings suggest that genetic variation in inflammation-related genes may be related to the risk of colorectal neoplasia. PMID:23803696

  5. Innate immunity gene polymorphisms and the risk of colorectal neoplasia

    PubMed Central

    Berndt, Sonja I.

    2013-01-01

    Inherited variation in genes that regulate innate immunity and inflammation may contribute to colorectal neoplasia risk. To evaluate this association, we conducted a nested case–control study of 451 colorectal cancer cases, 694 colorectal advanced adenoma cases and 696 controls of European descent within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. A total of 935 tag single-nucleotide polymorphisms (SNPs) in 98 genes were evaluated. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association with colorectal neoplasia. Sixteen SNPs were associated with colorectal neoplasia risk at P < 0.01, but after adjustment for multiple testing, only rs2838732 (ITGB2) remained suggestively associated with colorectal neoplasia (ORper T allele = 0.68, 95% CI: 0.57–0.83, P = 7.7 × 10–5, adjusted P = 0.07). ITGB2 codes for the CD18 protein in the integrin beta chain family. The ITGB2 association was stronger for colorectal cancer (ORper T allele = 0.41, 95% CI: 0.30–0.55, P = 2.4 × 10− 9) than for adenoma (ORper T allele = 0.84, 95%CI: 0.69–1.03, P = 0.08), but it did not replicate in the validation study. The ITGB2 rs2838732 association was significantly modified by smoking status (P value for interaction = 0.003). Among never and former smokers, it was inversely associated with colorectal neoplasia (ORper T allele = 0.5, 95% CI: 0.37–0.69 and ORper T allele = 0.72, 95% CI: 0.54–0.95, respectively), but no association was seen among current smokers. Other notable findings were observed for SNPs in BPI/LBP and MYD88. Although the results need to be replicated, our findings suggest that genetic variation in inflammation-related genes may be related to the risk of colorectal neoplasia. PMID:23803696

  6. Ventromedial hypothalamic lesions change the expression of neuron-related genes and immune-related genes in rat liver.

    PubMed

    Kiba, Takayoshi; Kintaka, Yuri; Suzuki, Yoko; Nakata, Eiko; Ishigaki, Yasuhito; Inoue, Shuji

    2009-05-01

    There are no reports that hypothalamus can directly affect the expression of neuron-related genes and immune-related genes in liver. We identified genes of which expression profiles showed significant modulation in rat liver after ventromedial hypothalamic (VMH) lesions. Total RNA was extracted, and differences in the gene expression profiles between rats at day 3 after VMH lesioning and sham-VMH lesioned rats were investigated using DNA microarray analysis. The result revealed that VMH lesions regulated the genes that were involved in functions related to neuronal development and immunofunction in the liver. Real-time PCR also confirmed that gene expression of SULT4A1 was upregulated, but expression of ACSL1 and CISH were downregulated at day 3 after VMH lesions. VMH lesions may change the expression of neuron-related genes and immune-related genes in rat liver. PMID:19429097

  7. Repeated observation of immune gene sets enrichment in women with non-small cell lung cancer.

    PubMed

    Araujo, Jhajaira M; Prado, Alexandra; Cardenas, Nadezhda K; Zaharia, Mayer; Dyer, Richard; Doimi, Franco; Bravo, Leny; Pinillos, Luis; Morante, Zaida; Aguilar, Alfredo; Mas, Luis A; Gomez, Henry L; Vallejos, Carlos S; Rolfo, Christian; Pinto, Joseph A

    2016-04-12

    There are different biological and clinical patterns of lung cancer between genders indicating intrinsic differences leading to increased sensitivity to cigarette smoke-induced DNA damage, mutational patterns of KRAS and better clinical outcomes in women while differences between genders at gene-expression levels was not previously reported. Here we show an enrichment of immune genes in NSCLC in women compared to men. We found in a GSEA analysis (by biological processes annotated from Gene Ontology) of six public datasets a repeated observation of immune gene sets enrichment in women. "Immune system process", "immune response", "defense response", "cellular defense response" and "regulation of immune system process" were the gene sets most over-represented while APOBEC3G, APOBEC3F, LAT, CD1D and CCL5 represented the top-five core genes. Characterization of immune cell composition with the platform CIBERSORT showed no differences between genders; however, there were differences when tumor tissues were compared to normal tissues. Our results suggest different immune responses in NSCLC between genders that could be related with the different clinical outcome. PMID:26958810

  8. Repeated observation of immune gene sets enrichment in women with non-small cell lung cancer

    PubMed Central

    Araujo, Jhajaira M.; Prado, Alexandra; Cardenas, Nadezhda K.; Zaharia, Mayer; Dyer, Richard; Doimi, Franco; Bravo, Leny; Pinillos, Luis; Morante, Zaida; Aguilar, Alfredo; Mas, Luis A.; Gomez, Henry L.; Vallejos, Carlos S.; Rolfo, Christian; Pinto, Joseph A.

    2016-01-01

    There are different biological and clinical patterns of lung cancer between genders indicating intrinsic differences leading to increased sensitivity to cigarette smoke-induced DNA damage, mutational patterns of KRAS and better clinical outcomes in women while differences between genders at gene-expression levels was not previously reported. Here we show an enrichment of immune genes in NSCLC in women compared to men. We found in a GSEA analysis (by biological processes annotated from Gene Ontology) of six public datasets a repeated observation of immune gene sets enrichment in women. “Immune system process”, “immune response”, “defense response”, “cellular defense response” and “regulation of immune system process” were the gene sets most over-represented while APOBEC3G, APOBEC3F, LAT, CD1D and CCL5 represented the top-five core genes. Characterization of immune cell composition with the platform CIBERSORT showed no differences between genders; however, there were differences when tumor tissues were compared to normal tissues. Our results suggest different immune responses in NSCLC between genders that could be related with the different clinical outcome. PMID:26958810

  9. The immune gene repertoire encoded in the purple sea urchin genome.

    PubMed

    Hibino, Taku; Loza-Coll, Mariano; Messier, Cynthia; Majeske, Audrey J; Cohen, Avis H; Terwilliger, David P; Buckley, Katherine M; Brockton, Virginia; Nair, Sham V; Berney, Kevin; Fugmann, Sebastian D; Anderson, Michele K; Pancer, Zeev; Cameron, R Andrew; Smith, L Courtney; Rast, Jonathan P

    2006-12-01

    Echinoderms occupy a critical and largely unexplored phylogenetic vantage point from which to infer both the early evolution of bilaterian immunity and the underpinnings of the vertebrate adaptive immune system. Here we present an initial survey of the purple sea urchin genome for genes associated with immunity. An elaborate repertoire of potential immune receptors, regulators and effectors is present, including unprecedented expansions of innate pathogen recognition genes. These include a diverse array of 222 Toll-like receptor (TLR) genes and a coordinate expansion of directly associated signaling adaptors. Notably, a subset of sea urchin TLR genes encodes receptors with structural characteristics previously identified only in protostomes. A similarly expanded set of 203 NOD/NALP-like cytoplasmic recognition proteins is present. These genes have previously been identified only in vertebrates where they are represented in much lower numbers. Genes that mediate the alternative and lectin complement pathways are described, while gene homologues of the terminal pathway are not present. We have also identified several homologues of genes that function in jawed vertebrate adaptive immunity. The most striking of these is a gene cluster with similarity to the jawed vertebrate Recombination Activating Genes 1 and 2 (RAG1/2). Sea urchins are long-lived, complex organisms and these findings reveal an innate immune system of unprecedented complexity. Whether the presumably intense selective processes that molded these gene families also gave rise to novel immune mechanisms akin to adaptive systems remains to be seen. The genome sequence provides immediate opportunities to apply the advantages of the sea urchin model toward problems in developmental and evolutionary immunobiology. PMID:17027739

  10. Intestinal immune gene response to bacterial challenge in rainbow trout (Oncorhynchus mykiss)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The mucosal immune system of fish is poorly understood and defined models for studying this system are lacking. The objective of this study was to evaluate different challenge paradigms and pathogens to examine the magnitude of change in intestinal immune gene expression. Rainbow trout were expos...

  11. Modulation of rainbow trout (Oncorhynchus mykiss) intestinal immune gene expression following bacterial challenge

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The mucosal immune system of fish is still poorly understood, and defined models for studying natural host-pathogen interaction are lacking. The objective of this study was to evaluate different challenge paradigms and pathogens to examine the magnitude of change in intestinal immune gene expressio...

  12. Bifunctional Gene Cluster lnqBCDEF Mediates Bacteriocin Production and Immunity with Differential Genetic Requirements

    PubMed Central

    Iwatani, Shun; Horikiri, Yuko; Zendo, Takeshi; Nakayama, Jiro

    2013-01-01

    A comprehensive gene disruption of lacticin Q biosynthetic cluster lnqQBCDEF was carried out. The results demonstrated the necessity of the complete set of lnqQBCDEF for lacticin Q production, whereas immunity was flexible, with LnqEF (ABC transporter) being essential for and LnqBCD partially contributing to immunity. PMID:23335763

  13. Electronic Sorting of Immune Cell Subpopulations Based on Highly Plastic Genes.

    PubMed

    Wang, Pingzhang; Han, Wenling; Ma, Dalong

    2016-07-15

    Immune cells are highly heterogeneous and plastic with regard to gene expression and cell phenotype. In this study, we categorized genes into those with low and high gene plasticity, and those categories revealed different functions and applications. We proposed that highly plastic genes could be suited for the labeling of immune cell subpopulations; thus, novel immune cell subpopulations could be identified by gene plasticity analysis. For this purpose, we systematically analyzed highly plastic genes in human and mouse immune cells. In total, 1,379 human and 883 mouse genes were identified as being extremely plastic. We also expanded our previous immunoinformatic method, electronic sorting, which surveys big data to perform virtual analysis. This approach used correlation analysis and took dosage changes into account, which allowed us to identify the differentially expressed genes. A test with human CD4(+) T cells supported the method's feasibility, effectiveness, and predictability. For example, with the use of human nonregulatory T cells, we found that FOXP3(hi)CD4(+) T cells were highly expressive of certain known molecules, such as CD25 and CTLA4, and that this process of investigation did not require isolating or inducing these immune cells in vitro. Therefore, the sorting process helped us to discover the potential signature genes or marker molecules and to conduct functional evaluations for immune cell subpopulations. Finally, in human CD4(+) T cells, 747 potential immune cell subpopulations and their candidate signature genes were identified, which provides a useful resource for big data-driven knowledge discoveries. PMID:27288532

  14. Post-marketing surveillance of adverse events following immunization with inactivated quadrivalent and trivalent influenza vaccine in health care providers in Western Australia.

    PubMed

    Regan, Annette K; Tracey, Lauren; Gibbs, Robyn

    2015-11-17

    In 2015, inactivated quadrivalent influenza vaccine (QIV) was first introduced into the Australian market. A routine vaccine safety surveillance system in Western Australia was used to conduct post-licensure surveillance of adverse events following immunization with inactivated QIV and trivalent influenza vaccines (TIV) in a sample of 1685 healthcare providers (HCPs). A similar percentage of HCPs who received QIV reported having any reaction seven days post-vaccination as HCPs who received TIV (13.6 vs. 12.8%, respectively; p=0.66). However, a slightly higher percentage of HCPs who received QIV reported pain or swelling at the injection site as compared to HCPs who received TIV (6.9% vs. 4.2%, respectively; p=0.02). No serious vaccine-associated adverse events were detected during follow-up of either vaccine. Acknowledging the study limitations, the results of this post-marketing surveillance support the safety of QIV, suggesting there is little difference in the reactogenicity of QIV as compared to TIV. PMID:26476362

  15. Identification of immunity related genes to study the Physalis peruviana--Fusarium oxysporum pathosystem.

    PubMed

    Enciso-Rodríguez, Felix E; González, Carolina; Rodríguez, Edwin A; López, Camilo E; Landsman, David; Barrero, Luz Stella; Mariño-Ramírez, Leonardo

    2013-01-01

    The Cape gooseberry (Physalisperuviana L) is an Andean exotic fruit with high nutritional value and appealing medicinal properties. However, its cultivation faces important phytosanitary problems mainly due to pathogens like Fusarium oxysporum, Cercosporaphysalidis and Alternaria spp. Here we used the Cape gooseberry foliar transcriptome to search for proteins that encode conserved domains related to plant immunity including: NBS (Nucleotide Binding Site), CC (Coiled-Coil), TIR (Toll/Interleukin-1 Receptor). We identified 74 immunity related gene candidates in P. peruviana which have the typical resistance gene (R-gene) architecture, 17 Receptor like kinase (RLKs) candidates related to PAMP-Triggered Immunity (PTI), eight (TIR-NBS-LRR, or TNL) and nine (CC-NBS-LRR, or CNL) candidates related to Effector-Triggered Immunity (ETI) genes among others. These candidate genes were categorized by molecular function (98%), biological process (85%) and cellular component (79%) using gene ontology. Some of the most interesting predicted roles were those associated with binding and transferase activity. We designed 94 primers pairs from the 74 immunity-related genes (IRGs) to amplify the corresponding genomic regions on six genotypes that included resistant and susceptible materials. From these, we selected 17 single band amplicons and sequenced them in 14 F. oxysporum resistant and susceptible genotypes. Sequence polymorphisms were analyzed through preliminary candidate gene association, which allowed the detection of one SNP at the PpIRG-63 marker revealing a nonsynonymous mutation in the predicted LRR domain suggesting functional roles for resistance. PMID:23844210

  16. Identification of Immunity Related Genes to Study the Physalis peruviana – Fusarium oxysporum Pathosystem

    PubMed Central

    Enciso-Rodríguez, Felix E.; González, Carolina; Rodríguez, Edwin A.; López, Camilo E.; Landsman, David; Barrero, Luz Stella; Mariño-Ramírez, Leonardo

    2013-01-01

    The Cape gooseberry (Physalisperuviana L) is an Andean exotic fruit with high nutritional value and appealing medicinal properties. However, its cultivation faces important phytosanitary problems mainly due to pathogens like Fusarium oxysporum, Cercosporaphysalidis and Alternaria spp. Here we used the Cape gooseberry foliar transcriptome to search for proteins that encode conserved domains related to plant immunity including: NBS (Nucleotide Binding Site), CC (Coiled-Coil), TIR (Toll/Interleukin-1 Receptor). We identified 74 immunity related gene candidates in P. peruviana which have the typical resistance gene (R-gene) architecture, 17 Receptor like kinase (RLKs) candidates related to PAMP-Triggered Immunity (PTI), eight (TIR-NBS-LRR, or TNL) and nine (CC–NBS-LRR, or CNL) candidates related to Effector-Triggered Immunity (ETI) genes among others. These candidate genes were categorized by molecular function (98%), biological process (85%) and cellular component (79%) using gene ontology. Some of the most interesting predicted roles were those associated with binding and transferase activity. We designed 94 primers pairs from the 74 immunity-related genes (IRGs) to amplify the corresponding genomic regions on six genotypes that included resistant and susceptible materials. From these, we selected 17 single band amplicons and sequenced them in 14 F. oxysporum resistant and susceptible genotypes. Sequence polymorphisms were analyzed through preliminary candidate gene association, which allowed the detection of one SNP at the PpIRG-63 marker revealing a nonsynonymous mutation in the predicted LRR domain suggesting functional roles for resistance. PMID:23844210

  17. Manipulating the in vivo immune response by targeted gene knockdown

    PubMed Central

    Lieberman, Judy

    2015-01-01

    Aptamers, nucleic acids selected for high affinity binding to proteins, can be used to activate or antagonize immune mediators or receptors in a location and cell-type specific manner and to enhance antigen presentation. They can also be linked to other molecules (other aptamers, siRNAs or miRNAs, proteins, toxins) to produce multifunctional compounds for targeted immune modulation in vivo. Aptamer-siRNA chimeras (AsiCs) that induce efficient cell-specific knockdown in immune cells in vitro and in vivo can be used as an immunological research tool or potentially as an immunomodulating therapeutic. PMID:26149459

  18. Manipulating the in vivo immune response by targeted gene knockdown.

    PubMed

    Lieberman, Judy

    2015-08-01

    Aptamers, nucleic acids selected for high affinity binding to proteins, can be used to activate or antagonize immune mediators or receptors in a location and cell-type specific manner and to enhance antigen presentation. They can also be linked to other molecules (other aptamers, siRNAs or miRNAs, proteins, toxins) to produce multifunctional compounds for targeted immune modulation in vivo. Aptamer-siRNA chimeras (AsiCs) that induce efficient cell-specific knockdown in immune cells in vitro and in vivo can be used as an immunological research tool or potentially as an immunomodulating therapeutic. PMID:26149459

  19. Immunizations

    MedlinePlus

    ... How Can I Help a Friend Who Cuts? Immunizations KidsHealth > For Teens > Immunizations Print A A A ... That Shot? en español Las vacunas Why Are Vaccinations Important? Measles, mumps, and whooping cough may seem ...

  20. Immunization

    MedlinePlus

    ... a lot worse. Some are even life-threatening. Immunization shots, or vaccinations, are essential. They protect against things like measles, ... B, polio, tetanus, diphtheria, and pertussis (whooping cough). Immunizations are important for adults as well as children. ...

  1. Immunization

    MedlinePlus

    ... a lot worse. Some are even life-threatening. Immunization shots, or vaccinations, are essential. They protect against ... B, polio, tetanus, diphtheria, and pertussis (whooping cough). Immunizations are important for adults as well as children. ...

  2. Evolutionary Dynamics of Immune-Related Genes and Pathways in Disease-Vector Mosquitoes

    PubMed Central

    Waterhouse, Robert M.; Kriventseva, Evgenia V.; Meister, Stephan; Xi, Zhiyong; Alvarez, Kanwal S.; Bartholomay, Lyric C.; Barillas-Mury, Carolina; Bian, Guowu; Blandin, Stephanie; Christensen, Bruce M.; Dong, Yuemei; Jiang, Haobo; Kanost, Michael R.; Koutsos, Anastasios C.; Levashina, Elena A.; Li, Jianyong; Ligoxygakis, Petros; MacCallum, Robert M.; Mayhew, George F.; Mendes, Antonio; Michel, Kristin; Osta, Mike A.; Paskewitz, Susan; Shin, Sang Woon; Vlachou, Dina; Wang, Lihui; Wei, Weiqi; Zheng, Liangbiao; Zou, Zhen; Severson, David W.; Raikhel, Alexander S.; Kafatos, Fotis C.; Dimopoulos, George; Zdobnov, Evgeny M.; Christophides, George K.

    2007-01-01

    Mosquitoes are vectors of parasitic and viral diseases of immense importance for public health. The acquisition of the genome sequence of the yellow fever and Dengue vector, Aedes aegypti (Aa), has enabled a comparative phylogenomic analysis of the insect immune repertoire: in Aa, the malaria vector Anopheles gambiae (Ag), and the fruit fly Drosophila melanogaster (Dm). Analysis of immune signaling pathways and response modules reveals both conservative and rapidly evolving features associated with different functional gene categories and particular aspects of immune reactions. These dynamics reflect in part continuous readjustment between accommodation and rejection of pathogens and suggest how innate immunity may have evolved. PMID:17588928

  3. Evolutionary dynamics of immune-related genes and pathways in disease-vector mosquitoes.

    PubMed

    Waterhouse, Robert M; Kriventseva, Evgenia V; Meister, Stephan; Xi, Zhiyong; Alvarez, Kanwal S; Bartholomay, Lyric C; Barillas-Mury, Carolina; Bian, Guowu; Blandin, Stephanie; Christensen, Bruce M; Dong, Yuemei; Jiang, Haobo; Kanost, Michael R; Koutsos, Anastasios C; Levashina, Elena A; Li, Jianyong; Ligoxygakis, Petros; Maccallum, Robert M; Mayhew, George F; Mendes, Antonio; Michel, Kristin; Osta, Mike A; Paskewitz, Susan; Shin, Sang Woon; Vlachou, Dina; Wang, Lihui; Wei, Weiqi; Zheng, Liangbiao; Zou, Zhen; Severson, David W; Raikhel, Alexander S; Kafatos, Fotis C; Dimopoulos, George; Zdobnov, Evgeny M; Christophides, George K

    2007-06-22

    Mosquitoes are vectors of parasitic and viral diseases of immense importance for public health. The acquisition of the genome sequence of the yellow fever and Dengue vector, Aedes aegypti (Aa), has enabled a comparative phylogenomic analysis of the insect immune repertoire: in Aa, the malaria vector Anopheles gambiae (Ag), and the fruit fly Drosophila melanogaster (Dm). Analysis of immune signaling pathways and response modules reveals both conservative and rapidly evolving features associated with different functional gene categories and particular aspects of immune reactions. These dynamics reflect in part continuous readjustment between accommodation and rejection of pathogens and suggest how innate immunity may have evolved. PMID:17588928

  4. Genes of the adaptive immune system are expressed early in zebrafish larval development following lipopolysaccharide stimulation

    NASA Astrophysics Data System (ADS)

    Li, Fengling; Zhang, Shicui; Wang, Zhiping; Li, Hongyan

    2011-03-01

    Information regarding immunocompetence of the adaptive immune system (AIS) in zebrafish Danio rerio remains limited. Here, we stimulated an immune response in fish embryos, larvae and adults using lipopolysaccharide (LPS) and measured the upregulation of a number of AIS-related genes ( Rag2, AID, TCRAC, IgLC-1, mIg, sIg, IgZ and DAB) 3 and 18 h later. We found that all of the genes evaluated were strongly induced following LPS stimulation, with most of them responding at 8 d post fertilization. This confirms that a functional adaptive immune response is present in D. rerio larvae, and provides a window for further functional analyses.

  5. Multiplexed Component Analysis to Identify Genes Contributing to the Immune Response during Acute SIV Infection

    PubMed Central

    Hosseini, Iraj; Gama, Lucio; Mac Gabhann, Feilim

    2015-01-01

    Immune response genes play an important role during acute HIV and SIV infection. Using an SIV macaque model of AIDS and CNS disease, our overall goal was to assess how the expression of genes associated with immune and inflammatory responses are longitudinally changed in different organs or cells during SIV infection. To compare RNA expression of a panel of 88 immune-related genes across time points and among three tissues – spleen, mesenteric lymph nodes (MLN) and peripheral blood mononuclear cells (PBMC) – we designed a set of Nanostring probes. To identify significant genes during acute SIV infection and to investigate whether these genes are tissue-specific or have global roles, we introduce a novel multiplexed component analysis (MCA) method. This combines multivariate analysis methods with multiple preprocessing methods to create a set of 12 “judges”; each judge emphasizes particular types of change in gene expression to which cells could respond, for example, the absolute or relative size of expression change from baseline. Compared to bivariate analysis methods, our MCA method improved classification rates. This analysis allows us to identify three categories of genes: (a) consensus genes likely to contribute highly to the immune response; (b) genes that would contribute highly to the immune response only if certain assumptions are met – e.g. that the cell responds to relative expression change rather than absolute expression change; and (c) genes whose contribution to immune response appears to be modest. We then compared the results across the three tissues of interest; some genes are consistently highly-contributing in all tissues, while others are specific for certain tissues. Our analysis identified CCL8, CXCL10, CXCL11, MxA, OAS2, and OAS1 as top contributing genes, all of which are stimulated by type I interferon. This suggests that the cytokine storm during acute SIV infection is a systemic innate immune response against viral replication

  6. Immunity-related genes in Ixodes scapularis—perspectives from genome information

    PubMed Central

    Smith, Alexis A.; Pal, Utpal

    2014-01-01

    Ixodes scapularis, commonly known as the deer tick, transmits a wide array of human and animal pathogens including Borrelia burgdorferi. Despite substantial advances in our understanding of immunity in model arthropods, including other disease vectors, precisely how I. scapularis immunity functions and influences persistence of invading pathogens remains largely unknown. This review provides a comprehensive analysis of the recently sequenced I. scapularis genome for the occurrence of immune-related genes and related pathways. We will also discuss the potential influence of immunity-related genes on the persistence of tick-borne pathogens with an emphasis on the Lyme disease pathogen B. burgdorferi. Further enhancement of our knowledge of tick immune responses is critical to understanding the molecular basis of the persistence of tick-borne pathogens and development of novel interventions against the relevant infections. PMID:25202684

  7. Sequential Infection with Common Pathogens Promotes Human-like Immune Gene Expression and Altered Vaccine Response.

    PubMed

    Reese, Tiffany A; Bi, Kevin; Kambal, Amal; Filali-Mouhim, Ali; Beura, Lalit K; Bürger, Matheus C; Pulendran, Bali; Sekaly, Rafick-Pierre; Jameson, Stephen C; Masopust, David; Haining, W Nicholas; Virgin, Herbert W

    2016-05-11

    Immune responses differ between laboratory mice and humans. Chronic infection with viruses and parasites are common in humans, but are absent in laboratory mice, and thus represent potential contributors to inter-species differences in immunity. To test this, we sequentially infected laboratory mice with herpesviruses, influenza, and an intestinal helminth and compared their blood immune signatures to mock-infected mice before and after vaccination against yellow fever virus (YFV-17D). Sequential infection altered pre- and post-vaccination gene expression, cytokines, and antibodies in blood. Sequential pathogen exposure induced gene signatures that recapitulated those seen in blood from pet store-raised versus laboratory mice, and adult versus cord blood in humans. Therefore, basal and vaccine-induced murine immune responses are altered by infection with agents common outside of barrier facilities. This raises the possibility that we can improve mouse models of vaccination and immunity by selective microbial exposure of laboratory animals to mimic that of humans. PMID:27107939

  8. Species-wide Genetic Incompatibility Analysis Identifies Immune Genes as Hotspots of Deleterious Epistasis

    PubMed Central

    Chae, Eunyoung; Bomblies, Kirsten; Kim, Sang-Tae; Karelina, Darya; Zaidem, Maricris; Ossowski, Stephan; Martín-Pizarro, Carmen; Laitinen, Roosa A. E.; Rowan, Beth A.; Tenenboim, Hezi; Lechner, Sarah; Demar, Monika; Habring-Müller, Anette; Lanz, Christa; Rätsch, Gunnar; Weigel, Detlef

    2014-01-01

    Summary Intraspecific genetic incompatibilities prevent the assembly of specific alleles into single genotypes and influence genome- and species-wide patterns of sequence variation. A common incompatibility in plants is hybrid necrosis, characterized by autoimmune responses due to epistatic interactions between natural genetic variants. By systematically testing thousands of F1 hybrids of Arabidopsis thaliana strains, we identified a small number of incompatibility hotspots in the genome, often in regions densely populated by NLR immune receptor genes. In several cases, these immune receptor loci interact with each other, suggestive of conflict within the immune system. A particularly dangerous locus is a highly variable cluster of NLR genes, DANGEROUS MIX2 (DM2), which causes multiple, independent incompatibilities with genes that encode a range of biochemical functions, including NLRs. Our findings suggest that deleterious interactions of immune receptors at the front lines of host-pathogen co-evolution limit the combinations of favorable disease resistance alleles accessible to plant genomes. PMID:25467443

  9. Genomic Signatures of Selective Pressures and Introgression from Archaic Hominins at Human Innate Immunity Genes.

    PubMed

    Deschamps, Matthieu; Laval, Guillaume; Fagny, Maud; Itan, Yuval; Abel, Laurent; Casanova, Jean-Laurent; Patin, Etienne; Quintana-Murci, Lluis

    2016-01-01

    Human genes governing innate immunity provide a valuable tool for the study of the selective pressure imposed by microorganisms on host genomes. A comprehensive, genome-wide study of how selective constraints and adaptations have driven the evolution of innate immunity genes is missing. Using full-genome sequence variation from the 1000 Genomes Project, we first show that innate immunity genes have globally evolved under stronger purifying selection than the remainder of protein-coding genes. We identify a gene set under the strongest selective constraints, mutations in which are likely to predispose individuals to life-threatening disease, as illustrated by STAT1 and TRAF3. We then evaluate the occurrence of local adaptation and detect 57 high-scoring signals of positive selection at innate immunity genes, variation in which has been associated with susceptibility to common infectious or autoimmune diseases. Furthermore, we show that most adaptations targeting coding variation have occurred in the last 6,000-13,000 years, the period at which populations shifted from hunting and gathering to farming. Finally, we show that innate immunity genes present higher Neandertal introgression than the remainder of the coding genome. Notably, among the genes presenting the highest Neandertal ancestry, we find the TLR6-TLR1-TLR10 cluster, which also contains functional adaptive variation in Europeans. This study identifies highly constrained genes that fulfill essential, non-redundant functions in host survival and reveals others that are more permissive to change-containing variation acquired from archaic hominins or adaptive variants in specific populations-improving our understanding of the relative biological importance of innate immunity pathways in natural conditions. PMID:26748513

  10. Genomic Signatures of Selective Pressures and Introgression from Archaic Hominins at Human Innate Immunity Genes

    PubMed Central

    Deschamps, Matthieu; Laval, Guillaume; Fagny, Maud; Itan, Yuval; Abel, Laurent; Casanova, Jean-Laurent; Patin, Etienne; Quintana-Murci, Lluis

    2016-01-01

    Human genes governing innate immunity provide a valuable tool for the study of the selective pressure imposed by microorganisms on host genomes. A comprehensive, genome-wide study of how selective constraints and adaptations have driven the evolution of innate immunity genes is missing. Using full-genome sequence variation from the 1000 Genomes Project, we first show that innate immunity genes have globally evolved under stronger purifying selection than the remainder of protein-coding genes. We identify a gene set under the strongest selective constraints, mutations in which are likely to predispose individuals to life-threatening disease, as illustrated by STAT1 and TRAF3. We then evaluate the occurrence of local adaptation and detect 57 high-scoring signals of positive selection at innate immunity genes, variation in which has been associated with susceptibility to common infectious or autoimmune diseases. Furthermore, we show that most adaptations targeting coding variation have occurred in the last 6,000–13,000 years, the period at which populations shifted from hunting and gathering to farming. Finally, we show that innate immunity genes present higher Neandertal introgression than the remainder of the coding genome. Notably, among the genes presenting the highest Neandertal ancestry, we find the TLR6-TLR1-TLR10 cluster, which also contains functional adaptive variation in Europeans. This study identifies highly constrained genes that fulfill essential, non-redundant functions in host survival and reveals others that are more permissive to change—containing variation acquired from archaic hominins or adaptive variants in specific populations—improving our understanding of the relative biological importance of innate immunity pathways in natural conditions. PMID:26748513

  11. Tissue-Specific Immune Gene Expression in the Migratory Locust, Locusta Migratoria.

    PubMed

    Pulpitel, Tamara; Pernice, Mathieu; Simpson, Stephen J; Ponton, Fleur

    2015-01-01

    The ability of hosts to respond to infection involves several complex immune recognition pathways. Broadly conserved pathogen-associated molecular patterns (PAMPs) allow individuals to target a range of invading microbes. Recently, studies on insect innate immunity have found evidence that a single pathogen can activate different immune pathways across species. In this study, expression changes in immune genes encoding peptidoglycan-recognition protein SA (PGRP-SA), gram-negative binding protein 1 (GNBP1) and prophenoloxidase (ProPO) were investigated in Locusta migratoria, following an immune challenge using injected lipopolysaccharide (LPS) solution from Escherichia coli. Since immune activation might also be tissue-specific, gene expression levels were followed across a range of tissue types. For PGRP-SA, expression increased in response to LPS within all seven of the tissue-types assayed and differed significantly between tissues. Expression of GNBP1 similarly varied across tissue types, yet showed no clear expression difference between LPS-injected and uninfected locusts. Increases in ProPO expression in response to LPS, however, could only be detected in the gut sections. This study has revealed tissue-specific immune response to add a new level of complexity to insect immune studies. In addition to variation in recognition pathways identified in previous works, tissue-specificity should be carefully considered in similar works. PMID:26463191

  12. Immune-Related Functions of the Hivep Gene Family in East African Cichlid Fishes

    PubMed Central

    Diepeveen, Eveline T.; Roth, Olivia; Salzburger, Walter

    2013-01-01

    Immune-related genes are often characterized by adaptive protein evolution. Selection on immune genes can be particularly strong when hosts encounter novel parasites, for instance, after the colonization of a new habitat or upon the exploitation of vacant ecological niches in an adaptive radiation. We examined a set of new candidate immune genes in East African cichlid fishes. More specifically, we studied the signatures of selection in five paralogs of the human immunodeficiency virus type I enhancer-binding protein (Hivep) gene family, tested their involvement in the immune defense, and related our results to explosive speciation and adaptive radiation events in cichlids. We found signatures of long-term positive selection in four Hivep paralogs and lineage-specific positive selection in Hivep3b in two radiating cichlid lineages. Exposure of the cichlid Astatotilapia burtoni to a vaccination with Vibrio anguillarum bacteria resulted in a positive correlation between immune response parameters and expression levels of three Hivep loci. This work provides the first evidence for a role of Hivep paralogs in teleost immune defense and links the signatures of positive selection to host–pathogen interactions within an adaptive radiation. PMID:24142922

  13. Expression of immune-related genes in embryos and larvae of sea cucumber Apostichopus japonicus.

    PubMed

    Yang, Aifu; Zhou, Zunchun; Dong, Ying; Jiang, Bei; Wang, Xiaoyu; Chen, Zhong; Guan, Xiaoyan; Wang, Bai; Sun, Dapeng

    2010-11-01

    The echinoderm immunity system has been extensively investigated in adults in several classes such as echinoid and holothuroidea. However, the defense mechanism in embryos and larvae remains largely unexplored. To profile the immune-related genes expression in embryos and larvae and to monitor the stimulation of the innate immune response by lipopolysaccharides (LPS) challenge, we investigated the expression patterns of nine immune-related genes in embryos and larvae of sea cucumber (Apostichopus japonicus) at eleven developmental stages using quantitative real-time PCR (qRT-PCR). The expression of six encoding proteins including heat shock protein70 (Hsp70), Hsp90, Hsp gp96, thymosin-beta, ferritin and DD104 protein was detected at all eleven development stages according to mRNA expression data. However, the expression of mannan-binding C-type lectin (MBCL) was detected at early auricularia to juvenile stages, while lysozyme and serine proteinase inhibitor (SPI) were detected only at juvenile stage. Out of these nine genes, three (MBCL, lysozyme and SPI) were found to be up-regulated in mRNA expression upon LPS challenge, whereas the other six showed no significant change. Our study presents a first preliminary view into the expression patterns of immune-related genes at different developmental stages of sea cucumber, which increases the available information on echinoderm immunity. PMID:20673800

  14. Immune Responses of Piglets Immunized by a Recombinant Plasmid Containing Porcine Circovirus Type 2 and Porcine Interleukin-18 Genes

    PubMed Central

    Chen, Guang-Lei; Fu, Peng-Fei; Wang, Lin-Qing

    2014-01-01

    Abstract In this study, two recombinant plasmids containing the ORF2 gene of porcine circovirus type 2 (PCV2) with or without porcine interleukin-18 (IL-18) were constructed and evaluated for their ability to protect piglets against PCV2 challenge. Transient expression of the plasmids in PK-15 cells could be detected using Western blot. Piglets were given two intramuscular immunizations 3 weeks apart and were challenged with a virulent Wuzhi strain of PCV2 at 42 days after the initial immunization. All animals vaccinated with pBudCE4.1-ORF2 or with pBudCE4.1-ORF2/IL18 developed PCV2-specific antibody and T-lymphocyte proliferative responses. The levels of T-lymphocyte proliferation in piglets immunized with pBudCE4.1-ORF2/IL18 were significantly higher than in those immunized with pBudCE4.1-ORF2, and pBudCE4.1-ORF2/IL18 stimulated a significantly increased production of IFN-γ and IL-2. Furthermore, PCV2 challenge experiments showed that the DNA vaccine-immunized groups can partially prevent PCV2 viremia and significantly reduce the amount of PCV2 virus in the lymphoid tissues, and the piglets immunized by pBudCE4.1-ORF2/IL18 exhibit a marked inhibition of PCV2 replication compared to the pBudCE4.1-ORF2 group. These data demonstrate that the plasmid pBudCE4.1-ORF2/IL18 may be an effective approach for increasing PCV2 DNA vaccine immunogenicity. PMID:25268976

  15. Association of variants in innate immune genes with asthma and eczema

    PubMed Central

    Sharma, Sunita; Poon, Audrey; Himes, Blanca E.; Lasky-Su, Jessica; Sordillo, Joanne E.; Belanger, Kathleen; Milton, Donald K.; Bracken, Michael B.; Triche, Elizabeth W.; Leaderer, Brian P.; Gold, Diane R.; Litonjua, Augusto A.

    2012-01-01

    Background The innate immune pathway is important in the pathogenesis of asthma and eczema. However, only a few variants in these genes have been associated with either disease. We investigate the association between polymorphisms of genes in the innate immune pathway with childhood asthma and eczema. In addition, we compare individual associations with those discovered using a multivariate approach. Methods Using a novel method, case control based association testing (C2BAT), 569 single nucleotide polymorphisms (SNPs) in 44 innate immune genes were tested for association with asthma and eczema in children from the Boston Home Allergens and Asthma Study and the Connecticut Childhood Asthma Study. The screening algorithm was used to identify the top SNPs associated with asthma and eczema. We next investigated the interaction of innate immune variants with asthma and eczema risk using Bayesian networks. Results After correction for multiple comparisons, 7 SNPs in 6 genes (CARD25, TGFB1, LY96, ACAA1, DEFB1, and IFNG) were associated with asthma (adjusted p-value<0.02), while 5 SNPs in 3 different genes (CD80, STAT4, and IRAKI) were significantly associated with eczema (adjusted p-value < 0.02). None of these SNPs were associated with both asthma and eczema. Bayesian network analysis identified 4 SNPs that were predictive of asthma and 10 SNPs that predicted eczema. Of the genes identified using Bayesian networks, only CD80 was associated with eczema in the single-SNP study. Using novel methodology that allows for screening and replication in the same population, we have identified associations of innate immune genes with asthma and eczema. Bayesian network analysis suggests that additional SNPs influence disease susceptibility via SNP interactions. Conclusion Our findings suggest that innate immune genes contribute to the pathogenesis of asthma and eczema, and that these diseases likely have different genetic determinants. PMID:22192168

  16. Intradermal Gene Immunization: The Possible Role of DNA Uptake in the Induction of Cellular Immunity to Viruses

    NASA Astrophysics Data System (ADS)

    Raz, Eyal; Carson, Dennis A.; Parker, Suezanne E.; Parr, Tyler B.; Abai, Anna M.; Aichinger, Gerald; Gromkowski, Stanislaw H.; Singh, Malini; Lew, Denise; Yankauckas, Michelle A.; Baird, Stephen M.; Rhodes, Gary H.

    1994-09-01

    The skin and mucous membranes are the anatomical sites where most viruses are first encountered by the immune system. Previous experiments have suggested that striated muscle cells are unique among mammalian cell types in their capacity to take up and express free DNA in the absence of a viral vector or physical carrier. However, we have found that mice injected into the superficial skin with free (naked) plasmid DNA encoding the influenza nucleoprotein gene had discrete foci of epidermal and dermal cells, including cells with dendritic morphology, that contained immunoreactive nucleoprotein antigen. A single intradermal administration of 0.3-15 μ g of free plasmid DNA induced anti-nucleoprotein-specific antibody and cytotoxic T lymphocytes that persisted for at least 68-70 weeks after vaccination. Intradermal gene administration induced higher antibody titers than did direct gene injection into skeletal muscle and did not cause local inflammation or necrosis. Compared with control animals, the gene-injected mice were resistant to challenge with a heterologous strain of influenza virus. These results indicate that the cells of the skin can take up and express free foreign DNA and induce cellular and humoral immune responses against the encoded protein. We suggest that DNA uptake by the skin-associated lymphoid tissues may play a role in the induction of cytotoxic T cells against viruses and other intracellular pathogens.

  17. Revealing shared and distinct gene network organization in Arabidopsis immune responses by integrative analysis.

    PubMed

    Dong, Xiaobao; Jiang, Zhenhong; Peng, You-Liang; Zhang, Ziding

    2015-03-01

    Pattern-triggered immunity (PTI) and effector-triggered immunity (ETI) are two main plant immune responses to counter pathogen invasion. Genome-wide gene network organizing principles leading to quantitative differences between PTI and ETI have remained elusive. We combined an advanced machine learning method and modular network analysis to systematically characterize the organizing principles of Arabidopsis (Arabidopsis thaliana) PTI and ETI at three network resolutions. At the single network node/edge level, we ranked genes and gene interactions based on their ability to distinguish immune response from normal growth and successfully identified many immune-related genes associated with PTI and ETI. Topological analysis revealed that the top-ranked gene interactions tend to link network modules. At the subnetwork level, we identified a subnetwork shared by PTI and ETI encompassing 1,159 genes and 1,289 interactions. This subnetwork is enriched in interactions linking network modules and is also a hotspot of attack by pathogen effectors. The subnetwork likely represents a core component in the coordination of multiple biological processes to favor defense over development. Finally, we constructed modular network models for PTI and ETI to explain the quantitative differences in the global network architecture. Our results indicate that the defense modules in ETI are organized into relatively independent structures, explaining the robustness of ETI to genetic mutations and effector attacks. Taken together, the multiscale comparisons of PTI and ETI provide a systems biology perspective on plant immunity and emphasize coordination among network modules to establish a robust immune response. PMID:25614062

  18. Feminizing Wolbachia: a transcriptomics approach with insights on the immune response genes in Armadillidium vulgare

    PubMed Central

    2012-01-01

    Background Wolbachia are vertically transmitted bacteria known to be the most widespread endosymbiont in arthropods. They induce various alterations of the reproduction of their host, including feminization of genetic males in isopod crustaceans. In the pill bug Armadillidium vulgare, the presence of Wolbachia is also associated with detrimental effects on host fertility and lifespan. Deleterious effects have been demonstrated on hemocyte density, phenoloxidase activity, and natural hemolymph septicemia, suggesting that infected individuals could have defective immune capacities. Since nothing is known about the molecular mechanisms involved in Wolbachia-A. vulgare interactions and its secondary immunocompetence modulation, we developed a transcriptomics strategy and compared A. vulgare gene expression between Wolbachia-infected animals (i.e., “symbiotic” animals) and uninfected ones (i.e., “asymbiotic” animals) as well as between animals challenged or not challenged by a pathogenic bacteria. Results Since very little genetic data is available on A. vulgare, we produced several EST libraries and generated a total of 28 606 ESTs. Analyses of these ESTs revealed that immune processes were over-represented in most experimental conditions (responses to a symbiont and to a pathogen). Considering canonical crustacean immune pathways, these genes encode antimicrobial peptides or are involved in pathogen recognition, detoxification, and autophagy. By RT-qPCR, we demonstrated a general trend towards gene under-expression in symbiotic whole animals and ovaries whereas the same gene set tends to be over-expressed in symbiotic immune tissues. Conclusion This study allowed us to generate the first reference transcriptome ever obtained in the Isopoda group and to identify genes involved in the major known crustacean immune pathways encompassing cellular and humoral responses. Expression of immune-related genes revealed a modulation of host immunity when females are

  19. Revealing Shared and Distinct Gene Network Organization in Arabidopsis Immune Responses by Integrative Analysis1

    PubMed Central

    Dong, Xiaobao; Jiang, Zhenhong; Peng, You-Liang; Zhang, Ziding

    2015-01-01

    Pattern-triggered immunity (PTI) and effector-triggered immunity (ETI) are two main plant immune responses to counter pathogen invasion. Genome-wide gene network organizing principles leading to quantitative differences between PTI and ETI have remained elusive. We combined an advanced machine learning method and modular network analysis to systematically characterize the organizing principles of Arabidopsis (Arabidopsis thaliana) PTI and ETI at three network resolutions. At the single network node/edge level, we ranked genes and gene interactions based on their ability to distinguish immune response from normal growth and successfully identified many immune-related genes associated with PTI and ETI. Topological analysis revealed that the top-ranked gene interactions tend to link network modules. At the subnetwork level, we identified a subnetwork shared by PTI and ETI encompassing 1,159 genes and 1,289 interactions. This subnetwork is enriched in interactions linking network modules and is also a hotspot of attack by pathogen effectors. The subnetwork likely represents a core component in the coordination of multiple biological processes to favor defense over development. Finally, we constructed modular network models for PTI and ETI to explain the quantitative differences in the global network architecture. Our results indicate that the defense modules in ETI are organized into relatively independent structures, explaining the robustness of ETI to genetic mutations and effector attacks. Taken together, the multiscale comparisons of PTI and ETI provide a systems biology perspective on plant immunity and emphasize coordination among network modules to establish a robust immune response. PMID:25614062

  20. Strategies to Modulate Immune Responses: A New Frontier for Gene Therapy

    PubMed Central

    Arruda, Valder R; Favaro, Patricia; Finn, Jonathan D

    2009-01-01

    The success of gene therapy strategies to cure disease relies on the control of unwanted immune responses to transgene products, genetically modified cells and/or to the vector. Effective treatment of an established immune response is much harder to achieve than prevention of a response before it has had a chance to develop. However, preventive strategies are not always effective in avoiding immune responses, thus the use of drugs to induce immunosuppression (IS) is required. The growing discovery of novel drugs provides a conceptual shift from using generalized, moderately intensive immunosuppressive regimens towards a refined approach to attain the optimal balance of naive cells, effector cells, memory cells, and regulatory cells, harnessing the natural tolerance mechanisms of the body. We review several strategies based on transient IS coupled with gene therapy for sustained immune tolerance induction to the therapeutic transgene. PMID:19584819

  1. Characterization of the rainbow trout spleen transcriptome and identification of immune-related genes.

    PubMed

    Ali, Ali; Rexroad, Caird E; Thorgaard, Gary H; Yao, Jianbo; Salem, Mohamed

    2014-01-01

    Resistance against diseases affects profitability of rainbow trout. Limited information is available about functions and mechanisms of teleost immune pathways. Immunogenomics provides powerful tools to determine disease resistance genes/gene pathways and develop genetic markers for genomic selection. RNA-Seq sequencing of the rainbow trout spleen yielded 93,532,200 reads (100 bp). High quality reads were assembled into 43,047 contigs. 26,333 (61.17%) of the contigs had hits to the NR protein database and 7024 (16.32%) had hits to the KEGG database. Gene ontology showed significant percentages of transcripts assigned to binding (51%), signaling (7%), response to stimuli (9%) and receptor activity (4%) suggesting existence of many immune-related genes. KEGG annotation revealed 2825 sequences belonging to "organismal systems" with the highest number of sequences, 842 (29.81%), assigned to immune system. A number of sequences were identified for the first time in rainbow trout belonging to Toll-like receptor signaling (35), B cell receptor signaling pathway (44), T cell receptor signaling pathway (56), chemokine signaling pathway (73), Fc gamma R-mediated phagocytosis (52), leukocyte transendothelial migration (60) and NK cell mediated cytotoxicity (42). In addition, 51 transcripts were identified as spleen-specific genes. The list includes 277 full-length cDNAs. The presence of a large number of immune-related genes and pathways similar to other vertebrates suggests that innate and adaptive immunity in fish are conserved. This study provides deep-sequence data of rainbow trout spleen transcriptome and identifies many new immune-related genes and full-length cDNAs. This data will help identify allelic variations suitable for genomic selection and genetic manipulation in aquaculture. PMID:25352861

  2. Characterization of the rainbow trout spleen transcriptome and identification of immune-related genes

    PubMed Central

    Ali, Ali; Rexroad, Caird E.; Thorgaard, Gary H.; Yao, Jianbo; Salem, Mohamed

    2014-01-01

    Resistance against diseases affects profitability of rainbow trout. Limited information is available about functions and mechanisms of teleost immune pathways. Immunogenomics provides powerful tools to determine disease resistance genes/gene pathways and develop genetic markers for genomic selection. RNA-Seq sequencing of the rainbow trout spleen yielded 93,532,200 reads (100 bp). High quality reads were assembled into 43,047 contigs. 26,333 (61.17%) of the contigs had hits to the NR protein database and 7024 (16.32%) had hits to the KEGG database. Gene ontology showed significant percentages of transcripts assigned to binding (51%), signaling (7%), response to stimuli (9%) and receptor activity (4%) suggesting existence of many immune-related genes. KEGG annotation revealed 2825 sequences belonging to “organismal systems” with the highest number of sequences, 842 (29.81%), assigned to immune system. A number of sequences were identified for the first time in rainbow trout belonging to Toll-like receptor signaling (35), B cell receptor signaling pathway (44), T cell receptor signaling pathway (56), chemokine signaling pathway (73), Fc gamma R-mediated phagocytosis (52), leukocyte transendothelial migration (60) and NK cell mediated cytotoxicity (42). In addition, 51 transcripts were identified as spleen-specific genes. The list includes 277 full-length cDNAs. The presence of a large number of immune-related genes and pathways similar to other vertebrates suggests that innate and adaptive immunity in fish are conserved. This study provides deep-sequence data of rainbow trout spleen transcriptome and identifies many new immune-related genes and full-length cDNAs. This data will help identify allelic variations suitable for genomic selection and genetic manipulation in aquaculture. PMID:25352861

  3. Influence of Immune Responses in Gene/Stem Cell Therapies for Muscular Dystrophies

    PubMed Central

    Sitzia, Clementina; Erratico, Silvia; Torrente, Yvan

    2014-01-01

    Muscular dystrophies (MDs) are a heterogeneous group of diseases, caused by mutations in different components of sarcolemma, extracellular matrix, or enzymes. Inflammation and innate or adaptive immune response activation are prominent features of MDs. Various therapies under development are directed toward rescuing the dystrophic muscle damage using gene transfer or cell therapy. Here we discussed current knowledge about involvement of immune system responses to experimental therapies in MDs. PMID:24959590

  4. Expression of Putative Immune Response Genes during Early Ontogeny in the Coral Acropora millepora

    PubMed Central

    Puill-Stephan, Eneour; Seneca, François O.; Miller, David J.; van Oppen, Madeleine J. H.; Willis, Bette L.

    2012-01-01

    Background Corals, like many other marine invertebrates, lack a mature allorecognition system in early life history stages. Indeed, in early ontogeny, when corals acquire and establish associations with various surface microbiota and dinoflagellate endosymbionts, they do not efficiently distinguish between closely and distantly related individuals from the same population. However, very little is known about the molecular components that underpin allorecognition and immunity responses or how they change through early ontogeny in corals. Methodology/Principal Findings Patterns in the expression of four putative immune response genes (apextrin, complement C3, and two CELIII type lectin genes) were examined in juvenile colonies of Acropora millepora throughout a six-month post-settlement period using quantitative real-time PCR (qPCR). Expression of a CELIII type lectin gene peaked in the fourth month for most of the coral juveniles sampled and was significantly higher at this time than at any other sampling time during the six months following settlement. The timing of this increase in expression levels of putative immune response genes may be linked to allorecognition maturation which occurs around this time in A.millepora. Alternatively, the increase may represent a response to immune challenges, such as would be involved in the recognition of symbionts (such as Symbiodinium spp. or bacteria) during winnowing processes as symbioses are fine-tuned. Conclusions/Significance Our data, although preliminary, are consistent with the hypothesis that lectins may play an important role in the maturation of allorecognition responses in corals. The co-expression of lectins with apextrin during development of coral juveniles also raises the possibility that these proteins, which are components of innate immunity in other invertebrates, may influence the innate immune systems of corals through a common pathway or system. However, further studies investigating the expression of

  5. Exploiting Gene-Expression Deconvolution to Probe the Genetics of the Immune System

    PubMed Central

    Steuerman, Yael; Gat-Viks, Irit

    2016-01-01

    Sequence variation can affect the physiological state of the immune system. Major experimental efforts targeted at understanding the genetic control of the abundance of immune cell subpopulations. However, these studies are typically focused on a limited number of immune cell types, mainly due to the use of relatively low throughput cell-sorting technologies. Here we present an algorithm that can reveal the genetic basis of inter-individual variation in the abundance of immune cell types using only gene expression and genotyping measurements as input. Our algorithm predicts the abundance of immune cell subpopulations based on the RNA levels of informative marker genes within a complex tissue, and then provides the genetic control on these predicted immune traits as output. A key feature of the approach is the integration of predictions from various sets of marker genes and refinement of these sets to avoid spurious signals. Our evaluation of both synthetic and real biological data shows the significant benefits of the new approach. Our method, VoCAL, is implemented in the freely available R package ComICS. PMID:27035464

  6. Exploiting Gene-Expression Deconvolution to Probe the Genetics of the Immune System.

    PubMed

    Steuerman, Yael; Gat-Viks, Irit

    2016-04-01

    Sequence variation can affect the physiological state of the immune system. Major experimental efforts targeted at understanding the genetic control of the abundance of immune cell subpopulations. However, these studies are typically focused on a limited number of immune cell types, mainly due to the use of relatively low throughput cell-sorting technologies. Here we present an algorithm that can reveal the genetic basis of inter-individual variation in the abundance of immune cell types using only gene expression and genotyping measurements as input. Our algorithm predicts the abundance of immune cell subpopulations based on the RNA levels of informative marker genes within a complex tissue, and then provides the genetic control on these predicted immune traits as output. A key feature of the approach is the integration of predictions from various sets of marker genes and refinement of these sets to avoid spurious signals. Our evaluation of both synthetic and real biological data shows the significant benefits of the new approach. Our method, VoCAL, is implemented in the freely available R package ComICS. PMID:27035464

  7. De novo annotation of the immune-enriched transcriptome provides insights into immune system genes of Chinese sturgeon (Acipenser sinensis).

    PubMed

    Zhu, Rong; Du, He-Jun; Li, Shun-Yi; Li, Ya-Dong; Ni, Hong; Yu, Xue-Jing; Yang, Yan-Yan; Fan, Yu-Ding; Jiang, Nan; Zeng, Ling-Bing; Wang, Xing-Guo

    2016-08-01

    Chinese sturgeon (Acipenser sinensis), one of the oldest extant actinopterygian fishes with very high evolutionary, economical and conservation interest, is considered to be one of the critically endangered aquatic animals in China. Up to date, the immune system of this species remains largely undetermined with little sequence information publicly available. Herein, the first comprehensive transcriptome of immune tissues for Chinese sturgeon was characterized using Illumina deep sequencing. Over 67 million high-quality reads were generated and de novo assembled into the final set of 91,739 unique sequences. The annotation pipeline revealed that 25,871 unigenes were successfully annotated in the public databases, of which only 2002 had significant match to the existing sequences for the genus Acipenser. Overall 22,827 unigenes were categorized into 52 GO terms, 12,742 were classified into 26 KOG categories, and 4968 were assigned to 339 KEGG pathways. A more detailed annotation search showed the presence of a notable representation of immune-related genes, which suggests that this non-teleost actinopterygian fish harbors the same intermediates as in the well known immune pathways from mammals and teleosts, such as pattern recognition receptor (PRR) signaling pathway, JAK-STAT signaling pathway, complement and coagulation pathway, T-cell receptor (TCR) and B-cell receptor (BCR) signaling pathways. Additional genetic marker discovery led to the retrieval of 20,056 simple sequence repeats (SSRs) and 327,140 single nucleotide polymorphisms (SNPs). This immune-enriched transcriptome of Chinese sturgeon represents a rich resource that adds to the currently nascent field of chondrostean fish immunogenetics and furthers the conservation and management of this valuable fish. PMID:27368537

  8. Selection and Evaluation of Tissue Specific Reference Genes in Lucilia sericata during an Immune Challenge

    PubMed Central

    Baumann, Andre; Lehmann, Rüdiger; Beckert, Annika; Vilcinskas, Andreas; Franta, Zdeněk

    2015-01-01

    The larvae of the common green bottle fly Lucilia sericata (Diptera: Calliphoridae) have been used for centuries to promote wound healing, but the molecular basis of their antimicrobial, debridement and healing functions remains largely unknown. The analysis of differential gene expression in specific larval tissues before and after immune challenge could be used to identify key molecular factors, but the most sensitive and reproducible method qRT-PCR requires validated reference genes. We therefore selected 10 candidate reference genes encoding products from different functional classes (18S rRNA, 28S rRNA, actin, β-tubulin, RPS3, RPLP0, EF1α, PKA, GAPDH and GST1). Two widely applied algorithms (GeNorm and Normfinder) were used to analyze reference gene candidates in different larval tissues associated with secretion, digestion, and antimicrobial activity (midgut, hindgut, salivary glands, crop and fat body). The Gram-negative bacterium Pseudomonas aeruginosa was then used to boost the larval immune system and the stability of reference gene expression was tested in comparison to three immune genes (lucimycin, defensin-1 and attacin-2), which target different pathogen classes. We observed no differential expression of the antifungal peptide lucimycin, whereas the representative targeting Gram-positive bacteria (defensin-1) was upregulated in salivary glands, crop, nerve ganglion and reached its maximum in fat body (up to 300-fold). The strongest upregulation in all immune challenged tissues (over 50,000-fold induction in the fat body) was monitored for attacin-2, the representative targeting Gram-negative bacteria. Here we identified and validated a set of reference genes that allows the accurate normalization of gene expression in specific tissues of L. sericata after immune challenge. PMID:26252388

  9. Complement C3 gene: Expression characterization and innate immune response in razor clam Sinonovacula constricta.

    PubMed

    Peng, Maoxiao; Niu, Donghong; Wang, Fei; Chen, Zhiyi; Li, Jiale

    2016-08-01

    Complement component 3 (C3) is central to the complement system, playing an important role in immune defense, immune regulation and immune pathology. Several C3 genes have been characterized in invertebrates but very few in shellfish. The C3 gene was identified from the razor clam Sinonovacula constricta, referred to here as Sc-C3. It was found to be highly homologous with the C3 gene of Ruditapes decussatus. All eight model motifs of the C3 gene were found to be included in the thiolester bond and the C345C region. Sc-C3 was widely expressed in all healthy tissues with expression being highest in hemolymph. A significant difference in expression was revealed at the umbo larvae development stage. The expression of Sc-C3 was highly regulated in the hemolymph and liver, with a distinct response pattern being noted after a challenge with Micrococcus lysodeikticus and Vibrio parahemolyticus. It is therefore suggested that a complicated and unique response pathway may be present in S. constricta. Further, serum of S. constricta containing Sc-C3 was extracted. This was activated by LPS or bacterium for verification for function. The more obvious immune function of Sc-C3 was described as an effective membrane rupture in hemocyte cells of rabbit, V. parahemolyticus and Vibrio anguillarum. Thus, Sc-C3 plays an essential role in the immune defense of S. constricta. PMID:27231190

  10. Microgravity and Immunity: Changes in Lymphocyte Gene Expression

    NASA Technical Reports Server (NTRS)

    Risin, D.; Pellis, N. R.; Ward, N. E.; Risin, S. A.

    2006-01-01

    Earlier studies had shown that modeled and true microgravity (MG) cause multiple direct effects on human lymphocytes. MG inhibits lymphocyte locomotion, suppresses polyclonal and antigen-specific activation, affects signal transduction mechanisms, as well as activation-induced apoptosis. In this study we assessed changes in gene expression associated with lymphocyte exposure to microgravity in an attempt to identify microgravity-sensitive genes (MGSG) in general and specifically those genes that might be responsible for the functional and structural changes observed earlier. Two sets of experiments targeting different goals were conducted. In the first set, T-lymphocytes from normal donors were activated with antiCD3 and IL2 and then cultured in 1g (static) and modeled MG (MMG) conditions (Rotating Wall Vessel bioreactor) for 24 hours. This setting allowed searching for MGSG by comparison of gene expression patterns in zero and 1 g gravity. In the second set - activated T-cells after culturing for 24 hours in 1g and MMG were exposed three hours before harvesting to a secondary activation stimulus (PHA) thus triggering the apoptotic pathway. Total RNA was extracted using the RNeasy isolation kit (Qiagen, Valencia, CA). Affymetrix Gene Chips (U133A), allowing testing for 18,400 human genes, were used for microarray analysis. In the first set of experiments MMG exposure resulted in altered expression of 89 genes, 10 of them were up-regulated and 79 down-regulated. In the second set, changes in expression were revealed in 85 genes, 20 were up-regulated and 65 were down-regulated. The analysis revealed that significant numbers of MGS genes are associated with signal transduction and apoptotic pathways. Interestingly, the majority of genes that responded by up- or down-regulation in the alternative sets of experiments were not the same, possibly reflecting different functional states of the examined T-lymphocyte populations. The responder genes (MGSG) might play an

  11. Induction of innate immune gene expression following methyl methanesulfonate-induced DNA damage in sea urchins.

    PubMed

    Reinardy, H C; Chapman, J; Bodnar, A G

    2016-02-01

    Sea urchins are noted for the absence of neoplastic disease and represent a novel model to investigate cellular and systemic cancer protection mechanisms. Following intracoelomic injection of the DNA alkylating agent methyl methanesulfonate, DNA damage was detected in sea urchin cells and tissues (coelomocytes, muscle, oesophagus, ampullae and gonad) by the alkaline unwinding, fast micromethod. Gene expression analyses of the coelomocytes indicated upregulation of innate immune markers, including genes involved in NF-κB signalling. Results suggest that activation of the innate immune system following DNA damage may contribute to the naturally occurring resistance to neoplastic disease observed in sea urchins. PMID:26911343

  12. Hepatitis A immunity in the District of Aveiro (Portugal): an eleven-year surveillance study (2002-2012).

    PubMed

    Pereira, Sara; Linhares, Inês; Neves, António Ferreira; Almeida, Adelaide

    2014-01-01

    Hepatitis A is a common viral liver disease and brings serious health and economic problems as its epidemiologic pattern changes over time. National serosurveys from developed countries have indicated a decline in HAV (hepatitis A virus) seroprevalence over time due to the improvement of economic and sanitation levels. The hepatitis A virus (HAV) immunity rate was surveyed throughout an eleven-year period by sex and age group in Aveiro District. In this retrospective study, blood samples from patients of Aveiro District, in ambulatory regime, collected at the Clinical Analysis Laboratory Avelab between 2002 and 2012 were screened for the presence of antibodies against HAV antigen using a chemiluminescence immunoassay. The global immunity (positive total anti-HAV) was 60% and only 0.3% of the patients presented recent infection by HAV (positive IgM anti-HAV). The HAV immunity was age-dependent (p < 0.05), but no significant differences (p > 0.05) between sexes were observed. The immunity was similar throughout the study period (p > 0.05). The results of this study indicate that young people (especially under 25 years old) from District of Aveiro are susceptible to HAV infection, constituting a high risk group. The elderly should be also a concern in the future of Hepatitis A infection. PMID:24638206

  13. Hepatitis A Immunity in the District of Aveiro (Portugal): An Eleven-Year Surveillance Study (2002–2012)

    PubMed Central

    Pereira, Sara; Linhares, Inês; Neves, António Ferreira; Almeida, Adelaide

    2014-01-01

    Hepatitis A is a common viral liver disease and brings serious health and economic problems as its epidemiologic pattern changes over time. National serosurveys from developed countries have indicated a decline in HAV (hepatitis A virus) seroprevalence over time due to the improvement of economic and sanitation levels. The hepatitis A virus (HAV) immunity rate was surveyed throughout an eleven-year period by sex and age group in Aveiro District. In this retrospective study, blood samples from patients of Aveiro District, in ambulatory regime, collected at the Clinical Analysis Laboratory Avelab between 2002 and 2012 were screened for the presence of antibodies against HAV antigen using a chemiluminescence immunoassay. The global immunity (positive total anti-HAV) was 60% and only 0.3% of the patients presented recent infection by HAV (positive IgM anti-HAV). The HAV immunity was age-dependent (p < 0.05), but no significant differences (p > 0.05) between sexes were observed. The immunity was similar throughout the study period (p > 0.05). The results of this study indicate that young people (especially under 25 years old) from District of Aveiro are susceptible to HAV infection, constituting a high risk group. The elderly should be also a concern in the future of Hepatitis A infection. PMID:24638206

  14. Genome-wide screen for Mycobacterium tuberculosis genes that regulate host immunity.

    PubMed

    Beaulieu, Aimee M; Rath, Poonam; Imhof, Marianne; Siddall, Mark E; Roberts, Julia; Schnappinger, Dirk; Nathan, Carl F

    2010-01-01

    In spite of its highly immunogenic properties, Mycobacterium tuberculosis (Mtb) establishes persistent infection in otherwise healthy individuals, making it one of the most widespread and deadly human pathogens. Mtb's prolonged survival may reflect production of microbial factors that prevent even more vigorous immunity (quantitative effect) or that divert the immune response to a non-sterilizing mode (qualitative effect). Disruption of Mtb genes has produced a list of several dozen candidate immunomodulatory factors. Here we used robotic fluorescence microscopy to screen 10,100 loss-of-function transposon mutants of Mtb for their impact on the expression of promoter-reporter constructs for 12 host immune response genes in a mouse macrophage cell line. The screen identified 364 candidate immunoregulatory genes. To illustrate the utility of the candidate list, we confirmed the impact of 35 Mtb mutant strains on expression of endogenous immune response genes in primary macrophages. Detailed analysis focused on a strain of Mtb in which a transposon disrupts Rv0431, a gene encoding a conserved protein of unknown function. This mutant elicited much more macrophage TNFα, IL-12p40 and IL-6 in vitro than wild type Mtb, and was attenuated in the mouse. The mutant list provides a platform for exploring the immunobiology of tuberculosis, for example, by combining immunoregulatory mutations in a candidate vaccine strain. PMID:21170273

  15. Forager bees (Apis mellifera) highly express immune and detoxification genes in tissues associated with nectar processing

    PubMed Central

    Vannette, Rachel L.; Mohamed, Abbas; Johnson, Brian R.

    2015-01-01

    Pollinators, including honey bees, routinely encounter potentially harmful microorganisms and phytochemicals during foraging. However, the mechanisms by which honey bees manage these potential threats are poorly understood. In this study, we examine the expression of antimicrobial, immune and detoxification genes in Apis mellifera and compare between forager and nurse bees using tissue-specific RNA-seq and qPCR. Our analysis revealed extensive tissue-specific expression of antimicrobial, immune signaling, and detoxification genes. Variation in gene expression between worker stages was pronounced in the mandibular and hypopharyngeal gland (HPG), where foragers were enriched in transcripts that encode antimicrobial peptides (AMPs) and immune response. Additionally, forager HPGs and mandibular glands were enriched in transcripts encoding detoxification enzymes, including some associated with xenobiotic metabolism. Using qPCR on an independent dataset, we verified differential expression of three AMP and three P450 genes between foragers and nurses. High expression of AMP genes in nectar-processing tissues suggests that these peptides may contribute to antimicrobial properties of honey or to honey bee defense against environmentally-acquired microorganisms. Together, these results suggest that worker role and tissue-specific expression of AMPs, and immune and detoxification enzymes may contribute to defense against microorganisms and xenobiotic compounds acquired while foraging. PMID:26549293

  16. Lack of genetic diversity across diverse immune genes in an endangered mammal, the Tasmanian devil (Sarcophilus harrisii).

    PubMed

    Morris, Katrina M; Wright, Belinda; Grueber, Catherine E; Hogg, Carolyn; Belov, Katherine

    2015-08-01

    The Tasmanian devil (Sarcophilus harrisii) is threatened with extinction due to the spread of devil facial tumour disease. Polymorphisms in immune genes can provide adaptive potential to resist diseases. Previous studies in diversity at immune loci in wild species have almost exclusively focused on genes of the major histocompatibility complex (MHC); however, these genes only account for a fraction of immune gene diversity. Devils lack diversity at functionally important immunity loci, including MHC and Toll-like receptor genes. Whether there are polymorphisms at devil immune genes outside these two families is unknown. Here, we identify polymorphisms in a wide range of key immune genes, and develop assays to type single nucleotide polymorphisms (SNPs) within a subset of these genes. A total of 167 immune genes were examined, including cytokines, chemokines and natural killer cell receptors. Using genome-level data from ten devils, SNPs within coding regions, introns and 10 kb flanking genes of interest were identified. We found low polymorphism across 167 immune genes examined bioinformatically using whole-genome data. From this data, we developed long amplicon assays to target nine genes. These amplicons were sequenced in 29-220 devils and found to contain 78 SNPs, including eight SNPS within exons. Despite the extreme paucity of genetic diversity within these genes, signatures of balancing selection were exhibited by one chemokine gene, suggesting that remaining diversity may hold adaptive potential. The low functional diversity may leave devils highly vulnerable to infectious disease, and therefore, monitoring and preserving remaining diversity will be critical for the long-term management of this species. Examining genetic variation in diverse immune genes should be a priority for threatened wildlife species. This study can act as a model for broad-scale immunogenetic diversity analysis in threatened species. PMID:26119928

  17. Immune-related genes associated with intestinal tissue in the sea cucumber Holothuria glaberrima.

    PubMed

    Ramírez-Gómez, Francisco; Ortíz-Pineda, Pablo A; Rojas-Cartagena, Carmencita; Suárez-Castillo, Edna C; García-Arrarás, José E; García-Ararrás, José E

    2008-01-01

    We have analyzed 5,173 expressed sequence tags (ESTs) from three cDNA libraries of normal and regenerating intestinal tissue of the sea cucumber Holothuria glaberrima and found 22 putative immune-related genes. These sequences showed similarities (e-value approx 10(-8)) to genes involved in immune processes or expressed by immune cells. Sequences were analyzed using bioinformatic tools to determine a putative identity. In addition, phylogenetic analyses were performed to find relationships with similar proteins in other organisms. The mRNAs for ten sequences were detected in coelomocytes by using reverse transcription-polymerase chain reaction (RT-PCR). Moreover, five of them showed a significant increase in expression after an LPS challenge, while the other five showed no significant changes. These results show the variety of immune molecules that may be found in holothurians and support the idea that the invertebrate immune system is more than a collection of simple innate responses. Our study also provides new data of importance in deciphering the evolution and development of the immune system. PMID:18092157

  18. An MHC class I immune evasion gene of Marek’s Disease Virus

    PubMed Central

    Hearn, Cari; Preeyanon, Likit; Hunt, Henry D.

    2014-01-01

    Marek’s Disease Virus (MDV) is a widespread α-herpesvirus of chickens that causes T cell tumors. Acute, but not latent, MDV infection has previously been shown to lead to downregulation of cell-surface MHC class I (Virology 282:198–205 (2001)), but the gene(s) involved have not been identified. Here we demonstrate that an MDV gene, MDV012, is capable of reducing surface expression of MHC class I on chicken cells. Co-expression of an MHC class I-binding peptide targeted to the endoplasmic reticulum (bypassing the requirement for the TAP peptide transporter) partially rescued MHC class I expression in the presence of MDV012, suggesting that MDV012 is a TAP-blocking MHC class I immune evasion protein. This is the first unique non-mammalian MHC class I immune evasion gene identified, and suggests that α-herpesviruses have conserved this function for at least 100 million years. PMID:25462349

  19. A gene associated with social immunity in the burying beetle Nicrophorus vespilloides

    PubMed Central

    Palmer, William J.; Duarte, Ana; Schrader, Matthew; Day, Jonathan P.; Kilner, Rebecca; Jiggins, Francis M.

    2016-01-01

    Some group-living species exhibit social immunity, where the immune response of one individual can protect others in the group from infection. In burying beetles, this is part of parental care. Larvae feed on vertebrate carcasses which their parents smear with exudates that inhibit microbial growth. We have sequenced the transcriptome of the burying beetle Nicrophorus vespilloides and identified six genes that encode lysozymes—a type of antimicrobial enzyme that has previously been implicated in social immunity in burying beetles. When females start breeding and producing antimicrobial anal exudates, we found that the expression of one of these genes was increased by approximately 1000 times to become one of the most abundant transcripts in the transcriptome. Females varied considerably in the antimicrobial properties of their anal exudates, and this was strongly correlated with the expression of this lysozyme. We conclude that we have likely identified a gene encoding a key effector molecule in social immunity and that it was recruited during evolution from a function in personal immunity. PMID:26817769

  20. Trans-Species Polymorphism in Immune Genes: General Pattern or MHC-Restricted Phenomenon?

    PubMed Central

    Vinkler, Michal

    2015-01-01

    Immunity exhibits extraordinarily high levels of variation. Evolution of the immune system in response to host-pathogen interactions in particular ecological contexts appears to be frequently associated with diversifying selection increasing the genetic variability. Many studies have documented that immunologically relevant polymorphism observed today may be tens of millions years old and may predate the emergence of present species. This pattern can be explained by the concept of trans-species polymorphism (TSP) predicting the maintenance and sharing of favourable functionally important alleles of immune-related genes between species due to ongoing balancing selection. Despite the generality of this concept explaining the long-lasting adaptive variation inherited from ancestors, current research in TSP has vastly focused only on major histocompatibility complex (MHC). In this review we summarise the evidence available on TSP in human and animal immune genes to reveal that TSP is not a MHC-specific evolutionary pattern. Further research should clearly pay more attention to the investigation of TSP in innate immune genes and especially pattern recognition receptors which are promising candidates for this type of evolution. More effort should also be made to distinguish TSP from convergent evolution and adaptive introgression. Identification of balanced TSP variants may represent an accurate approach in evolutionary medicine to recognise disease-resistance alleles. PMID:26090501

  1. Expression analysis of immune response genes in fish epithelial cells following ranavirus infection.

    PubMed

    Holopainen, Riikka; Tapiovaara, Hannele; Honkanen, Jarno

    2012-06-01

    Ranaviruses (family Iridoviridae) are a growing threat to fish and amphibian populations worldwide. The immune response to ranavirus infection has been studied in amphibians, but little is known about the responses elicited in piscine hosts. In this study, the immune response and apoptosis induced by ranaviruses were investigated in fish epithelial cells. Epithelioma papulosum cyprini (EPC) cells were infected with four different viral isolates: epizootic haematopoietic necrosis virus (EHNV), frog virus 3 (FV3), European catfish virus (ECV) and doctor fish virus (DFV). Quantitative real-time PCR (qPCR) assays were developed to measure the mRNA expression of immune response genes during ranavirus infection. The target genes included tumour necrosis factor α (TNF-α), interleukin-1β (IL-1β), β2-microglobulin (β2M), interleukin-10 (IL-10) and transforming growth factor β (TGF-β). All ranaviruses elicited changes in immune gene expression. EHNV and FV3 caused a strong pro-inflammatory response with an increase in the expression of both IL-1β and TNF-α, whereas ECV and DFV evoked transient up-regulation of regulatory cytokine TGF-β. Additionally, all viral isolates induced increased β2M expression as well as apoptosis in the EPC cells. Our results indicate that epithelial cells can serve as an in vitro model for studying the mechanisms of immune response in the piscine host in the first stages of ranavirus infection. PMID:22452879

  2. Identification of immune inducible genes from the velvet worm Epiperipatus biolleyi (Onychophora).

    PubMed

    Altincicek, Boran; Vilcinskas, Andreas

    2008-01-01

    Onychophora are the next relatives of Arthropoda and, hence, represent an important taxon to unravel relationships among Insecta, Crustacea, Arachnida, and Myriapoda. Here, we screened for immune inducible genes from the onychophoran Epiperipatus biolleyi (Peripatidae) by injecting crude bacterial LPS and applying the suppression subtractive hybridization technique. Our analysis of 288 cDNAs resulted in identification of 36 novel genes in E. biolleyi whose potential homologues from other animals are known to mediate immune-related signaling (e.g. mitogen-activated protein kinase kinase 1 and immunoglobulin enhancer binding protein), to be involved in cellular processes (e.g. perilipin and myosin light chain), or to act as immune effector molecules (e.g. lysosomal beta-galactosidase, a putative antimicrobial peptide and a potential thiolester containing protein). Comparisons with homologous genes from other animals including the two most favored ecdysozoan model organisms of innate immunity research, the nematode Caenorhabditis elegans and the fruit fly Drosophila melanogaster, provide further insights into the origin and evolution of Arthropoda immunity. PMID:18598713

  3. TGFβ receptor 1: an immune susceptibility gene in HPV-associated cancer.

    PubMed

    Levovitz, Chaya; Chen, Dan; Ivansson, Emma; Gyllensten, Ulf; Finnigan, John P; Alshawish, Sara; Zhang, Weijia; Schadt, Eric E; Posner, Marshal R; Genden, Eric M; Boffetta, Paolo; Sikora, Andrew G

    2014-12-01

    Only a minority of those exposed to human papillomavirus (HPV) develop HPV-related cervical and oropharyngeal cancer. Because host immunity affects infection and progression to cancer, we tested the hypothesis that genetic variation in immune-related genes is a determinant of susceptibility to oropharyngeal cancer and other HPV-associated cancers by performing a multitier integrative computational analysis with oropharyngeal cancer data from a head and neck cancer genome-wide association study (GWAS). Independent analyses, including single-gene, gene-interconnectivity, protein-protein interaction, gene expression, and pathway analysis, identified immune genes and pathways significantly associated with oropharyngeal cancer. TGFβR1, which intersected all tiers of analysis and thus selected for validation, replicated significantly in the head and neck cancer GWAS limited to HPV-seropositive cases and an independent cervical cancer GWAS. The TGFβR1 containing p38-MAPK pathway was significantly associated with oropharyngeal cancer and cervical cancer, and TGFβR1 was overexpressed in oropharyngeal cancer, cervical cancer, and HPV(+) head and neck cancer tumors. These concordant analyses implicate TGFβR1 signaling as a process dysregulated across HPV-related cancers. This study demonstrates that genetic variation in immune-related genes is associated with susceptibility to oropharyngeal cancer and implicates TGFβR1/TGFβ signaling in the development of both oropharyngeal cancer and cervical cancer. Better understanding of the immunogenetic basis of susceptibility to HPV-associated cancers may provide insight into host/virus interactions and immune processes dysregulated in the minority of HPV-exposed individuals who progress to cancer. PMID:25273091

  4. TGFβ Receptor 1: An Immune Susceptibility Gene in HPV-Associated Cancer

    PubMed Central

    Levovitz, Chaya; Chen, Dan; Ivansson, Emma; Gyllensten, Ulf; Finnigan, John P.; Alshawish, Sara; Zhang, Weijia; Schadt, Eric E.; Posner, Marshal R.; Genden, Eric M.; Boffetta, Paolo; Sikora, Andrew G.

    2015-01-01

    Only a minority of those exposed to human papillomavirus (HPV) develop HPV-related cervical and oropharyngeal cancer. Because host immunity affects infection and progression to cancer, we tested the hypothesis that genetic variation in immune-related genes is a determinant of susceptibility to oropharyngeal cancer and other HPV-associated cancers by performing a multitier integrative computational analysis with oropharyngeal cancer data from a head and neck cancer genome-wide association study (GWAS). Independent analyses, including single-gene, gene-interconnectivity, protein–protein interaction, gene expression, and pathway analysis, identified immune genes and pathways significantly associated with oropharyngeal cancer. TGFβR1, which intersected all tiers of analysis and thus selected for validation, replicated significantly in the head and neck cancer GWAS limited to HPV-seropositive cases and an independent cervical cancer GWAS. The TGFβR1 containing p38–MAPK pathway was significantly associated with oropharyngeal cancer and cervical cancer, and TGFβR1 was overexpressed in oropharyngeal cancer, cervical cancer, and HPV+ head and neck cancer tumors. These concordant analyses implicate TGFβR1 signaling as a process dysregulated across HPV-related cancers. This study demonstrates that genetic variation in immune-related genes is associated with susceptibility to oropharyngeal cancer and implicates TGFβR1/TGFβ signaling in the development of both oropharyngeal cancer and cervical cancer. Better understanding of the immunogenetic basis of susceptibility to HPV-associated cancers may provide insight into host/virus interactions and immune processes dysregulated in the minority of HPV-exposed individuals who progress to cancer. PMID:25273091

  5. Immunizations.

    PubMed

    Sanford, Christopher A; Jong, Elaine C

    2016-03-01

    Vaccinations are a cornerstone of the pretravel consultation. The pretravel provider should assess a traveler's past medical history, planned itinerary, activities, mode of travel, and duration of stay and make appropriate vaccine recommendations. Given that domestic vaccine-preventable illnesses are more common in international travelers than are exotic or low-income nation-associated vaccine-preventable illnesses, clinicians should first ensure that travelers are current regarding routine immunizations. Additional immunizations may be indicated in some travelers. Familiarity with geographic distribution and seasonality of infectious diseases is essential. Clinicians should be cognizant of which vaccines are live, as there exist contraindications for live vaccines. PMID:26900111

  6. Borrelia burgdorferi sensu lato infection pressure shapes innate immune gene evolution in natural rodent populations across Europe

    PubMed Central

    Tschirren, Barbara

    2015-01-01

    Although parasite-mediated selection is assumed to be the main driver of immune gene evolution, empirical evidence that parasites induce allele frequency changes at host immune genes in time and/or space remains scarce. Here, I show that the frequency of a protective gene variant of the innate immune receptor Toll-like receptor 2 in natural bank vole (Myodes glareolus) populations is positively associated with the strength of Borrelia burgdorferi sensu lato infection risk across the European continent. Thereby, this study provides rare evidence for the role of spatially variable infection pressures in moulding the vertebrate immune system. PMID:26018834

  7. Borrelia burgdorferi sensu lato infection pressure shapes innate immune gene evolution in natural rodent populations across Europe.

    PubMed

    Tschirren, Barbara

    2015-05-01

    Although parasite-mediated selection is assumed to be the main driver of immune gene evolution, empirical evidence that parasites induce allele frequency changes at host immune genes in time and/or space remains scarce. Here, I show that the frequency of a protective gene variant of the innate immune receptor Toll-like receptor 2 in natural bank vole (Myodes glareolus) populations is positively associated with the strength of Borrelia burgdorferi sensu lato infection risk across the European continent. Thereby, this study provides rare evidence for the role of spatially variable infection pressures in moulding the vertebrate immune system. PMID:26018834

  8. Innate Immune Activity Conditions the Effect of Regulatory Variants upon Monocyte Gene Expression

    PubMed Central

    Fairfax, Benjamin P.; Naranbhai, Vivek; Wong, Daniel; Lau, Evelyn; Jostins, Luke; Plant, Katharine; Andrews, Robert; McGee, Chris; Knight, Julian C.

    2014-01-01

    To systematically investigate the impact of immune stimulation upon regulatory variant activity, we exposed primary monocytes from 432 healthy Europeans to interferon-γ (IFN-γ) or differing durations of lipopolysaccharide and mapped expression quantitative trait loci (eQTLs). More than half of cis-eQTLs identified, involving hundreds of genes and associated pathways, are detected specifically in stimulated monocytes. Induced innate immune activity reveals multiple master regulatory trans-eQTLs including the major histocompatibility complex (MHC), coding variants altering enzyme and receptor function, an IFN-β cytokine network showing temporal specificity, and an interferon regulatory factor 2 (IRF2) transcription factor–modulated network. Induced eQTL are significantly enriched for genome-wide association study loci, identifying context-specific associations to putative causal genes including CARD9, ATM, and IRF8. Thus, applying pathophysiologically relevant immune stimuli assists resolution of functional genetic variants. PMID:24604202

  9. Testosterone regulates thyroid cancer progression by modifying tumor suppressor genes and tumor immunity

    PubMed Central

    Zhang, Lisa J.; Xiong, Yin; Nilubol, Naris; He, Mei; Bommareddi, Swaroop; Zhu, Xuguang; Jia, Li; Xiao, Zhen; Park, Jeong-Won; Xu, Xia; Patel, Dhaval; Willingham, Mark C.; Cheng, Sheue-yann; Kebebew, Electron

    2015-01-01

    Cancer gender disparity has been observed for a variety of human malignancies. Thyroid cancer is one such cancer with a higher incidence in women, but more aggressive disease in men. There is scant evidence on the role of sex hormones on cancer initiation/progression. Using a transgenic mouse model of follicular thyroid cancer (FTC), we found castration led to lower rates of cancer in females and less advanced cancer in males. Mechanistically, less advanced cancer in castrated males was due to increased expression of tumor suppressor (Glipr1, Sfrp1) and immune-regulatory genes and higher tumor infiltration with M1 macrophages and CD8 cells. Functional study showed that GLIPR1 reduced cell growth and increased chemokine secretion (Ccl5) that activates immune cells. Our data demonstrate that testosterone regulates thyroid cancer progression by reducing tumor suppressor gene expression and tumor immunity. PMID:25576159

  10. Innate immune activity conditions the effect of regulatory variants upon monocyte gene expression.

    PubMed

    Fairfax, Benjamin P; Humburg, Peter; Makino, Seiko; Naranbhai, Vivek; Wong, Daniel; Lau, Evelyn; Jostins, Luke; Plant, Katharine; Andrews, Robert; McGee, Chris; Knight, Julian C

    2014-03-01

    To systematically investigate the impact of immune stimulation upon regulatory variant activity, we exposed primary monocytes from 432 healthy Europeans to interferon-γ (IFN-γ) or differing durations of lipopolysaccharide and mapped expression quantitative trait loci (eQTLs). More than half of cis-eQTLs identified, involving hundreds of genes and associated pathways, are detected specifically in stimulated monocytes. Induced innate immune activity reveals multiple master regulatory trans-eQTLs including the major histocompatibility complex (MHC), coding variants altering enzyme and receptor function, an IFN-β cytokine network showing temporal specificity, and an interferon regulatory factor 2 (IRF2) transcription factor-modulated network. Induced eQTL are significantly enriched for genome-wide association study loci, identifying context-specific associations to putative causal genes including CARD9, ATM, and IRF8. Thus, applying pathophysiologically relevant immune stimuli assists resolution of functional genetic variants. PMID:24604202

  11. Protein-poor diet reduces host-specific immune gene expression in Bombus terrestris

    PubMed Central

    Brunner, Franziska S.; Schmid-Hempel, Paul; Barribeau, Seth M.

    2014-01-01

    Parasites infect hosts non-randomly as genotypes of hosts vary in susceptibility to the same genotypes of parasites, but this specificity may be modulated by environmental factors such as nutrition. Nutrition plays an important role for any physiological investment. As immune responses are costly, resource limitation should negatively affect immunity through trade-offs with other physiological requirements. Consequently, nutritional limitation should diminish immune capacity in general, but does it also dampen differences among hosts? We investigated the effect of short-term pollen deprivation on the immune responses of our model host Bombus terrestris when infected with the highly prevalent natural parasite Crithidia bombi. Bumblebees deprived of pollen, their protein source, show reduced immune responses to infection. They failed to upregulate a number of genes, including antimicrobial peptides, in response to infection. In particular, they also showed less specific immune expression patterns across individuals and colonies. These findings provide evidence for how immune responses on the individual-level vary with important elements of the environment and illustrate how nutrition can functionally alter not only general resistance, but also alter the pattern of specific host–parasite interactions. PMID:24850921

  12. Combining Cytotoxic and Immune-Mediated Gene Therapy to Treat Brain Tumors

    PubMed Central

    Curtin, James F.; King, Gwendalyn D.; Candolfi, Marianela; Greeno, Remy B.; Kroeger, Kurt M.; Lowenstein, Pedro R.; Castro, Maria G.

    2006-01-01

    Glioblastoma (GBM) is a type of intracranial brain tumor, for which there is no cure. In spite of advances in surgery, chemotherapy and radiotherapy, patients die within a year of diagnosis. Therefore, there is a critical need to develop novel therapeutic approaches for this disease. Gene therapy, which is the use of genes or other nucleic acids as drugs, is a powerful new treatment strategy which can be developed to treat GBM. Several treatment modalities are amenable for gene therapy implementation, e.g. conditional cytotoxic approaches, targeted delivery of toxins into the tumor mass, immune stimulatory strategies, and these will all be the focus of this review. Both conditional cytotoxicity and targeted toxin mediated tumor death, are aimed at eliminating an established tumor mass and preventing further growth. Tumors employ several defensive strategies that suppress and inhibit anti-tumor immune responses. A better understanding of the mechanisms involved in eliciting anti-tumor immune responses has identified promising targets for immunotherapy. Immunotherapy is designed to aid the immune system to recognize and destroy tumor cells in order to eliminate the tumor burden. Also, immune-therapeutic strategies have the added advantage that an activated immune system has the capability of recognizing tumor cells at distant sites from the primary tumor, therefore targeting metastasis distant from the primary tumor locale. Pre-clinical models and clinical trials have demonstrated that in spite of their location within the central nervous system (CNS), a tissue described as ‘immune privileged’, brain tumors can be effectively targeted by the activated immune system following various immunotherapeutic strategies. This review will highlight recent advances in brain tumor immunotherapy, with particular emphasis on advances made using gene therapy strategies, as well as reviewing other novel therapies that can be used in combination with immunotherapy. Another

  13. Disruption of Rpp1-mediated soybean rust immunity by virus-induced gene silencing

    PubMed Central

    Cooper, Bret; Campbell, Kimberly B; McMahon, Michael B; Luster, Douglas G

    2013-01-01

    Phakopsora pachyrhizi, a fungus that causes rust disease on soybean, has potential to impart significant yield loss and disrupt food security and animal feed production. Rpp1 is a soybean gene that confers immunity to soybean rust, and it is important to understand how it regulates the soybean defense system and to use this knowledge to protect commercial crops. It was previously discovered that some soybean proteins resembling transcription factors accumulate in the nucleus of Rpp1 soybeans. To determine if they contribute to immunity, Bean pod mottle virus was used to attenuate or silence the expression of their genes. Rpp1 plants subjected to virus-induced gene silencing exhibited reduced amounts of RNA for 5 of the tested genes, and the plants developed rust-like symptoms after subsequent inoculation with fungal spores. Symptoms were associated with the accumulation of rust fungal RNA and protein. Silenced plants also had reduced amounts of RNA for the soybean Myb84 transcription factor and soybean isoflavone O-methyltransferase, both of which are important to phenylpropanoid biosynthesis and lignin formation, crucial components of rust resistance. These results help resolve some of the genes that contribute to Rpp1-mediated immunity and improve upon the knowledge of the soybean defense system. It is possible that these genes could be manipulated to enhance rust resistance in otherwise susceptible soybean cultivars. PMID:24401541

  14. Differential expression of immune genes of adult honey bee (Apis mellifera) after inoculated by Nosema ceranae

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Nosema ceranae is a microsporidium parasite infecting adult honey bees (Apis mellifera) and is known to have affects at both the individual and colony level. In this study, the expression levels were measured for four antimicrobial peptide encoding genes that are associated with bee humoral immunity...

  15. KINETIC CHANGES IN IMMUNE-RELATED GENE EXPRESSION AND INTESTINAL LYMPHOCYTE SUBPOPULATIONS FOLLOWING E. MAXIMA INFECTION

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Coccidiosis, a major intestinal parasitic disease of poultry, induces a cell-mediated immune response against the etiologic agent of the disease, Eimeria. In the current study, the expression levels of gene transcripts encoding pro-inflammatory, Th1, and Th2 cytokines, as well as chemokines and int...

  16. Immunization.

    ERIC Educational Resources Information Center

    Guerin, Nicole; And Others

    1986-01-01

    Contents of this double journal issue concern immunization and primary health care of children. The issue decribes vaccine storage and sterilization techniques, giving particular emphasis to the role of the cold chain, i.e., the maintenance of a specific temperature range to assure potency of vaccines as they are moved from a national storage…

  17. Innate immune-stimulating and immune genes up-regulating activities of three types of alginate from Sargassum siliquosum in Pacific white shrimp, Litopenaeus vannamei.

    PubMed

    Yudiati, Ervia; Isnansetyo, Alim; Murwantoko; Ayuningtyas; Triyanto; Handayani, Christina Retna

    2016-07-01

    The Total Haemocyte Count (THC), phenoloxidase (PO), Superoxide Dismutase (SOD) activity, Phagocytic Activity/Index and Total Protein Plasma (TPP) were examined after feeding the white shrimp Litopenaeus vannamei with diets supplemented with three different types of alginates (acid, calcium and sodium alginates). Immune-related genes expression was evaluated by quantitative Real Time PCR (qRT-PCR). Results indicated that the immune parameters directly increased according to the doses of alginates and time. The 2.0 g kg(-1) of acid and sodium alginate treatments were gave better results. Four immune-related genes expression i.e. LGBP, Toll, Lectin, proPO were up regulated. It is therefore concluded that the supplementation of alginate of Sargassum siliquosum on the diet of L. vannamei enhanced the innate immunity as well as the expression of immune-related genes. It is the first report on the simultaneous evaluation of three alginate types to enhance innate immune parameters and immune-related genes expression in L. vannamei. PMID:26993614

  18. DNA vaccination using expression vectors carrying FIV structural genes induces immune response against feline immunodeficiency virus.

    PubMed

    Cuisinier, A M; Mallet, V; Meyer, A; Caldora, C; Aubert, A

    1997-07-01

    Following inactivated virus vaccination trials, the surface glycoprotein gp120 of the feline immunodeficiency virus (FIV) was considered as one of the determinants for protection. However, several vaccination trials using recombinant Env protein or some peptides failed to induce protection. To understand the role of the gp120 protein in vivo, we vaccinated cats with naked DNA coding for FIV structural proteins gp120 and p10. We analyzed the ability of these vaccinations to induce immune protection and to influence the onset of infection. Injection in cat muscles of expression vectors coding for the FIV gp120 protein induced a humoral response. Cats immunized twice with the gp120 gene showed different patterns after challenge. Two cats were, like the control cats, infected from the second week after infection onwards. The two others maintained a low proviral load with no modification of their antibody pattern. The immune response induced by gp120 DNA injection could control the level of viral replication. This protective-like immune response was not correlated to the humoral response. All the cats immunized with the gp120 gene followed by the p10 gene were infected, like the control cats, from the second week but they developed a complete humoral response against viral proteins after challenge. Furthermore, they showed a sudden but transient drop of the proviral load at 4 weeks after infection. Under these conditions, one injection of the p10 gene after one injection of the gp120 gene was not sufficient to stimulate protection. On the contrary, after a period, it seems to facilitate virus replication. PMID:9269051

  19. A comprehensive transcriptome and immune-gene repertoire of the lepidopteran model host Galleria mellonella

    PubMed Central

    2011-01-01

    Background The larvae of the greater wax moth Galleria mellonella are increasingly used (i) as mini-hosts to study pathogenesis and virulence factors of prominent bacterial and fungal human pathogens, (ii) as a whole-animal high throughput infection system for testing pathogen mutant libraries, and (iii) as a reliable host model to evaluate the efficacy of antibiotics against human pathogens. In order to compensate for the lack of genomic information in Galleria, we subjected the transcriptome of different developmental stages and immune-challenged larvae to next generation sequencing. Results We performed a Galleria transcriptome characterization on the Roche 454-FLX platform combined with traditional Sanger sequencing to obtain a comprehensive transcriptome. To maximize sequence diversity, we pooled RNA extracted from different developmental stages, larval tissues including hemocytes, and from immune-challenged larvae and normalized the cDNA pool. We generated a total of 789,105 pyrosequencing and 12,032 high-quality Sanger EST sequences which clustered into 18,690 contigs with an average length of 1,132 bases. Approximately 40% of the ESTs were significantly similar (E ≤ e-03) to proteins of other insects, of which 45% have a reported function. We identified a large number of genes encoding proteins with established functions in immunity related sensing of microbial signatures and signaling, as well as effector molecules such as antimicrobial peptides and inhibitors of microbial proteinases. In addition, we found genes known as mediators of melanization or contributing to stress responses. Using the transcriptomic data, we identified hemolymph peptides and proteins induced upon immune challenge by 2D-gelelectrophoresis combined with mass spectrometric analysis. Conclusion Here, we have developed extensive transcriptomic resources for Galleria. The data obtained is rich in gene transcripts related to immunity, expanding remarkably our knowledge about immune and

  20. Genes involved in immunity to the lantibiotic nisin produced by Lactococcus lactis 6F3.

    PubMed Central

    Siegers, K; Entian, K D

    1995-01-01

    The lantibiotic nisin is produced by several strains of Lactococcus lactis. The complete gene cluster for nisin biosynthesis in L. lactis 6F3 comprises 15 kb of DNA. As described previously, the structural gene nisA is followed by the genes nisB, nisT, nisC, nisI, nisP, nisR, and nisK. Further analysis revealed three additional open reading frames, nisF, nisE, and nisG, adjacent to nisK. Approximately 1 kb downstream of the nisG gene, three open reading frames in the opposite orientation have been identified. One of the reading frames, sacR, belongs to the sucrose operon, indicating that all genes belonging to the nisin gene cluster of L. lactis 6F3 have now been identified. Proteins NisF and NisE show strong homology to members of the family of ATP-binding cassette (ABC) transporters, and nisG encodes a hydrophobic protein which might act similarly to the immunity proteins described for several colicins. Gene disruption mutants carrying mutations in the genes nisF, nisE, and nisG were still able to produce nisin. However, in comparison with the wild-type strain, these mutants were more sensitive to nisin. This indicates that besides nisI the newly identified genes are also involved in immunity to nisin. The NisF-NisE ABC transporter is homologous to an ABC transporter of Bacillus subtilis and the MbcF-MbcE transporter of Escherichia coli, which are involved in immunity to subtilin and microcin B17, respectively. PMID:7793910

  1. Chemokine gene expression in lung CD8 T cells correlates with protective immunity in mice immunized intra-nasally with Adenovirus-85A

    PubMed Central

    2010-01-01

    Background Immunization of BALB/c mice with a recombinant adenovirus expressing Mycobacterium tuberculosis (M. tuberculosis) antigen 85A (Ad85A) protects against aerosol challenge with M. tuberculosis only when it is administered intra-nasally (i.n.). Immunization with Ad85A induces a lung-resident population of activated CD8 T cells that is antigen dependent, highly activated and mediates protection by early inhibition of M. tuberculosis growth. In order to determine why the i.n. route is so effective compared to parenteral immunization, we used microarray analysis to compare gene expression profiles of pulmonary and splenic CD8 T cells after i.n. or intra-dermal (i.d.) immunization. Method Total RNA from CD8 T cells was isolated from lungs or spleens of mice immunized with Ad85A by the i.n. or i.d. route. The gene profiles generated from each condition were compared. Statistically significant (p ≤ 0.05) differentially expressed genes were analyzed to determine if they mapped to particular molecular functions, biological processes or pathways using Gene Ontology and Panther DB mapping tools. Results CD8 T cells from lungs of i.n. immunized mice expressed a large number of chemokines chemotactic for resting and activated T cells as well as activation and survival genes. Lung lymphocytes from i.n. immunized mice also express the chemokine receptor gene Cxcr6, which is thought to aid long-term retention of antigen-responding T cells in the lungs. Expression of CXCR6 on CD8 T cells was confirmed by flow cytometry. Conclusions Our microarray analysis represents the first ex vivo study comparing gene expression profiles of CD8 T cells isolated from distinct sites after immunization with an adenoviral vector by different routes. It confirms earlier phenotypic data indicating that lung i.n. cells are more activated than lung i.d. CD8 T cells. The sustained expression of chemokines and activation genes enables CD8 T cells to remain in the lungs for extended periods after

  2. Widespread Decreased Expression of Immune Function Genes in Human Peripheral Blood Following Radiation Exposure

    PubMed Central

    Paul, Sunirmal; Smilenov, Lubomir B.; Amundson, Sally A.

    2014-01-01

    We report a large-scale reduced expression of genes in pathways related to cell-type specific immunity functions that emerges from microarray analysis 48 h after ex vivo γ-ray irradiation (0, 0.5, 2, 5, 8 Gy) of human peripheral blood from five donors. This response is similar to that seen in patients at 24 h after the start of total-body irradiation and strengthens the rationale for the ex vivo model as an adjunct to human in vivo studies. The most marked response was in genes associated with natural killer (NK) cell immune functions, reflecting a relative loss of NK cells from the population. T- and B-cell mediated immunity genes were also significantly represented in the radiation response. Combined with our previous studies, a single gene expression signature was able to predict radiation dose range with 97% accuracy at times from 6–48 h after exposure. Gene expression signatures that may report on the loss or functional deactivation of blood cell subpopulations after radiation exposure may be particularly useful both for triage biodosimetry and for monitoring the effect of radiation mitigating treatments. PMID:24168352

  3. Identification of Toxoplasma gondii Genes Responsive to the Host Immune Response during In Vivo Infection

    PubMed Central

    Skariah, Sini; Mordue, Dana G.

    2012-01-01

    Toxoplasma gondii is an obligate intracellular protozoa parasite that causes the disease toxoplasmosis. It resides within host cells in a parasitophorous vacuole distinct from the host cell endocytic system. T. gondii was used as a model to investigate how obligate intracellular parasites alter their gene expression in response to the host immune response during infection compared to growth in host cells in vitro. While bacterial pathogens clearly alter gene expression to adapt to the host environment during infection, the degree to which the external environment affects gene expression by obligate intracellular pathogens sequestered within host cells is less clear. The global transcriptome of T. gondii was analyzed in vivo in the presence and absence of the IFN-γ-dependent host innate immune response. The parasites' in vivo transcriptome was also compared to its transcriptome in vitro in fibroblast cells. Our results indicate that the parasite transcriptome is significantly altered during in vivo infection in the presence, but not absence, of IFN–γ-dependent immunity compared with fibroblasts infected in vitro. Many of the parasite genes increased in vivo appear to be common to an early general stress response by the parasite; surprisingly putative oocyst stage specific genes were also disproportionately increased during infection. PMID:23071600

  4. Expression analysis of 13 ovine immune response candidate genes in Visna/Maedi disease progression.

    PubMed

    Larruskain, Amaia; Bernales, Irantzu; Luján, Lluis; de Andrés, Damián; Amorena, Beatriz; Jugo, Begoña M

    2013-07-01

    Visna/Maedi virus (VMV) is a lentivirus that infects cells of the monocyte/macrophage lineage in sheep. Infection with VMV may lead to Visna/Maedi (VM) disease, which causes a multisystemic inflammatory disorder causing pneumonia, encephalitis, mastitis and arthritis. The role of ovine immune response genes in the development of VM disease is not fully understood. In this work, sheep of the Rasa Aragonesa breed were divided into two groups depending on the presence/absence of VM-characteristic clinical lesions in the aforementioned organs and the relative levels of candidate gene expression, including cytokines and innate immunity loci were measured by qPCR in the lung and udder. Sheep with lung lesions showed differential expression in five target genes: CCR5, TLR7, and TLR8 were up regulated and IL2 and TNFα down regulated. TNFα up regulation was detected in the udder. PMID:23582860

  5. DNA Vaccines: Protective Immunizations by Parenteral, Mucosal, and Gene-Gun Inoculations

    NASA Astrophysics Data System (ADS)

    Fynan, Ellen F.; Webster, Robert G.; Fuller, Deborah H.; Haynes, Joel R.; Santoro, Joseph C.; Robinson, Harriet L.

    1993-12-01

    Plasmid DNAs expressing influenza virus hemagglutinin glycoproteins have been tested for their ability to raise protective immunity against lethal influenza challenges of the same subtype. In trials using two inoculations of from 50 to 300 μg of purified DNA in saline, 67-95% of test mice and 25-63% of test chickens have been protected against a lethal influenza challenge. Parenteral routes of inoculation that achieved good protection included intramuscular and intravenous injections. Successful mucosal routes of vaccination included DNA drops administered to the nares or trachea. By far the most efficient DNA immunizations were achieved by using a gene gun to deliver DNA-coated gold beads to the epidermis. In mice, 95% protection was achieved by two immunizations with beads loaded with as little as 0.4 μg of DNA. The breadth of routes supporting successful DNA immunizations, coupled with the very small amounts of DNA required for gene-gun immunizations, highlight the potential of this remarkably simple technique for the development of subunit vaccines.

  6. Genomic analysis of the immune gene repertoire of amphioxus reveals extraordinary innate complexity and diversity

    PubMed Central

    Huang, Shengfeng; Yuan, Shaochun; Guo, Lei; Yu, Yanhong; Li, Jun; Wu, Tao; Liu, Tong; Yang, Manyi; Wu, Kui; Liu, Huiling; Ge, Jin; Yu, Yingcai; Huang, Huiqing; Dong, Meiling; Yu, Cuiling; Chen, Shangwu; Xu, Anlong

    2008-01-01

    It has been speculated that before vertebrates evolved somatic diversity-based adaptive immunity, the germline-encoded diversity of innate immunity may have been more developed. Amphioxus occupies the basal position of the chordate phylum and hence is an important reference to the evolution of vertebrate immunity. Here we report the first comprehensive genomic survey of the immune gene repertoire of the amphioxus Branchiostoma floridae. It has been reported that the purple sea urchin has a vastly expanded innate receptor repertoire not previously seen in other species, which includes 222 toll-like receptors (TLRs), 203 NOD/NALP-like receptors (NLRs), and 218 scavenger receptors (SRs). We discovered that the amphioxus genome contains comparable expansion with 71 TLR gene models, 118 NLR models, and 270 SR models. Amphioxus also expands other receptor-like families, including 1215 C-type lectin models, 240 LRR and IGcam-containing models, 1363 other LRR-containing models, 75 C1q-like models, 98 ficolin-like models, and hundreds of models containing complement-related domains. The expansion is not restricted to receptors but is likely to extend to intermediate signal transducers because there are 58 TIR adapter-like models, 36 TRAF models, 44 initiator caspase models, and 541 death-fold domain-containing models in the genome. Amphioxus also has a sophisticated TNF system and a complicated complement system not previously seen in other invertebrates. Besides the increase of gene number, domain combinations of immune proteins are also increased. Altogether, this survey suggests that the amphioxus, a species without vertebrate-type adaptive immunity, holds extraordinary innate complexity and diversity. PMID:18562681

  7. Genomic analysis of the immune gene repertoire of amphioxus reveals extraordinary innate complexity and diversity.

    PubMed

    Huang, Shengfeng; Yuan, Shaochun; Guo, Lei; Yu, Yanhong; Li, Jun; Wu, Tao; Liu, Tong; Yang, Manyi; Wu, Kui; Liu, Huiling; Ge, Jin; Yu, Yingcai; Huang, Huiqing; Dong, Meiling; Yu, Cuiling; Chen, Shangwu; Xu, Anlong

    2008-07-01

    It has been speculated that before vertebrates evolved somatic diversity-based adaptive immunity, the germline-encoded diversity of innate immunity may have been more developed. Amphioxus occupies the basal position of the chordate phylum and hence is an important reference to the evolution of vertebrate immunity. Here we report the first comprehensive genomic survey of the immune gene repertoire of the amphioxus Branchiostoma floridae. It has been reported that the purple sea urchin has a vastly expanded innate receptor repertoire not previously seen in other species, which includes 222 toll-like receptors (TLRs), 203 NOD/NALP-like receptors (NLRs), and 218 scavenger receptors (SRs). We discovered that the amphioxus genome contains comparable expansion with 71 TLR gene models, 118 NLR models, and 270 SR models. Amphioxus also expands other receptor-like families, including 1215 C-type lectin models, 240 LRR and IGcam-containing models, 1363 other LRR-containing models, 75 C1q-like models, 98 ficolin-like models, and hundreds of models containing complement-related domains. The expansion is not restricted to receptors but is likely to extend to intermediate signal transducers because there are 58 TIR adapter-like models, 36 TRAF models, 44 initiator caspase models, and 541 death-fold domain-containing models in the genome. Amphioxus also has a sophisticated TNF system and a complicated complement system not previously seen in other invertebrates. Besides the increase of gene number, domain combinations of immune proteins are also increased. Altogether, this survey suggests that the amphioxus, a species without vertebrate-type adaptive immunity, holds extraordinary innate complexity and diversity. PMID:18562681

  8. In ovo carbohydrate supplementation modulates growth and immunity-related genes in broiler chickens.

    PubMed

    Bhanja, S K; Goel, A; Pandey, N; Mehra, M; Majumdar, S; Mandal, A B

    2015-02-01

    A study was undertaken to investigate the role of in ovo administrated carbohydrates on the expression pattern of growth and immune-related genes. In ovo injections (n = 400) were carried out on the 14th day of incubation into the yolk sac/amnion of the broiler chicken embryos. Expression of growth-related genes: chicken growth hormone (cGH), insulin-like growth factor-I & II (IGF-I & II) and mucin were studied in hepatic and jejunum tissues of late-term embryo and early post-hatch chicks. Expression of candidate immune genes: Interleukin-2, 6, 10 and 12 (IL-2, IL-6, IL-10 and IL-12), Tumour necrosis factor-alpha (TNF-α) and Interferon gamma (IFN-γ) were studied in peripheral blood monocyte cells of in ovo-injected and control birds following antigenic stimulation with sheep RBC (SRBC) or mitogen concanavalin A (Con-A). Glucose injection significantly increased the expression of IGF-II gene during embryonic period and both cGH and IGF-II in early post-hatch period, while ribose-injected chicks had higher expression of IGF-II gene during embryonic stage. Enhanced mucin gene expression was also observed in fructose-injected chicks during embryonic age. Glucose-injected chicks had higher expression of IL-6 or IL-10, while those injected with fructose or ribose had higher expression of IL-2, IL-12 and IFN gamma. It is concluded that in ovo supplementation of carbohydrates might help in improving the growth of late-term embryos and chicks. In ovo glucose could modulate humoral-related immunity, while fructose or ribose might help in improving the cellular immunity in broiler chickens. PMID:24797673

  9. Immune Recognition of Gene Transfer Vectors: Focus on Adenovirus as a Paradigm

    PubMed Central

    Aldhamen, Yasser Ali; Seregin, Sergey S.; Amalfitano, Andrea

    2011-01-01

    Recombinant Adenovirus (Ad) based vectors have been utilized extensively as a gene transfer platform in multiple pre-clinical and clinical applications. These applications are numerous, and inclusive of both gene therapy and vaccine based approaches to human or animal diseases. The widespread utilization of these vectors in both animal models, as well as numerous human clinical trials (Ad-based vectors surpass all other gene transfer vectors relative to numbers of patients treated, as well as number of clinical trials overall), has shed light on how this virus vector interacts with both the innate and adaptive immune systems. The ability to generate and administer large amounts of this vector likely contributes not only to their ability to allow for highly efficient gene transfer, but also their elicitation of host immune responses to the vector and/or the transgene the vector expresses in vivo. These facts, coupled with utilization of several models that allow for full detection of these responses has predicted several observations made in human trials, an important point as lack of similar capabilities by other vector systems may prevent detection of such responses until only after human trials are initiated. Finally, induction of innate or adaptive immune responses by Ad vectors may be detrimental in one setting (i.e., gene therapy) and be entirely beneficial in another (i.e., prophylactic or therapeutic vaccine based applications). Herein, we review the current understanding of innate and adaptive immune responses to Ad vectors, as well some recent advances that attempt to capitalize on this understanding so as to further broaden the safe and efficient use of Ad-based gene transfer therapies in general. PMID:22566830

  10. Molecular Evolution of Immune Genes in the Malaria Mosquito Anopheles gambiae

    PubMed Central

    Lehmann, Tovi; Hume, Jen C. C.; Licht, Monica; Burns, Christopher S.; Wollenberg, Kurt; Simard, Fred; Ribeiro, Jose' M. C.

    2009-01-01

    Background As pathogens that circumvent the host immune response are favoured by selection, so are host alleles that reduce parasite load. Such evolutionary processes leave their signature on the genes involved. Deciphering modes of selection operating on immune genes might reveal the nature of host-pathogen interactions and factors that govern susceptibility in host populations. Such understanding would have important public health implications. Methodology/Findings We analyzed polymorphisms in four mosquito immune genes (SP14D1, GNBP, defensin, and gambicin) to decipher selection effects, presumably mediated by pathogens. Using samples of Anopheles arabiensis, An. quadriannulatus and four An. gambiae populations, as well as published sequences from other Culicidae, we contrasted patterns of polymorphisms between different functional units of the same gene within and between populations. Our results revealed selection signatures operating on different time scales. At the most recent time scale, within-population diversity revealed purifying selection. Between populations and between species variation revealed reduced differentiation (GNBP and gambicin) at coding vs. noncoding- regions, consistent with balancing selection. McDonald-Kreitman tests between An. quadriannulatus and both sibling species revealed higher fixation rate of synonymous than nonsynonymous substitutions (GNBP) in accordance with frequency dependent balancing selection. At the longest time scale (>100 my), PAML analysis using distant Culicid taxa revealed positive selection at one codon in gambicin. Patterns of genetic variation were independent of exposure to human pathogens. Significance and Conclusions Purifying selection is the most common form of selection operating on immune genes as it was detected on a contemporary time scale on all genes. Selection for “hypervariability” was not detected, but negative balancing selection, detected at a recent evolutionary time scale between sibling

  11. Interleukin-23R gene polymorphism in pediatric Egyptian patients with primary immune thrombocytopenia.

    PubMed

    Farawela, Hala M; Botros, Shahira K A; El-Ghamrawy, Mona; Ebrahim, Eman O

    2016-06-01

    Primary immune thrombocytopenia is an acquired autoimmune disorder caused by the production of antiplatelet antibodies. These autoantibodies opsonize platelets for splenic clearance, resulting in low levels of circulating platelets. The current case-control study aimed at detecting the frequency of interleukin-23 receptor rs1884444 single nucleotide polymorphism in Egyptian children with primary immune thrombocytopenia and its possible role as a genetic marker for disease risk. Interleukin-23 receptor rs1884444 single nucleotide polymorphism was studied in 50 patients with primary immune thrombocytopenia and 100 healthy age and sex-matched controls by polymerase chain reaction amplification of the target gene followed by allele-specific restriction enzyme digestion. Regarding the distribution of the genotypes of the interleukin-23 receptor rs1884444 polymorphism, no statistically significant difference was found between cases and control groups. The variant genotypes (GT/TT) frequency was 10% in primary immune thrombocytopenia cases versus 7% in the control groups [P value = 0.755, odds ratio (OR): 0.326, 95% confidence interval (CI): 0.099-1.076]. Similarly, no difference was found between acute and chronic cases. The variant genotypes GT/TT frequency was 10.7% in acute versus 9.1% in chronic primary immune thrombocytopenia (P value = 0.849). The variant genotypes GT/TT were not found to be a risk factor for acute primary (P value = 0.807, OR: 0.641, 95% CI: 0.16-2.563) or chronic primary immune thrombocytopenia (P value = 0.914, OR: 0.762, 95% CI: 0.153-3.797). Our study suggests the possibility that interleukin-23 receptor gene polymorphism may not contribute to the susceptibility of development of primary immune thrombocytopenia in Egyptian children. PMID:26859125

  12. Immunogenic Subtypes of Breast Cancer Delineated by Gene Classifiers of Immune Responsiveness.

    PubMed

    Miller, Lance D; Chou, Jeff A; Black, Michael A; Print, Cristin; Chifman, Julia; Alistar, Angela; Putti, Thomas; Zhou, Xiaobo; Bedognetti, Davide; Hendrickx, Wouter; Pullikuth, Ashok; Rennhack, Jonathan; Andrechek, Eran R; Demaria, Sandra; Wang, Ena; Marincola, Francesco M

    2016-07-01

    The abundance and functional orientation of tumor-infiltrating lymphocytes in breast cancer is associated with distant metastasis-free survival, yet how this association is influenced by tumor phenotypic heterogeneity is poorly understood. Here, a bioinformatics approach defined tumor biologic attributes that influence this association and delineated tumor subtypes that may differ in their ability to sustain durable antitumor immune responses. A large database of breast tumor expression profiles and associated clinical data was compiled, from which the ability of phenotypic markers to significantly influence the prognostic performance of a classification model that incorporates immune cell-specific gene signatures was ascertained. Markers of cell proliferation and intrinsic molecular subtype reproducibly distinguished two breast cancer subtypes that we refer to as immune benefit-enabled (IBE) and immune benefit-disabled (IBD). The IBE tumors, comprised mostly of highly proliferative tumors of the basal-like, HER2-enriched, and luminal B subtypes, could be stratified by the immune classifier into significantly different prognostic groups, while IBD tumors could not, indicating the potential for productive engagement of metastasis-protective immunity in IBE tumors, but not in IBD tumors. The prognostic stratification in IBE was independent of conventional variables. Gene network analysis predicted the activation of TNFα/IFNγ signaling pathways in IBE tumors and the activation of the transforming growth factor-β pathway in IBD tumors. This prediction supports a model in which breast tumors can be distinguished on the basis of their potential for metastasis-protective immune responsiveness. Whether IBE and IBD represent clinically relevant contexts for evaluating sensitivity to immunotherapeutic agents warrants further investigation. Cancer Immunol Res; 4(7); 600-10. ©2016 AACR. PMID:27197066

  13. Identification of Immunity-related Genes in Arabidopsis and Cassava Using Genomic Data

    PubMed Central

    Leal, Luis Guillermo; Perez, Álvaro; Quintero, Andrés; Bayona, Ángela; Ortiz, Juan Felipe; Gangadharan, Anju; Mackey, David; López, Camilo; López-Kleine, Liliana

    2013-01-01

    Recent advances in genomic and post-genomic technologies have provided the opportunity to generate a previously unimaginable amount of information. However, biological knowledge is still needed to improve the understanding of complex mechanisms such as plant immune responses. Better knowledge of this process could improve crop production and management. Here, we used holistic analysis to combine our own microarray and RNA-seq data with public genomic data from Arabidopsis and cassava in order to acquire biological knowledge about the relationships between proteins encoded by immunity-related genes (IRGs) and other genes. This approach was based on a kernel method adapted for the construction of gene networks. The obtained results allowed us to propose a list of new IRGs. A putative function in the immunity pathway was predicted for the new IRGs. The analysis of networks revealed that our predicted IRGs are either well documented or recognized in previous co-expression studies. In addition to robust relationships between IRGs, there is evidence suggesting that other cellular processes may be also strongly related to immunity. PMID:24316329

  14. Protein Poly(ADP-ribosyl)ation Regulates Arabidopsis Immune Gene Expression and Defense Responses

    PubMed Central

    Feng, Baomin; Liu, Chenglong; de Oliveira, Marcos V. V.; Intorne, Aline C.; Li, Bo; Babilonia, Kevin; de Souza Filho, Gonçalo A.; Shan, Libo; He, Ping

    2015-01-01

    Perception of microbe-associated molecular patterns (MAMPs) elicits transcriptional reprogramming in hosts and activates defense to pathogen attacks. The molecular mechanisms underlying plant pattern-triggered immunity remain elusive. A genetic screen identified Arabidopsis poly(ADP-ribose) glycohydrolase 1 (atparg1) mutant with elevated immune gene expression upon multiple MAMP and pathogen treatments. Poly(ADP-ribose) glycohydrolase (PARG) is predicted to remove poly(ADP-ribose) polymers on acceptor proteins modified by poly(ADP-ribose) polymerases (PARPs) with three PARPs and two PARGs in Arabidopsis genome. AtPARP1 and AtPARP2 possess poly(ADP-ribose) polymerase activity, and the activity of AtPARP2 was enhanced by MAMP treatment. AtPARG1, but not AtPARG2, carries glycohydrolase activity in vivo and in vitro. Importantly, mutation (G450R) in atparg1 blocks its activity and the corresponding residue is highly conserved and essential for human HsPARG activity. Consistently, mutant atparp1atparp2 plants exhibited compromised immune gene activation and enhanced susceptibility to pathogen infections. Our study indicates that protein poly(ADP-ribosyl)ation plays critical roles in plant immune gene expression and defense to pathogen attacks. PMID:25569773

  15. The surprisingly complex immune gene repertoire of a simple sponge, exemplified by the NLR genes: a capacity for specificity?

    PubMed

    Degnan, Sandie M

    2015-02-01

    Most bacteria are not pathogenic to animals, and may instead serve beneficial functions. The requisite need for animals to differentiate between microbial friend and foe is likely borne from a deep evolutionary imperative to recognise self from non-self, a service ably provided by the innate immune system. Recent findings from an ancient lineage of simple animals - marine sponges - have revealed an unexpectedly large and diverse suite of genes belonging to one family of pattern recognition receptors, namely the NLR genes. Because NLRs can recognise a broad spectrum of microbial ligands, they may play a critical role in mediating the animal-bacterial crosstalk needed for sophisticated discrimination between microbes of various relationships. The building blocks for an advanced NLR-based immune specificity encoded in the genome of the coral reef sponge Amphimedon queenslandica may provide a specialisation and diversity of responses that equals, or even exceeds, that of vertebrate NLRs. PMID:25058852

  16. Pretransplant Immune- and Apoptosis-Related Gene Expression Is Associated with Kidney Allograft Function

    PubMed Central

    Kamińska, Dorota; Kościelska-Kasprzak, Katarzyna; Chudoba, Paweł; Mazanowska, Oktawia; Banasik, Mirosław; Żabinska, Marcelina; Boratyńska, Maria; Lepiesza, Agnieszka; Gomółkiewicz, Agnieszka; Dzięgiel, Piotr; Klinger, Marian

    2016-01-01

    Renal transplant candidates present immune dysregulation, caused by chronic uremia. The aim of the study was to investigate whether pretransplant peripheral blood gene expression of immune factors affects clinical outcome of renal allograft recipients. Methods. In a prospective study, we analyzed pretransplant peripheral blood gene expression in87 renal transplant candidates with real-time PCR on custom-designed low density arrays (TaqMan). Results. Immediate posttransplant graft function (14-day GFR) was influenced negatively by TGFB1 (P = 0.039) and positively by IL-2 gene expression (P = 0.040). Pretransplant blood mRNA expression of apoptosis-related genes (CASP3, FAS, and IL-18) and Th1-derived cytokine gene IFNG correlated positively with short- (6-month GFR CASP3: P = 0.027, FAS: P = 0.021, and IFNG: P = 0.029) and long-term graft function (24-month GFR CASP3: P = 0.003, FAS: P = 0.033, IL-18: P = 0.044, and IFNG: P = 0.04). Conclusion. Lowered pretransplant Th1-derived cytokine and apoptosis-related gene expressions were a hallmark of subsequent worse kidney function but not of acute rejection rate. The pretransplant IFNG and CASP3 and FAS and IL-18 genes' expression in the recipients' peripheral blood is the possible candidate for novel biomarker of short- and long-term allograft function. PMID:27382192

  17. Microarray data on gene modulation by HIV-1 in immune cells: 2000-2006.

    PubMed

    Giri, Malavika S; Nebozhyn, Michael; Showe, Louise; Montaner, Luis J

    2006-11-01

    Here, we review 34 HIV microarray studies in human immune cells over the period of 2000-March 2006 with emphasis on analytical approaches used and conceptual advances on HIV modulation of target cells (CD4 T cell, macrophage) and nontargets such as NK cell, B cell, and dendritic cell subsets. Results to date address advances on gene modulation associated with immune dysregulation, susceptibility to apoptosis, virus replication, and viral persistence following in vitro or in vivo infection/exposure to HIV-1 virus or HIV-1 accessory proteins. In addition to gene modulation associated with known functional correlates of HIV infection and replication (e.g., T cell apoptosis), microarray data have yielded novel, potential mechanisms of HIV-mediated pathogenesis such as modulation of cholesterol biosynthetic genes in CD4 T cells (relevant to virus replication and infectivity) and modulation of proteasomes and histone deacetylases in chronically infected cell lines (relevant to virus latency). Intrinsic challenges in summarizing gene modulation studies remain in development of sound approaches for comparing data obtained using different platforms and analytical tools, deriving unifying concepts to distil the large volumes of data collected, and the necessity to impose a focus for validation on a small fraction of genes. Notwithstanding these challenges, the field overall continues to demonstrate progress in expanding the pool of target genes validated to date in in vitro and in vivo datasets and understanding the functional correlates of gene modulation to HIV-1 pathogenesis in vivo. PMID:16940334

  18. Immune gene discovery by expressed sequence tag (EST) analysis of hemocytes in the ridgetail white prawn Exopalaemon carinicauda

    PubMed Central

    Duan, Yafei; Liu, Ping; Li, Jitao; Li, Jian; Chen, Ping

    2013-01-01

    The ridgetail white prawn Exopalaemon carinicauda is one of the most important commercial species in eastern China. However, little information of immune genes in E. carinicauda has been reported. To identify distinctive genes associated with immunity, an expressed sequence tag (EST) library was constructed from hemocytes of E. carinicauda. A total of 3411 clones were sequenced, yielding 2853 ESTs and the average sequence length is 436 bp. The cluster and assembly analysis yielded 1053 unique sequences including 329 contigs and 724 singletons. Blast analysis identified 593 (56.3%) of the unique sequences as orthologs of genes from other organisms (E-value < 1e-5). Based on the COG and Gene Ontology (GO), 593 unique sequences were classified. Through comparison with previous studies, 153 genes assembled from 367 ESTs have been identified as possibly involved in defense or immune functions. These genes are categorized into seven categories according to their putative functions in shrimp immune system: antimicrobial peptides, prophenoloxidase activating system, antioxidant defense systems, chaperone proteins, clottable proteins, pattern recognition receptors and other immune-related genes. According to EST abundance, the major immune-related genes were thioredoxin (141, 4.94% of all ESTs) and calmodulin (14, 0.49% of all ESTs). The EST sequences of E. carinicauda hemocytes provide important information of the immune system and lay the groundwork for development of molecular markers related to disease resistance in prawn species. PMID:23092732

  19. Global gene expression profiling reveals a suppressed immune response pathway associated with 3q amplification in squamous carcinoma of the lung

    PubMed Central

    Qian, Jun; Zou, Yong; Wang, Jing; Zhang, Bing; Massion, Pierre P.

    2015-01-01

    Chromosome 3q26–28 is a critical region of genomic amplification in non-small cell lung cancer (NSCLC), particularly lung squamous cell carcinomas (SCCs). No molecular therapeutic target has shown clinical utility for SCC, in contrast with adenocarcinomas of the lung. To identify novel candidate drivers in this region, we performed both Array Comparative Genomic Hybridization (array CGH, Agilent Human Genome CGH 244A oligo-microarrays) and Gene Expression Microarray (Agilent Human Gene Expression 4 × 44 K microarray) on 24 untreated lung SCC specimens. Using our previously published integrative genomics approach, we identified 12 top amplified driver genes within this region that are highly correlated and overexpressed in lung SCC. We further demonstrated one of the 12 top amplified driver Fragile X mental retardation-related protein 1 (FXR1) as a novel cancer gene in NSCLC and FXR1 executes its regulatory function by forming a novel complex with two other oncogenes, protein kinase C, iota ( PRKCI) and epithelial cell transforming 2 (ECT2) within the same amplicon in lung cancer cell. Here we report that immune response pathways are significantly suppressed in lung SCC and negatively associated with 3q driver gene expression, implying a potential role of 3q drivers in cancer immune-surveillance. In light of the attractive immunotherapy strategy using blockade of negative regulators of T cell function for multiple human cancer including lung SCC, our findings may provide a rationale for targeting 3q drivers in combination of immunotherapies for human tumors harboring the 3q amplicon. The data have been deposited in NCBI's Gene Expression Omnibus and are accessible through GEO Series accession number GSE40089. PMID:26484266

  20. Functional Annotation of Cotesia congregata Bracovirus: Identification of Viral Genes Expressed in Parasitized Host Immune Tissues

    PubMed Central

    Thézé, Julien; Cambier, Sébastien; Poulain, Julie; Da Silva, Corinne; Bézier, Annie; Musset, Karine; Moreau, Sébastien J. M.; Drezen, Jean-Michel

    2014-01-01

    ABSTRACT Bracoviruses (BVs) from the Polydnaviridae family are symbiotic viruses used as biological weapons by parasitoid wasps to manipulate lepidopteran host physiology and induce parasitism success. BV particles are produced by wasp ovaries and injected along with the eggs into the caterpillar host body, where viral gene expression is necessary for wasp development. Recent sequencing of the proviral genome of Cotesia congregata BV (CcBV) identified 222 predicted virulence genes present on 35 proviral segments integrated into the wasp genome. To date, the expressions of only a few selected candidate virulence genes have been studied in the caterpillar host, and we lacked a global vision of viral gene expression. In this study, a large-scale transcriptomic analysis by 454 sequencing of two immune tissues (fat body and hemocytes) of parasitized Manduca sexta caterpillar hosts allowed the detection of expression of 88 CcBV genes expressed 24 h after the onset of parasitism. We linked the expression profiles of these genes to several factors, showing that different regulatory mechanisms control viral gene expression in the host. These factors include the presence of signal peptides in encoded proteins, diversification of promoter regions, and, more surprisingly, gene position on the proviral genome. Indeed, most genes for which expression could be detected are localized in particular proviral regions globally producing higher numbers of circles. Moreover, this polydnavirus (PDV) transcriptomic analysis also reveals that a majority of CcBV genes possess at least one intron and an arthropod transcription start site, consistent with an insect origin of these virulence genes. IMPORTANCE Bracoviruses (BVs) are symbiotic polydnaviruses used by parasitoid wasps to manipulate lepidopteran host physiology, ensuring wasp offspring survival. To date, the expressions of only a few selected candidate BV virulence genes have been studied in caterpillar hosts. We performed a large

  1. Clinical and Epidemiologic Features of Severe Viral Gastroenteritis in Children: A 3-Year Surveillance, Multicentered Study in Taiwan With Partial Rotavirus Immunization.

    PubMed

    Chen, Chih-Jung; Wu, Fang-Tzy; Huang, Yhu-Chering; Chang, Wan-Chi; Wu, Ho-Sheng; Wu, Ching-Yi; Lin, Jen-Shiou; Huang, Fu-Chen; Hsiung, Chao A

    2015-08-01

    The global epidemiological landscape of childhood acute gastroenteritis (AGE) is changing after the introduction of 2 effective rotavirus vaccines in 2006. A comprehensive evaluation for viral etiology of childhood AGE in Taiwan, where rotavirus vaccination was provided by the private sector since 2006, is lacking.From 2009 to 2011, children younger than 5 years of age with AGE who were hospitalized at 3 sentinel hospitals were enrolled in this surveillance study. Stool specimens were tested for rotavirus, norovirus, enteric adenovirus, and astrovirus. The epidemiologic and clinical information was collected by questionnaire-based interviews and chart reviews.Viral agents were detected in 1055 (37.5%) of 2810 subjects, with rotavirus (21.2%) being the leading cause of disease, followed by norovirus (14.9%), enteric adenovirus (3.74%), astrovirus (2.10%), and a mixture of at least 2 of 4 above-mentioned viruses (4.06%). The majority (56%) of the viral AGE occurred in children <2 years of age. Rotavirus and norovirus were detected more frequently in cool seasons (P < 0.0001 for both), whereas no seasonal variation was observed for adenovirus and astrovirus. Adult households with diarrhea and a Vesikari score >10 were independent factors respectively associated with an increased risk of norovirus (adjusted odds ratio [aOR] 9.034, P = 0.0003) and rotavirus (aOR, 3.284, P < 0.0001) infections. Rotavirus immunization and female gender were protective factors against rotavirus (aOR, 0.198, P < 0.0001) and astrovirus (aOR, 0.382, P = 0.0299) infections, respectively.Rotavirus and norovirus are the 2 most important viral agents of childhood AGE in Taiwan with partial rotavirus immunization. In addition, different enteric viruses are associated with distinct epidemiologic and clinical features. PMID:26287425

  2. Transcriptome analysis reveals dysregulation of innate immune response genes and neuronal activity-dependent genes in autism

    PubMed Central

    Gupta, Simone; Ellis, Shannon E.; Ashar, Foram N.; Moes, Anna; Bader, Joel S.; Zhan, Jianan; West, Andrew B.; Arking, Dan E.

    2014-01-01

    Recent studies of genomic variation associated with autism have suggested the existence of extreme heterogeneity. Large-scale transcriptomics should complement these results to identify core molecular pathways underlying autism. Here we report results from a large-scale RNA sequencing effort, utilizing region-matched autism and control brains to identify neuronal and microglial genes robustly dysregulated in autism cortical brain. Remarkably, we note that a gene expression module corresponding to M2-activation states in microglia is negatively correlated with a differentially expressed neuronal module, implicating dysregulated microglial responses in concert with altered neuronal activity-dependent genes in autism brains. These observations provide pathways and candidate genes that highlight the interplay between innate immunity and neuronal activity in the aetiology of autism. PMID:25494366

  3. Genetic determinants of type 1 diabetes: immune response genes.

    PubMed

    Kumar, Neeraj; Kaur, Gurvinder; Mehra, Narinder

    2009-04-01

    Type 1 diabetes (T1D) is a polygenic autoimmune disease. Susceptibility to T1D is strongly linked to a major genetic locus that is the MHC, and several other minor loci including insulin, cytotoxic T-lymphocyte-associated antigen-4, PTPN22 and others that contribute to diabetes risk in an epistatic way. We have observed that there are three sets of DR3-positive autoimmunity-favoring haplotypes in the north-Indian population, including B50-DR3, B58-DR3 and B8-DR3. The classical Caucasian autoimmunity favoring AH8.1 (HLA-A1-B8-DR3) is rare in the Indian population, and has been replaced by a variant AH8.1v, which differs from the Caucasian AH8.1 at several gene loci. Similarly, there are additional HLA-DR3 haplotypes, A26-B8-DR3 (AH8.2), A24-B8-DR3 (AH8.3), A3-B8-DR3 (AH8.4) and A31-B8-DR3 (AH8.5), of which AH8.2 is the most common. The fact that disease-associated DR3-positive haplotypes show heterogeneity in different populations suggests that these might possess certain shared components that are involved in the development of autoimmunity. PMID:20477508

  4. ImmuCo: a database of gene co-expression in immune cells.

    PubMed

    Wang, Pingzhang; Qi, Huiying; Song, Shibin; Li, Shuang; Huang, Ningyu; Han, Wenling; Ma, Dalong

    2015-01-01

    Current gene co-expression databases and correlation networks do not support cell-specific analysis. Gene co-expression and expression correlation are subtly different phenomena, although both are likely to be functionally significant. Here, we report a new database, ImmuCo (http://immuco.bjmu.edu.cn), which is a cell-specific database that contains information about gene co-expression in immune cells, identifying co-expression and correlation between any two genes. The strength of co-expression of queried genes is indicated by signal values and detection calls, whereas expression correlation and strength are reflected by Pearson correlation coefficients. A scatter plot of the signal values is provided to directly illustrate the extent of co-expression and correlation. In addition, the database allows the analysis of cell-specific gene expression profile across multiple experimental conditions and can generate a list of genes that are highly correlated with the queried genes. Currently, the database covers 18 human cell groups and 10 mouse cell groups, including 20,283 human genes and 20,963 mouse genes. More than 8.6 × 10(8) and 7.4 × 10(8) probe set combinations are provided for querying each human and mouse cell group, respectively. Sample applications support the distinctive advantages of the database. PMID:25326331

  5. The innate immune repertoire in Cnidaria - ancestral complexity and stochastic gene loss

    PubMed Central

    Miller, David J; Hemmrich, Georg; Ball, Eldon E; Hayward, David C; Khalturin, Konstantin; Funayama, Noriko; Agata, Kiyokazu; Bosch, Thomas CG

    2007-01-01

    Background Characterization of the innate immune repertoire of extant cnidarians is of both fundamental and applied interest - it not only provides insights into the basic immunological 'tool kit' of the common ancestor of all animals, but is also likely to be important in understanding the global decline of coral reefs that is presently occurring. Recently, whole genome sequences became available for two cnidarians, Hydra magnipapillata and Nematostella vectensis, and large expressed sequence tag (EST) datasets are available for these and for the coral Acropora millepora. Results To better understand the basis of innate immunity in cnidarians, we scanned the available EST and genomic resources for some of the key components of the vertebrate innate immune repertoire, focusing on the Toll/Toll-like receptor (TLR) and complement pathways. A canonical Toll/TLR pathway is present in representatives of the basal cnidarian class Anthozoa, but neither a classic Toll/TLR receptor nor a conventional nuclear factor (NF)-κB could be identified in the anthozoan Hydra. Moreover, the detection of complement C3 and several membrane attack complex/perforin domain (MAC/PF) proteins suggests that a prototypic complement effector pathway may exist in anthozoans, but not in hydrozoans. Together with data for several other gene families, this implies that Hydra may have undergone substantial secondary gene loss during evolution. Such losses are not confined to Hydra, however, and at least one MAC/PF gene appears to have been lost from Nematostella. Conclusion Consideration of these patterns of gene distribution underscores the likely significance of gene loss during animal evolution whilst indicating ancient origins for many components of the vertebrate innate immune system. PMID:17437634

  6. Polymorphisms in Anopheles gambiae Immune Genes Associated with Natural Resistance to Plasmodium falciparum

    PubMed Central

    Harris, Caroline; Lambrechts, Louis; Rousset, François; Abate, Luc; Nsango, Sandrine E.; Fontenille, Didier; Morlais, Isabelle; Cohuet, Anna

    2010-01-01

    Many genes involved in the immune response of Anopheles gambiae, the main malaria vector in Africa, have been identified, but whether naturally occurring polymorphisms in these genes underlie variation in resistance to the human malaria parasite, Plasmodium falciparum, is currently unknown. Here we carried out a candidate gene association study to identify single nucleotide polymorphisms (SNPs) associated with natural resistance to P. falciparum. A. gambiae M form mosquitoes from Cameroon were experimentally challenged with three local wild P. falciparum isolates. Statistical associations were assessed between 157 SNPs selected from a set of 67 A. gambiae immune-related genes and the level of infection. Isolate-specific associations were accounted for by including the effect of the isolate in the analysis. Five SNPs were significantly associated to the infection phenotype, located within or upstream of AgMDL1, CEC1, Sp PPO activate, Sp SNAKElike, and TOLL6. Low overall and local linkage disequilibrium indicated high specificity in the loci found. Association between infection phenotype and two SNPs was isolate-specific, providing the first evidence of vector genotype by parasite isolate interactions at the molecular level. Four SNPs were associated to either oocyst presence or load, indicating that the genetic basis of infection prevalence and intensity may differ. The validity of the approach was verified by confirming the functional role of Sp SNAKElike in gene silencing assays. These results strongly support the role of genetic variation within or near these five A. gambiae immune genes, in concert with other genes, in natural resistance to P. falciparum. They emphasize the need to distinguish between infection prevalence and intensity and to account for the genetic specificity of vector-parasite interactions in dissecting the genetic basis of Anopheles resistance to human malaria. PMID:20862317

  7. Four plasmid genes are required for colicin V synthesis, export, and immunity.

    PubMed

    Gilson, L; Mahanty, H K; Kolter, R

    1987-06-01

    The colicin V production and immunity genes were isolated from plasmid pColV-K30. A HindIII-to-SalI fragment of 9.4 kilobases was cloned into the compatible vectors pBR322 and pACYC184. Mutants defective in colicin production were generated by Tn5 insertions and by constructing deletions in vitro. Physical analysis of these mutations identified a 4.4-kilobase region of this DNA which contains all the plasmid genes (cva) needed for the production of colicin V. The colicin V immunity determinant (cvi) is in a 700-base-pair fragment located within one end of this region. Complementation tests identified three genes, called cvaA, cvaB, and cvaC, required for colicin production. Analysis of the proteins labeled in minicells harboring various Tn5 insertions allowed us to identify protein products for the cvaA and cvaC genes. Mutations in cvaA and cvaB eliminated colicin activity in culture supernatants, but not within the cells. Mutations in cvaC, however, eliminated all detectable activity. From these results we conclude that the cvaC gene codes for the structural gene for colicin V, while cvaA and cvaB are apparently needed for the normal export of the colicin. PMID:3034857

  8. SARS-CoV Regulates Immune Function-Related Gene Expression in Human Monocytic Cells

    PubMed Central

    Hu, Wanchung; Yen, Yu-Ting; Singh, Sher; Kao, Chuan-Liang

    2012-01-01

    Abstract Severe acute respiratory syndrome (SARS) is characterized by acute respiratory distress syndrome (ARDS) and pulmonary fibrosis, and monocytes/macrophages are the key players in the pathogenesis of SARS. In this study, we compared the transcriptional profiles of SARS coronavirus (SARS-CoV)-infected monocytic cells against that infected by coronavirus 229E (CoV-229E). Total RNA was extracted from infected DC-SIGN-transfected monocytes (THP-1-DC-SIGN) at 6 and 24 h after infection, and the gene expression was profiled in oligonucleotide-based microarrays. Analysis of immune-related gene expression profiles showed that at 24 h after SARS-CoV infection: (1) IFN-α/β-inducible and cathepsin/proteasome genes were downregulated; (2) hypoxia/hyperoxia-related genes were upregulated; and (3) TLR/TLR-signaling, cytokine/cytokine receptor-related, chemokine/chemokine receptor-related, lysosome-related, MHC/chaperon-related, and fibrosis-related genes were differentially regulated. These results elucidate that SARS-CoV infection regulates immune-related genes in monocytes/macrophages, which may be important to the pathogenesis of SARS. PMID:22876772

  9. The Human Malaria Parasite Pfs47 Gene Mediates Evasion of the Mosquito Immune System

    PubMed Central

    Molina-Cruz, Alvaro; Garver, Lindsey S.; Alabaster, Amy; Bangiolo, Lois; Haile, Ashley; Winikor, Jared; Ortega, Corrie; van Schaijk, Ben C. L.; Sauerwein, Robert W.; Taylor-Salmon, Emma; Barillas-Mury, Carolina

    2013-01-01

    Summary The surface protein Pfs47 mediates Plasmodium falciparum evasion of the Anopheles gambiae complement-like immune system. Plasmodium falciparum transmission by Anopheles gambiae mosquitoes is remarkably efficient, resulting in a very high prevalence of human malaria infection in sub-Saharan Africa. A combination of genetic mapping, linkage group selection, and functional genomics was used to identify Pfs47 as a P. falciparum gene that allows the parasite to infect A. gambiae without activating the mosquito immune system. Disruption of Pfs47 greatly reduced parasite survival in the mosquito and this phenotype could be reverted by genetic complementation of the parasite or by disruption of the mosquito complement-like system. Pfs47 suppresses midgut nitration responses that are critical to activate the complement-like system. We provide direct experimental evidence that immune evasion mediated by Pfs47 is critical for efficient human malaria transmission by A. gambiae. PMID:23661646

  10. Characterization of immune-related genes in the yellow catfish Pelteobagrus fulvidraco in response to LPS challenge.

    PubMed

    Liu, Qiu-Ning; Xin, Zhao-Zhe; Chai, Xin-Yue; Jiang, Sen-Hao; Li, Chao-Feng; Zhang, Hua-Bin; Ge, Bao-Ming; Zhang, Dai-Zhen; Zhou, Chun-Lin; Tang, Bo-Ping

    2016-09-01

    Fish are considered an excellent model for studies in comparative immunology as they are a representative population of lower vertebrates linked to invertebrate evolution. To gain a better understanding of the immune response in fish, we constructed a subtractive cDNA library from the head kidney of lipopolysaccharide-stimulated yellow catfish (Pelteobagrus fulvidraco) using suppression subtractive hybridization (SSH). A total of 300 putative EST clones were identified which contained 95 genes, including 27 immune-related genes, 7 cytoskeleton-related genes, 3 genes involved in the cell cycle and apoptosis, 9 respiration and energy metabolism-related genes, 7 genes related to transport, 24 metabolism-related genes, 10 genes involved in stress responses, seven genes involved in regulation of transcription and translation and 59 unknown genes. Using real-time quantitative reverse transcription PCR, a subset of randomly selected genes involved in the immune response to lipopolysaccharide challenge were investigated to verify the reliability of the SSH data which identified 16 up-regulated genes. The genes identified in this study provide novel insight into the immune response in fish. PMID:27235365

  11. Discovery of a Novel Immune Gene Signature with Profound Prognostic Value in Colorectal Cancer: A Model of Cooperativity Disorientation Created in the Process from Development to Cancer.

    PubMed

    An, Ning; Shi, Xiaoyu; Zhang, Yueming; Lv, Ning; Feng, Lin; Di, Xuebing; Han, Naijun; Wang, Guiqi; Cheng, Shujun; Zhang, Kaitai

    2015-01-01

    Immune response-related genes play a major role in colorectal carcinogenesis by mediating inflammation or immune-surveillance evasion. Although remarkable progress has been made to investigate the underlying mechanism, the understanding of the complicated carcinogenesis process was enormously hindered by large-scale tumor heterogeneity. Development and carcinogenesis share striking similarities in their cellular behavior and underlying molecular mechanisms. The association between embryonic development and carcinogenesis makes embryonic development a viable reference model for studying cancer thereby circumventing the potentially misleading complexity of tumor heterogeneity. Here we proposed that the immune genes, responsible for intra-immune cooperativity disorientation (defined in this study as disruption of developmental expression correlation patterns during carcinogenesis), probably contain untapped prognostic resource of colorectal cancer. In this study, we determined the mRNA expression profile of 137 human biopsy samples, including samples from different stages of human colonic development, colorectal precancerous progression and colorectal cancer samples, among which 60 were also used to generate miRNA expression profile. We originally established Spearman correlation transition model to quantify the cooperativity disorientation associated with the transition from normal to precancerous to cancer tissue, in conjunction with miRNA-mRNA regulatory network and machine learning algorithm to identify genes with prognostic value. Finally, a 12-gene signature was extracted, whose prognostic value was evaluated using Kaplan-Meier survival analysis in five independent datasets. Using the log-rank test, the 12-gene signature was closely related to overall survival in four datasets (GSE17536, n = 177, p = 0.0054; GSE17537, n = 55, p = 0.0039; GSE39582, n = 562, p = 0.13; GSE39084, n = 70, p = 0.11), and significantly associated with disease-free survival in four

  12. Discovery of a Novel Immune Gene Signature with Profound Prognostic Value in Colorectal Cancer: A Model of Cooperativity Disorientation Created in the Process from Development to Cancer

    PubMed Central

    An, Ning; Shi, Xiaoyu; Zhang, Yueming; Lv, Ning; Feng, Lin; Di, Xuebing; Han, Naijun; Wang, Guiqi

    2015-01-01

    Immune response-related genes play a major role in colorectal carcinogenesis by mediating inflammation or immune-surveillance evasion. Although remarkable progress has been made to investigate the underlying mechanism, the understanding of the complicated carcinogenesis process was enormously hindered by large-scale tumor heterogeneity. Development and carcinogenesis share striking similarities in their cellular behavior and underlying molecular mechanisms. The association between embryonic development and carcinogenesis makes embryonic development a viable reference model for studying cancer thereby circumventing the potentially misleading complexity of tumor heterogeneity. Here we proposed that the immune genes, responsible for intra-immune cooperativity disorientation (defined in this study as disruption of developmental expression correlation patterns during carcinogenesis), probably contain untapped prognostic resource of colorectal cancer. In this study, we determined the mRNA expression profile of 137 human biopsy samples, including samples from different stages of human colonic development, colorectal precancerous progression and colorectal cancer samples, among which 60 were also used to generate miRNA expression profile. We originally established Spearman correlation transition model to quantify the cooperativity disorientation associated with the transition from normal to precancerous to cancer tissue, in conjunction with miRNA-mRNA regulatory network and machine learning algorithm to identify genes with prognostic value. Finally, a 12-gene signature was extracted, whose prognostic value was evaluated using Kaplan–Meier survival analysis in five independent datasets. Using the log-rank test, the 12-gene signature was closely related to overall survival in four datasets (GSE17536, n = 177, p = 0.0054; GSE17537, n = 55, p = 0.0039; GSE39582, n = 562, p = 0.13; GSE39084, n = 70, p = 0.11), and significantly associated with disease-free survival in four

  13. Immune response to dna vaccine expressing transferrin binding protein a gene of Pasteurella multocida.

    PubMed

    Singh, Satparkash; Singh, Vijendra Pal; Cheema, Pawanjit Singh; Sandey, Maninder; Ranjan, Rajeev; Gupta, Santosh Kumar; Sharma, Bhaskar

    2011-04-01

    Haemorrhagic Septicaemia (HS), an acute and fatal disease of cattle and buffalo is primarily caused by serotype B:2 or E:2 of Pasteurella multocida. The transferrin binding protein A (TbpA) has been found to act as immunogen and potent vaccine candidate in various Gram negative bacteria including P. multocida. The present study was carried out to evaluate the potential of this antigen as a DNA vaccine against HS in mice model. The tbpA gene of P. multocida serotype B:2 was cloned in a mammalian expression vector alone and along with murine IL2 gene as immunological adjuvant to produce monocistronic and bicistronic DNA vaccine constructs, respectively. The immune response to DNA vaccines was evaluated based on serum antibody titres and lymphocyte proliferation assay. A significant increase in humoral and cell mediated immune responses was observed in mice vaccinated with DNA vaccines as compared to non immunized group. Additionally, the bicistronic DNA vaccine provided superior immune response and protection level following challenge as compared to monocistronic construct. The study revealed that DNA vaccine presents a promising approach for the prevention of HS. PMID:24031690

  14. Immune-related gene expression in nurse honey bees (Apis mellifera) exposed to synthetic acaricides.

    PubMed

    Garrido, Paula Melisa; Antúnez, Karina; Martín, Mariana; Porrini, Martín Pablo; Zunino, Pablo; Eguaras, Martín Javier

    2013-01-01

    The mite Varroa destructor is an ectoparasite affecting honey bees worldwide. Synthetic acaricides have been among the principal tools available to beekeepers for its control, although several studies have shown its negative effects on honey bee physiology. Recent research suggests that those molecules strongly impact on immune signaling cascades and cellular immunity. In the present work, LC(50) in six-day-old bees were determined for the following acaricides: tau-fluvalinate, flumethrin, amitraz and coumaphos. According to this obtained value, a group of individuals was treated with each acaricide and then processed for qPCR analysis. Transcript levels for genes encoding antimicrobial peptides and immune-related proteins were assessed. Flumethrin increased the expression of hymenoptaecin when comparing treated and control bees. Significant differences were recorded between coumaphos and flumethrin treatments, while the first one reduced the expression of hymenoptaecin and abaecin, the last one up-regulated their expressions. No significant statistically changes were recorded in the expression levels of vitellogenin, lysozyme or glucose dehydrogenase among bees treated with acaricides and control bees. This work constitutes the first report, under laboratory conditions, about induction of immune related genes in response to synthetic miticides. PMID:23147024

  15. Cellular Immune Response Against Firefly Luciferase After Sleeping Beauty–Mediated Gene Transfer In Vivo

    PubMed Central

    Podetz-Pedersen, Kelly M.; Vezys, Vaiva; Somia, Nikunj V.; Russell, Stephen J.

    2014-01-01

    Abstract The Sleeping Beauty (SB) transposon system has been shown to mediate new gene sequence integration resulting in long-term expression. Here the effectiveness of hyperactive SB100X transposase was tested, and we found that hydrodynamic co-delivery of a firefly luciferase transposon (pT2/CaL) along with SB100X transposase (pCMV-SB100X) resulted in remarkably sustained, high levels of luciferase expression. However, after 4 weeks there was a rapid, animal-by-animal loss of luciferase expression that was not observed in immunodeficient mice. We hypothesized that this sustained, high-level luciferase expression achieved using the SB100X transposase elicits an immune response in pT2/CaL co-administered mice, which was supported by the rapid loss of luciferase expression upon challenge of previously treated animals and in naive animals adoptively transferred with splenocytes from previously treated animals. Specificity of the immune response to luciferase was demonstrated by increased cytokine expression in splenocytes after exposure to luciferase peptide in parallel with MHC I–luciferase peptide tetramer binding. This anti-luciferase immune response observed following continuous, high-level luciferase expression in vivo clearly impacts its use as an in vivo reporter. As both an immunogen and an extremely sensitive reporter, luciferase is also a useful model system for the study of immune responses following in vivo gene transfer and expression. PMID:25093708

  16. The molecular evolution of four anti-malarial immune genes in the Anopheles gambiae species complex

    PubMed Central

    2008-01-01

    Background If the insect innate immune system is to be used as a potential blocking step in transmission of malaria, then it will require targeting one or a few genes with highest relevance and ease of manipulation. The problem is to identify and manipulate those of most importance to malaria infection without the risk of decreasing the mosquito's ability to stave off infections by microbes in general. Molecular evolution methodologies and concepts can help identify such genes. Within the setting of a comparative molecular population genetic and phylogenetic framework, involving six species of the Anopheles gambiae complex, we investigated whether a set of four pre-selected immunity genes (gambicin, NOS, Rel2 and FBN9) might have evolved under selection pressure imposed by the malaria parasite. Results We document varying levels of polymorphism within and divergence between the species, in all four genes. Introgression and the sharing of ancestral polymorphisms, two processes that have been documented in the past, were verified in this study in all four studied genes. These processes appear to affect each gene in different ways and to different degrees. However, there is no evidence of positive selection acting on these genes. Conclusion Considering the results presented here in concert with previous studies, genes that interact directly with the Plasmodium parasite, and play little or no role in defense against other microbes, are probably the most likely candidates for a specific adaptive response against P. falciparum. Furthermore, since it is hard to establish direct evidence linking the adaptation of any candidate gene to P. falciparum infection, a comparative framework allowing at least an indirect link should be provided. Such a framework could be achieved, if a similar approach like the one involved here, was applied to all other anopheline complexes that transmit P. falciparum malaria. PMID:18325105

  17. Genome-wide characterization and expression profiling of immune genes in the diamondback moth, Plutella xylostella (L.)

    PubMed Central

    Xia, Xiaofeng; Yu, Liying; Xue, Minqian; Yu, Xiaoqiang; Vasseur, Liette; Gurr, Geoff M.; Baxter, Simon W.; Lin, Hailan; Lin, Junhan; You, Minsheng

    2015-01-01

    The diamondback moth, Plutella xylostella (L.), is a destructive pest that attacks cruciferous crops worldwide. Immune responses are important for interactions between insects and pathogens and information on these underpins the development of strategies for biocontrol-based pest management. Little, however, is known about immune genes and their regulation patterns in P. xylostella. A total of 149 immune-related genes in 20 gene families were identified through comparison of P. xylostella genome with the genomes of other insects. Complete and conserved Toll, IMD and JAK-STAT signaling pathways were found in P. xylostella. Genes involved in pathogen recognition were expanded and more diversified than genes associated with intracellular signal transduction. Gene expression profiles showed that the IMD pathway may regulate expression of antimicrobial peptide (AMP) genes in the midgut, and be related to an observed down-regulation of AMPs in experimental lines of insecticide-resistant P. xylostella. A bacterial feeding study demonstrated that P. xylostella could activate different AMPs in response to bacterial infection. This study has established a framework of comprehensive expression profiles that highlight cues for immune regulation in a major pest. Our work provides a foundation for further studies on the functions of P. xylostella immune genes and mechanisms of innate immunity. PMID:25943446

  18. [Roles of N-glycosylation in immunity of prME and NS1 gene of JEV].

    PubMed

    Zhang, Zi-Zhong; Wang, Xue; Zai, Jun-Jie; Sun, Le-Qiang; Song, Yun-Feng; Chen, Huan-Chun

    2012-05-01

    PrME and NS1 gene were the two main immuneprotect proteins of Japanese encephalitis virus (JEV), and they were also N-linked glycosylation proteins. To clear the effect of N-glycosylation on JEV immunity, the N-glycosylation site of prME and NS1 gene were eliminated by site-directed mutant PCR, subtituting the N to Q. And the the mutant genes were subcloned into eukaryotic expression plasmid. Four-weeks female mice were immuned with the wildtype and mutant gene by twice. The antibodies against prME were detected by ELISA and the neutralization antibodies were tested by viral neutralizing assay. The immunoprotection were determined by attack with JEV virulent strain. Compare with the wild-type gene immuned-groups, one N-glycan eliminated prME gene could induce a little higher ELISA antibody, neutralization antibody and immunoprotection, but the immunity of gene with both N-glycan absence was decreased. The similar status were observed in the wildtype and mutant NS1 groups. Thus these results show that the N-linked glycosylation in the prME and NS1 gene were correlated with the immunity, one glycan absent would enhance the immunity but both two loss would impair it. PMID:22764522

  19. Effect of inhibin gene immunization on antibody production and reproductive performance in Partridge Shank hens.

    PubMed

    Mao, Dagan; Bai, Wujiao; Hui, Fengming; Yang, Liguo; Cao, Shaoxian; Xu, Yinxue

    2016-04-01

    To investigate the effect of inhibin gene immunization on antibody production and reproductive performance in broiler breeder females, Partridge Shank hens aged 380 days were immunized with inhibin recombinant plasmid pcISI. One hundred and twenty hens were randomly assigned to four groups and treated intramuscularly with 25, 75, or 125 μg/300-μL inhibin recombinant plasmid pcISI (T1∼T3) or 300-μL saline as control (C), respectively. Booster immunization was given with the same dosage 20 days later. Blood and egg samples were collected to detect the antibody against inhibin by enzyme-linked immunosorbent assay and to evaluate egg performance. The ovaries were collected to classify the follicles and detect the FSH receptor (FSHR) messenger RNA (mRNA) expression by reverse transcription-PCR. The results showed that immunization against pcISI could elicit antibody against inhibin in both plasma and egg yolk compared with the control (P < 0.05), whereas booster immunization did not increase the antibody level in plasma. Vaccination promoted egg lay during the first 30 days after primary vaccination (P < 0.05) with no effect on egg quality and hatching rate. Immunization increased the amounts of dominant, small yellow and large white follicles in the ovary (P < 0.05). Reverse transcription-PCR results showed that immunization increased the FSHR mRNA in the large white follicles, whereas decreased the FSHR mRNA in the small yellow follicles (P < 0.05). In conclusion, inhibin vaccine pcISI can stimulate the production of antibody against inhibin as well as the follicle development and egg laying performance in Partridge Shank hens, which provides a good foundation for the application of inhibin DNA vaccine in avian production. PMID:26739531

  20. Antibody study in canine distemper virus nucleocapsid protein gene-immunized mice.

    PubMed

    Yuan, B; Li, X Y; Zhu, T; Yuan, L; Hu, J P; Chen, J; Gao, W; Ren, W Z

    2015-01-01

    The gene for the nucleocapsid (N) protein of canine distemper virus was cloned into the pMD-18T vector, and positive recombinant plasmids were obtained by enzyme digestion and sequencing. After digestion by both EcoRI and KpnI, the plasmid was directionally cloned into the eukaryotic expression vector pcDNA; the positive clone pcDNA-N was screened by electrophoresis and then transfected into COS-7 cells. Immunofluorescence analysis results showed that the canine distemper virus N protein was expressed in the cytoplasm of transfected COS-7 cells. After emulsification in Freund's adjuvant, the recombinant plasmid pcDNA-N was injected into the abdominal cavity of 8-week-old BABL/c mice, with the pcDNA original vector used as a negative control. Mice were immunized 3 times every 2 weeks. The blood of immunized mice was drawn 2 weeks after completing the immunizations to measure titer levels. The antibody titer in the pcDNA-N test was 10(1.62 ± 0.164), while in the control group this value was 10(0.52 ± 0.56), indicating that specific humoral immunity was induced in canine distemper virus nucleocapsid protein-immunized mice. PMID:25966074

  1. Identification and characterization of a TAB1 gene involved in innate immunity of amphioxus (Branchiostoma belcheri).

    PubMed

    Yin, Denghua; Li, Wenjuan; Fu, Meili; Chen, Liming; Ma, Fei; Jin, Ping

    2016-01-10

    Transforming growth factor-β activated kinase-1 (TAK1) is an essential regulator in toll-like receptor (TLR), tumor necrosis factor (TNF) and interleukin-1 (IL-1) signaling pathways, and plays very important roles in animal innate immunity. TAK1-binding protein, TAB1, can specifically regulate the activation of TAK1. However, the TAB1 gene in amphioxus has not yet been identified to date. In this study, we identified and characterized a TAB1 gene from Branchiostoma belcheri (designed as AmphiTAB1). Our results showed that the full-length cDNA of AmphiTAB1 is 2281bp long with an open reading frame (ORF) of 1659bp that encodes a predicted protein of 553 amino acids containing a typical PP2Cc domain. Phylogenetic analysis indicated that the AmphiTAB1 gene was located between invertebrates and vertebrates, suggesting that the AmphiTAB1 gene is a member of the TAB1 gene family. Real-time PCR analysis indicated that the AmphiTAB1 was ubiquitously and differentially expressed in six investigated tissues (gills, hepatic cecum, intestine, muscles, notochord and gonad). After lipopolysaccharide stimulation, the expression of AmphiTAB1 was significantly up-regulated at 6h, which shows that AmphiTAB1 may be involved in the host immune response. In addition, the recombinant TAB1 expressed in vitro shows a molecular mass of 62kDa and Western blot confirmed it, which proved it is an encoding isoform. Taken together, our findings provide an insight into innate immune response of amphioxus and evolution of the TAB1 gene family. PMID:26341057

  2. Genome-Wide Association Studies Suggest Limited Immune Gene Enrichment in Schizophrenia Compared to 5 Autoimmune Diseases.

    PubMed

    Pouget, Jennie G; Gonçalves, Vanessa F; Spain, Sarah L; Finucane, Hilary K; Raychaudhuri, Soumya; Kennedy, James L; Knight, Jo

    2016-09-01

    There has been intense debate over the immunological basis of schizophrenia, and the potential utility of adjunct immunotherapies. The major histocompatibility complex is consistently the most powerful region of association in genome-wide association studies (GWASs) of schizophrenia and has been interpreted as strong genetic evidence supporting the immune hypothesis. However, global pathway analyses provide inconsistent evidence of immune involvement in schizophrenia, and it remains unclear whether genetic data support an immune etiology per se. Here we empirically test the hypothesis that variation in immune genes contributes to schizophrenia. We show that there is no enrichment of immune loci outside of the MHC region in the largest genetic study of schizophrenia conducted to date, in contrast to 5 diseases of known immune origin. Among 108 regions of the genome previously associated with schizophrenia, we identify 6 immune candidates (DPP4, HSPD1, EGR1, CLU, ESAM, NFATC3) encoding proteins with alternative, nonimmune roles in the brain. While our findings do not refute evidence that has accumulated in support of the immune hypothesis, they suggest that genetically mediated alterations in immune function may not play a major role in schizophrenia susceptibility. Instead, there may be a role for pleiotropic effects of a small number of immune genes that also regulate brain development and plasticity. Whether immune alterations drive schizophrenia progression is an important question to be addressed by future research, especially in light of the growing interest in applying immunotherapies in schizophrenia. PMID:27242348

  3. Molecular clock of HIV-1 envelope genes under early immune selection

    DOE PAGESBeta

    Park, Sung Yong; Love, Tanzy M. T.; Perelson, Alan S.; Mack, Wendy J.; Lee, Ha Youn

    2016-06-01

    Here, the molecular clock hypothesis that genes or proteins evolve at a constant rate is a key tool to reveal phylogenetic relationships among species. Using the molecular clock, we can trace an infection back to transmission using HIV-1 sequences from a single time point. Whether or not a strict molecular clock applies to HIV-1’s early evolution in the presence of immune selection has not yet been fully examined.

  4. Extensive innate immune gene activation accompanies brain aging, increasing vulnerability to cognitive decline and neurodegeneration: a microarray study

    PubMed Central

    2012-01-01

    Background This study undertakes a systematic and comprehensive analysis of brain gene expression profiles of immune/inflammation-related genes in aging and Alzheimer’s disease (AD). Methods In a well-powered microarray study of young (20 to 59 years), aged (60 to 99 years), and AD (74 to 95 years) cases, gene responses were assessed in the hippocampus, entorhinal cortex, superior frontal gyrus, and post-central gyrus. Results Several novel concepts emerge. First, immune/inflammation-related genes showed major changes in gene expression over the course of cognitively normal aging, with the extent of gene response far greater in aging than in AD. Of the 759 immune-related probesets interrogated on the microarray, approximately 40% were significantly altered in the SFG, PCG and HC with increasing age, with the majority upregulated (64 to 86%). In contrast, far fewer immune/inflammation genes were significantly changed in the transition to AD (approximately 6% of immune-related probesets), with gene responses primarily restricted to the SFG and HC. Second, relatively few significant changes in immune/inflammation genes were detected in the EC either in aging or AD, although many genes in the EC showed similar trends in responses as in the other brain regions. Third, immune/inflammation genes undergo gender-specific patterns of response in aging and AD, with the most pronounced differences emerging in aging. Finally, there was widespread upregulation of genes reflecting activation of microglia and perivascular macrophages in the aging brain, coupled with a downregulation of select factors (TOLLIP, fractalkine) that when present curtail microglial/macrophage activation. Notably, essentially all pathways of the innate immune system were upregulated in aging, including numerous complement components, genes involved in toll-like receptor signaling and inflammasome signaling, as well as genes coding for immunoglobulin (Fc) receptors and human leukocyte antigens I

  5. Th1/Th2 Cytokines: An Easy Model to Study Gene Expression in Immune Cells

    PubMed Central

    González-Polo, Rosa A.; Soler, Germán; Fuentes, José M.

    2006-01-01

    This report describes a laboratory exercise that was incorporated into a Cell Biology and Molecular Biology advanced course. The exercise was made for a class size with eight students and was designed to reinforce the understanding of basic molecular biology techniques. Students used the techniques of reverse transcription and arginase activity measurement as well as nitric oxide determination to discover whether two specific genes were expressed by cytokine-stimulated dendritic cells. The experiment served as the basis for discussing the importance of differential gene expression inside the eukaryotic cell and the importance of cytokines in the immune system. PMID:17012221

  6. Marek's disease virus challenge induced immune-related gene expression and chicken repeat 1 (CR1) methylation alterations in chickens

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Marek’s disease virus (MDV) challenge induces lymphoma in susceptible chickens. Host genes, especially immune related genes, are activated by the virus. DNA methylation is an epigenetic mechanism that governs gene transcription. In the present study, we found that expression of signal transducer and...

  7. Esophageal Cancer Related Gene-4 (ECRG4) Interactions with the Innate Immunity Receptor Complex

    PubMed Central

    Podvin, Sonia; Dang, Xitong; Meads, Morgan; Kurabi, Arwa; Costantini, Todd; Eliceiri, Brian P.; Baird, Andrew; Coimbra, Raul

    2014-01-01

    Objective and design The human c2orf40 gene encodes a tumor suppressor gene called esophageal cancer-related gene-4 (ECRG4) with pro- and anti-inflammatory activities that depend on cell surface processing. Here, we investigated its physical and functional association with the innate immunity receptor complex. Methods Interactions between ECRG4 and the innate immunity receptor complex were assessed by flow cytometry, immunohistochemistry, confocal microscopy, co-immunoprecipitation. Phage display was used for ligand-targeting to cells that over express the TLR4-MD2-CD14. Results Immunoprecipitation and immunohistochemical studies demonstrate a physical interaction between ECRG4 and TLR4-MD2-CD14 on human granulocytes. Flow cytometry shows ECRG4 on the cell surface of a subset of CD14+ and CD16+ leukocytes. In a cohort of trauma patients, the C-terminal 16 amino acid domain of ECRG4 (ECRG4133–148), appears processed and shed, presumably at a thrombin-like consensus sequence. Phage targeting this putative ligand shows that this peptide sequence can internalizes into cells through the TLR4/CD14/MD2 complex but modulates inflammation through non-canonical, NFκB signal transduction. Conclusions ECRG4 is present on the surface of human monocytes and granulocytes. Its interaction with the human innate immunity receptor complex supports a role for cell surface activation of ECRG4 during inflammation and implicates this receptor in its mechanism of action. PMID:25511108

  8. Mutanome and expression of immune response genes in microsatellite stable colon cancer

    PubMed Central

    Sanz-Pamplona, Rebeca; Gil-Hoyos, Raúl; López-Doriga, Adriana; Alonso, M. Henar; Aussó, Susanna; Molleví, David G.; Santos, Cristina; Sanjuán, Xavier; Salazar, Ramón; Alemany, Ramón; Moreno, Víctor

    2016-01-01

    The aim of this study was to analyze the impact of the mutanome in the prognosis of microsatellite stable stage II CRC tumors. The exome of 42 stage II, microsatellite stable, colon tumors (21 of them relapse) and their paired mucosa were sequenced and analyzed. Although some pathways accumulated more mutations in patients exhibiting good or poor prognosis, no single somatic mutation was associated with prognosis. Exome sequencing data is also valuable to infer tumor neoantigens able to elicit a host immune response. Hence, putative neoantigens were identified by combining information about missense mutations in each tumor and HLAs genotypes of the patients. Under the hypothesis that neoantigens should be correctly presented in order to activate the immune response, expression levels of genes involved in the antigen presentation machinery were also assessed. In addition, CD8A level (as a marker of T-cell infiltration) was measured. We found that tumors with better prognosis showed a tendency to generate a higher number of immunogenic epitopes, and up-regulated genes involved in the antigen processing machinery. Moreover, tumors with higher T-cell infiltration also showed better prognosis. Stratifying by consensus molecular subtype, CMS4 tumors showed the highest association of expression levels of genes involved in the antigen presentation machinery with prognosis. Thus, we hypothesize that a subset of stage II microsatellite stable CRC tumors are able to generate an immune response in the host via MHC class I antigen presentation, directly related with a better prognosis. PMID:26871478

  9. Transcriptome profiling of immune tissues reveals habitat-specific gene expression between lake and river sticklebacks.

    PubMed

    Huang, Yun; Chain, Frédéric J J; Panchal, Mahesh; Eizaguirre, Christophe; Kalbe, Martin; Lenz, Tobias L; Samonte, Irene E; Stoll, Monika; Bornberg-Bauer, Erich; Reusch, Thorsten B H; Milinski, Manfred; Feulner, Philine G D

    2016-02-01

    The observation of habitat-specific phenotypes suggests the action of natural selection. The three-spined stickleback (Gasterosteus aculeatus) has repeatedly colonized and adapted to diverse freshwater habitats across the northern hemisphere since the last glaciation, while giving rise to recurring phenotypes associated with specific habitats. Parapatric lake and river populations of sticklebacks harbour distinct parasite communities, a factor proposed to contribute to adaptive differentiation between these ecotypes. However, little is known about the transcriptional response to the distinct parasite pressure of those fish in a natural setting. Here, we sampled wild-caught sticklebacks across four geographical locations from lake and river habitats differing in their parasite load. We compared gene expression profiles between lake and river populations using 77 whole-transcriptome libraries from two immune-relevant tissues, the head kidney and the spleen. Differential expression analyses revealed 139 genes with habitat-specific expression patterns across the sampled population pairs. Among the 139 differentially expressed genes, eight are annotated with an immune function and 42 have been identified as differentially expressed in previous experimental studies in which fish have been immune challenged. Together, these findings reinforce the hypothesis that parasites contribute to adaptation of sticklebacks in lake and river habitats. PMID:26749022

  10. Virulent Shigella flexneri subverts the host innate immune response through manipulation of antimicrobial peptide gene expression

    PubMed Central

    Sperandio, Brice; Regnault, Béatrice; Guo, Jianhua; Zhang, Zhi; Stanley, Samuel L.; Sansonetti, Philippe J.; Pédron, Thierry

    2008-01-01

    Antimicrobial factors are efficient defense components of the innate immunity, playing a crucial role in the intestinal homeostasis and protection against pathogens. In this study, we report that upon infection of polarized human intestinal cells in vitro, virulent Shigella flexneri suppress transcription of several genes encoding antimicrobial cationic peptides, particularly the human β-defensin hBD-3, which we show to be especially active against S. flexneri. This is an example of targeted survival strategy. We also identify the MxiE bacterial regulator, which controls a regulon encompassing a set of virulence plasmid-encoded effectors injected into host cells and regulating innate signaling, as being responsible for this dedicated regulatory process. In vivo, in a model of human intestinal xenotransplant, we confirm at the transcriptional and translational level, the presence of a dedicated MxiE-dependent system allowing S. flexneri to suppress expression of antimicrobial cationic peptides and promoting its deeper progression toward intestinal crypts. We demonstrate that this system is also able to down-regulate additional innate immunity genes, such as the chemokine CCL20 gene, leading to compromised recruitment of dendritic cells to the lamina propria of infected tissues. Thus, S. flexneri has developed a dedicated strategy to weaken the innate immunity to manage its survival and colonization ability in the intestine. PMID:18426984

  11. Gene Models, Expression Repertoire, and Immune Response of Plasmodium vivax Reticulocyte Binding Proteins

    PubMed Central

    Hietanen, Jenni; Chim-ong, Anongruk; Chiramanewong, Thanprakorn; Gruszczyk, Jakub; Roobsoong, Wanlapa; Sattabongkot, Jetsumon

    2015-01-01

    Members of the Plasmodium vivax reticulocyte binding protein (PvRBP) family are believed to mediate specific invasion of reticulocytes by P. vivax. In this study, we performed molecular characterization of genes encoding members of this protein family. Through cDNA sequencing, we constructed full-length gene models and verified genes that are protein coding and those that are pseudogenes. We also used quantitative PCR to measure their in vivo transcript abundances in clinical P. vivax isolates. Like genes encoding related invasion ligands of P. falciparum, Pvrbp expression levels vary broadly across different parasite isolates. Through antibody measurements, we found that host immune pressure may be the driving force behind the distinctly high diversity of one of the family members, PvRBP2c. Mild yet significant negative correlation was found between parasitemia and the PvRBP2b antibody level, suggesting that antibodies to the protein may interfere with invasion. PMID:26712206

  12. Mechanisms of HO-1 mediated attenuation of renal immune injury: a gene profiling study.

    PubMed

    Duann, Pu; Lianos, Elias A

    2011-10-01

    Using a mouse model of immune injury directed against the renal glomerular vasculature and resembling human forms of glomerulonephritis (GN), we assessed the effect of targeted expression of the cytoprotective enzyme heme oxygenase (HO)-1. A human (h) HO-1 complementary DNAN (cDNA) sequence was targeted to glomerular epithelial cells (GECs) using a GEC-specific murine nephrin promoter. Injury by administration of antibody against the glomerular basement membrane (anti-GBM) to transgenic (TG) mice with GEC-targeted hHO-1 was attenuated compared with wild-type (WT) controls. To explore changes in the expression of genes that could mediate this salutary effect, we performed gene expression profiling using a microarray analysis of RNA isolated from the renal cortex of WT or TG mice with or without anti-GBM antibody-induced injury. Significant increases in expression were detected in 9 major histocompatibility complex (MHC)-class II genes, 2 interferon-γ (IFN-γ)-inducible guanosine triphosphate (GTP)ases, and 3 genes of the ubiquitin-proteasome system. The increase in MHC-class II and proteasome gene expression in TG mice with injury was validated by real-time polymerase chain reaction (PCR) or Western blot analysis. The observations point to novel mechanisms underlying the cytoprotective effect of HO-1 in renal immune injury. PMID:21925121

  13. Gene Networks Specific for Innate Immunity Define Post-Traumatic Stress Disorder

    PubMed Central

    Breen, Michael S.; Maihofer, Adam X.; Glatt, Stephen J.; Tylee, Daniel S.; Chandler, Sharon D.; Tsuang, Ming T.; Risbrough, Victoria B.; Baker, Dewleen G.; O’Connor, Daniel T.; Nievergelt, Caroline M.; Woelk, Christopher H.

    2015-01-01

    The molecular factors involved in the development of Post-Traumatic Stress Disorder (PTSD) remain poorly understood. Previous transcriptomic studies investigating the mechanisms of PTSD apply targeted approaches to identify individual genes under a cross-sectional framework lack a holistic view of the behaviours and properties of these genes at the system-level. Here we sought to apply an unsupervised gene-network based approach to a prospective experimental design using whole-transcriptome RNA-Seq gene expression from peripheral blood leukocytes of U.S. Marines (N=188), obtained both pre- and post-deployment to conflict zones. We identified discrete groups of co-regulated genes (i.e., co-expression modules) and tested them for association to PTSD. We identified one module at both pre- and post-deployment containing putative causal signatures for PTSD development displaying an over-expression of genes enriched for functions of innate-immune response and interferon signalling (Type-I and Type-II). Importantly, these results were replicated in a second non-overlapping independent dataset of U.S. Marines (N=96), further outlining the role of innate immune and interferon signalling genes within co-expression modules to explain at least part of the causal pathophysiology for PTSD development. A second module, consequential of trauma exposure, contained PTSD resiliency signatures and an over-expression of genes involved in hemostasis and wound responsiveness suggesting that chronic levels of stress impair proper wound healing during/after exposure to the battlefield while highlighting the role of the hemostatic system as a clinical indicator of chronic-based stress. These findings provide novel insights for early preventative measures and advanced PTSD detection, which may lead to interventions that delay or perhaps abrogate the development of PTSD. PMID:25754082

  14. Immune response-associated gene analysis of 1,000 cancer patients using whole-exome sequencing and gene expression profiling-Project HOPE.

    PubMed

    Akiyama, Yasuto; Kondou, Ryota; Iizuka, Akira; Ohshima, Keiichi; Urakami, Kenichi; Nagashima, Takeshi; Shimoda, Yuji; Tanabe, Tomoe; Ohnami, Sumiko; Ohnami, Shumpei; Kusuhara, Masatoshi; Mochizuki, Tohru; Yamaguchi, Ken

    2016-01-01

    Project HOPE (High-tech Omics-based Patient Evaluation) has been progressing since its implementation in 2014 using whole-exome sequencing (WES) and gene expression profiling (GEP). With the aim of evaluating immune status in cancer patients, a gene panel consisting of 164 immune response-associated genes (56 antigen-presenting cell and T-cell-associated genes, 34 cytokine- and metabolism-associated genes, 47 TNF and TNF receptor superfamily genes, and 27 regulatory T-cell-associated genes) was established, and its expression and mutation status were investigated using 1,000 cancer patient-derived tumors. Regarding WES, sequencing and variant calling were performed using the Ion Proton system. The average number of single-nucleotide variants (SNVs) detected per sample was 183 ± 507, and the number of hypermutators with more than 500 total SNVs was 51 cases. Regarding GEP, seven immune response-associated genes (VTCN1, IL2RA, ULBP2, TREM1, MSR1, TNFSF9 and TNFRSF12A) were more than 2-fold overexpressed compared with normal tissues in more than 2 organs. Specifically, the positive rate of PD-L1 expression in all patients was 25.8%, and PD-L1 expression was significantly upregulated in hypermutators. The simultaneous analyses of WES and GEP based on immune response-associated genes are very intriguing tools to screen cancer patients suitable for immune checkpoint antibody therapy. PMID:27544999

  15. Innate immunity gene expression changes in critically ill patients with sepsis and disease-related malnutrition

    PubMed Central

    Sarnecka, Agnieszka; Dąbrowska, Aleksandra; Kosałka, Katarzyna; Wachowska, Ewelina; Bałan, Barbara J.; Jankowska, Marta; Korta, Teresa; Niewiński, Grzegorz; Kański, Andrzej; Mikaszewska-Sokolewicz, Małgorzata; Omidi, Mohammad; Majewska, Krystyna; Słotwińska, Sylwia M.

    2015-01-01

    The aim of this study was an attempt to determine whether the expression of genes involved in innate antibacterial response (TL R2, NOD 1, TRAF6, HMGB 1 and Hsp70) in peripheral blood leukocytes in critically ill patients, may undergo significant changes depending on the severity of the infection and the degree of malnutrition. The study was performed in a group of 128 patients with infections treated in the intensive care and surgical ward. In 103/80.5% of patients, infections had a severe course (sepsis, severe sepsis, septic shock, mechanical ventilation of the lungs). Clinical monitoring included diagnosis of severe infection (according to the criteria of the ACC P/SCC M), assessment of severity of the patient condition and risk of death (APACHE II and SAPS II), nutritional assessment (NRS 2002 and SGA scales) and the observation of the early results of treatment. Gene expression at the mRNA level was analyzed by real-time PCR. The results of the present study indicate that in critically ill patients treated in the IC U there are significant disturbances in the expression of genes associated with innate antimicrobial immunity, which may have a significant impact on the clinical outcome. The expression of these genes varies depending on the severity of the patient condition, severity of infection and nutritional status. Expression disorders of genes belonging to innate antimicrobial immunity should be diagnosed as early as possible, monitored during the treatment and taken into account during early therapeutic treatment (including early nutrition to support the functions of immune cells). PMID:26648775

  16. Autoselection of cytoplasmic yeast virus like elements encoding toxin/antitoxin systems involves a nuclear barrier for immunity gene expression.

    PubMed

    Kast, Alene; Voges, Raphael; Schroth, Michael; Schaffrath, Raffael; Klassen, Roland; Meinhardt, Friedhelm

    2015-05-01

    Cytoplasmic virus like elements (VLEs) from Kluyveromyces lactis (Kl), Pichia acaciae (Pa) and Debaryomyces robertsiae (Dr) are extremely A/T-rich (>75%) and encode toxic anticodon nucleases (ACNases) along with specific immunity proteins. Here we show that nuclear, not cytoplasmic expression of either immunity gene (PaORF4, KlORF3 or DrORF5) results in transcript fragmentation and is insufficient to establish immunity to the cognate ACNase. Since rapid amplification of 3' ends (RACE) as well as linker ligation of immunity transcripts expressed in the nucleus revealed polyadenylation to occur along with fragmentation, ORF-internal poly(A) site cleavage due to the high A/T content is likely to prevent functional expression of the immunity genes. Consistently, lowering the A/T content of PaORF4 to 55% and KlORF3 to 46% by gene synthesis entirely prevented transcript cleavage and permitted functional nuclear expression leading to full immunity against the respective ACNase toxin. Consistent with a specific adaptation of the immunity proteins to the cognate ACNases, cross-immunity to non-cognate ACNases is neither conferred by PaOrf4 nor KlOrf3. Thus, the high A/T content of cytoplasmic VLEs minimizes the potential of functional nuclear recruitment of VLE encoded genes, in particular those involved in autoselection of the VLEs via a toxin/antitoxin principle. PMID:25973601

  17. Additive effects of HLA alleles and innate immune genes determine viral outcome in HCV infection

    PubMed Central

    Fitzmaurice, Karen; Hurst, Jacob; Dring, Megan; Rauch, Andri; McLaren, Paul J; Günthard, Huldrych F; Gardiner, Clair; Klenerman, Paul

    2015-01-01

    Background Chronic HCV infection is a leading cause of liver-related morbidity globally. The innate and adaptive immune responses are thought to be important in determining viral outcomes. Polymorphisms associated with the IFNL3 (IL28B) gene are strongly associated with spontaneous clearance and treatment outcomes. Objective This study investigates the importance of HLA genes in the context of genetic variation associated with the innate immune genes IFNL3 and KIR2DS3. Design We assess the collective influence of HLA and innate immune genes on viral outcomes in an Irish cohort of women (n=319) who had been infected from a single source as well as a more heterogeneous cohort (Swiss Cohort, n=461). In the Irish cohort, a number of HLA alleles are associated with different outcomes, and the impact of IFNL3-linked polymorphisms is profound. Results Logistic regression was performed on data from the Irish cohort, and indicates that the HLA-A*03 (OR 0.36 (0.15 to 0.89), p=0.027) -B*27 (OR 0.12 (0.03 to 0.45), p=<0.001), -DRB1*01:01 (OR 0.2 (0.07 to 0.61), p=0.005), -DRB1*04:01 (OR 0.31 (0.12 to 0.85, p=0.02) and the CC IFNL3 rs12979860 genotypes (OR 0.1 (0.04 to 0.23), p<0.001) are significantly associated with viral clearance. Furthermore, DQB1*02:01 (OR 4.2 (2.04 to 8.66), p=0.008), KIR2DS3 (OR 4.36 (1.62 to 11.74), p=0.004) and the rs12979860 IFNL3 ‘T’ allele are associated with chronic infection. This study finds no interactive effect between IFNL3 and these Class I and II alleles in relation to viral clearance. There is a clear additive effect, however. Data from the Swiss cohort also confirms independent and additive effects of HLA Class I, II and IFNL3 genes in their prediction of viral outcome. Conclusions This data supports a critical role for the adaptive immune response in the control of HCV in concert with the innate immune response. PMID:24996883

  18. Pathway-focused genetic evaluation of immune and inflammation related genes with chronic fatigue syndrome.

    PubMed

    Rajeevan, Mangalathu S; Dimulescu, Irina; Murray, Janna; Falkenberg, Virginia R; Unger, Elizabeth R

    2015-08-01

    Recent evidence suggests immune and inflammatory alterations are important in chronic fatigue syndrome (CFS). This study was done to explore the association of functionally important genetic variants in inflammation and immune pathways with CFS. Peripheral blood DNA was isolated from 50 CFS and 121 non-fatigued (NF) control participants in a population-based study. Genotyping was performed with the Affymetrix Immune and Inflammation Chip that covers 11K single nucleotide polymorphisms (SNPs) following the manufacturer's protocol. Genotyping accuracy for specific genes was validated by pyrosequencing. Golden Helix SVS software was used for genetic analysis. SNP functional annotation was done using SPOT and GenomePipe programs. CFS was associated with 32 functionally important SNPs: 11 missense variants, 4 synonymous variants, 11 untranslated regulatory region (UTR) variants and 6 intronic variants. Some of these SNPs were in genes within pathways related to complement cascade (SERPINA5, CFB, CFH, MASP1 and C6), chemokines (CXCL16, CCR4, CCL27), cytokine signaling (IL18, IL17B, IL2RB), and toll-like receptor signaling (TIRAP, IRAK4). Of particular interest is association of CFS with two missense variants in genes of complement activation, rs4151667 (L9H) in CFB and rs1061170 (Y402H) in CFH. A 5' UTR polymorphism (rs11214105) in IL18 also associated with physical fatigue, body pain and score for CFS case defining symptoms. This study identified new associations of CFS with genetic variants in pathways including complement activation providing additional support for altered innate immune response in CFS. Additional studies are needed to validate the findings of this exploratory study. PMID:26116897

  19. Midgut expression of immune-related genes in Glossina palpalis gambiensis challenged with Trypanosoma brucei gambiense

    PubMed Central

    Hamidou Soumana, Illiassou; Tchicaya, Bernadette; Chuchana, Paul; Geiger, Anne

    2014-01-01

    Tsetse flies from the subspecies Glossina morsitans morsitans and Glossina palpalis gambiensis, respectively, transmit Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense. The former causes the acute form of sleeping sickness, and the latter provokes the chronic form. Although several articles have reported G. m. morsitans gene expression following trypanosome infection, no comparable investigation has been performed for G. p. gambiensis. This report presents results on the differential expression of immune-related genes in G. p. gambiensis challenged with T. b. gambiense. The aim was to characterize transcriptomic events occurring in the tsetse gut during the parasite establishment step, which is the crucial first step in the parasite development cycle within its vector. The selected genes were chosen from those previously shown to be highly expressed in G. m. morsitans, to allow further comparison of gene expression in both Glossina species. Using quantitative PCR, genes were amplified from the dissected midguts of trypanosome-stimulated, infected, non-infected, and self-cleared flies at three sampling timepoints (3, 10, and 20 days) after a bloodmeal. At the 3-day sampling point, transferrin transcripts were significantly up-regulated in trypanosome-challenged flies versus flies fed on non-infected mice. In self-cleared flies, serpin-2 and thioredoxin peroxidase-3 transcripts were significantly up-regulated 10 days after trypanosome challenge, whereas nitric oxide synthase and chitin-binding protein transcripts were up-regulated after 20 days. Although the expression levels of the other genes were highly variable, the expression of immune-related genes in G. p. gambiensis appears to be a time-dependent process. The possible biological significance of these findings is discussed, and the results are compared with previous reports for G. m. morsitans. PMID:25426112

  20. Dynamics of immune system gene expression upon bacterial challenge and wounding in a social insect (Bombus terrestris).

    PubMed

    Erler, Silvio; Popp, Mario; Lattorff, H Michael G

    2011-01-01

    The innate immune system which helps individuals to combat pathogens comprises a set of genes representing four immune system pathways (Toll, Imd, JNK and JAK/STAT). There is a lack of immune genes in social insects (e.g. honeybees) when compared to Diptera. Potentially, this might be compensated by an advanced system of social immunity (synergistic action of several individuals). The bumble bee, Bombus terrestris, is a primitively eusocial species with an annual life cycle and colonies headed by a single queen. We used this key pollinator to study the temporal dynamics of immune system gene expression in response to wounding and bacterial challenge.Antimicrobial peptides (AMP) (abaecin, defensin 1, hymenoptaecin) were strongly up-regulated by wounding and bacterial challenge, the latter showing a higher impact on the gene expression level. Sterile wounding down-regulated TEP A, an effector gene of the JAK/STAT pathway, and bacterial infection influenced genes of the Imd (relish) and JNK pathway (basket). Relish was up-regulated within the first hour after bacterial challenge, but decreased strongly afterwards. AMP expression following wounding and bacterial challenge correlates with the expression pattern of relish whereas correlated expression with dorsal was absent. Although expression of AMPs was high, continuous bacterial growth was observed throughout the experiment.Here we demonstrate for the first time the temporal dynamics of immune system gene expression in a social insect. Wounding and bacterial challenge affected the innate immune system significantly. Induction of AMP expression due to wounding might comprise a pre-adaptation to accompanying bacterial infections. Compared with solitary species this social insect exhibits reduced immune system efficiency, as bacterial growth could not be inhibited. A negative feedback loop regulating the Imd-pathway is suggested. AMPs, the end product of the Imd-pathway, inhibited the up-regulation of the transcription

  1. Immunosorbent Assay Based on Recombinant Hemagglutinin Protein Produced in a High-Efficiency Mammalian Expression System for Surveillance of Measles Immunity

    PubMed Central

    Bouche, Fabienne; Ammerlaan, Wim; Berthet, Francoise; Houard, Sophie; Schneider, Francois; Muller, Claude P.

    1998-01-01

    surveillance for immunity to measles and that such an assay could be more efficient in detecting susceptibility to measles. Furthermore, unlike whole MV-based antigens, H-protein would also be suitable for use in the development of a simple field test for the diagnosis of measles. PMID:9508302

  2. Polymorphisms in innate immunity genes and lung cancer risk in Xuanwei, China

    SciTech Connect

    Shen, M.; Vermeulen, R.; Rajaraman, P.; Menashe, I.; He, X.Z.; Chapman, R.S.; Yeager, M.; Thomas, G.; Burdett, L.; Hutchinson, A.; Yuenger, J.; Chanock, S.; Lan, Q.

    2009-05-15

    The high incidence of lung cancer in Xuanwei County, China has been attributed to exposure to indoor smoky coal emissions that contain polycyclic aromatic hydrocarbons (PAHs). The inflammatory response induced by coal smoke components may promote lung tumor development. We studied the association between single nucleotide polymorphisms (SNPs) in genes involved in innate immunity and lung cancer risk in a population-based case-control study (122 cases and 122 controls) in Xuanwei. A total of 1,360 tag SNPs in 149 gene regions were included in the analysis. FCER2 rs7249320 was the most significant SNP (OR: 0.30; 95% Cl: 0.16-0.55; P: 0.0001; false discovery rate value, 0.13) for variant carriers. The gene regions ALOX12B/ALOX15B and KLK2 were associated with increased lung cancer risk globally (false discovery rate value < 0.15). In addition, there were positive interactions between KLK15 rs3745523 and smoky coal use (OR: 9.40; P-interaction = 0.07) and between FCER2 rs7249320 and KLK2 rs2739476 (OR: 10.77; P-interaction = 0.003). Our results suggest that genetic polymorphisms in innate immunity genes may play a role in the genesis of lung cancer caused by PAH-containing coal smoke. Integrin/receptor and complement pathways as well as IgE regulation are particularly noteworthy.

  3. Polymorphisms in innate immunity genes and lung cancer risk in Xuanwei, China

    PubMed Central

    Shen, Min; Vermeulen, Roel; Rajaraman, Preetha; Menashe, Idan; He, Xingzhou; Chapman, Robert S.; Yeager, Meredith; Thomas, Gilles; Burdett, Laurie; Hutchinson, Amy; Yuenger, Jeff; Chanock, Stephen; Lan, Qing

    2009-01-01

    The high incidence of lung cancer in Xuanwei County, China has been attributed to exposure to indoor smoky coal emissions that contain polycyclic aromatic hydrocarbons. The inflammatory response induced by coal smoke components may promote lung tumor development. We studied the association between single nucleotide polymorphisms (SNP) in genes involved in innate immunity and lung cancer risk in a population-based case-control study (122 cases and 122 controls) in Xuanwei. A total of 1,360 tag SNPs in 149 gene regions were included in the analysis. FCER2 rs7249320 was the most significant SNP (OR: 0.30; 95% CI: 0.16–0.55; P, 0.0001; false discovery rate value, 0.13) for variant carriers. The gene regions ALOX12B/ALOX15B and KLK2 were associated with increased lung cancer risk globally (false discovery rate value < 0.15). In addition, there were positive interactions between KLK15 rs3745523 and smoky coal use (OR: 9.40; P interaction = 0.07), and between FCER2 rs7249320 and KLK2 rs2739476 (OR: 10.77; P interaction = 0.003). Our results suggest that genetic polymorphisms in innate immunity genes may play a role in the carcinogenesis of lung cancer caused by polycyclic aromatic hydrocarbon-containing coal smoke. Integrin/receptor and complement pathways as well as IgE regulation are particular noteworthy. PMID:19170196

  4. Perforin gene transfer into hematopoietic stem cells improves immune dysregulation in murine models of perforin deficiency.

    PubMed

    Carmo, Marlene; Risma, Kimberly A; Arumugam, Paritha; Tiwari, Swati; Hontz, Adrianne E; Montiel-Equihua, Claudia A; Alonso-Ferrero, Maria E; Blundell, Michael P; Schambach, Axel; Baum, Christopher; Malik, Punam; Thrasher, Adrian J; Jordan, Michael B; Gaspar, H Bobby

    2015-04-01

    Defects in perforin lead to the failure of T and NK cell cytotoxicity, hypercytokinemia, and the immune dysregulatory condition known as familial hemophagocytic lymphohistiocytosis (FHL). The only curative treatment is allogeneic hematopoietic stem cell transplantation which carries substantial risks. We used lentiviral vectors (LV) expressing the human perforin gene, under the transcriptional control of the ubiquitous phosphoglycerate kinase promoter or a lineage-specific perforin promoter, to correct the defect in different murine models. Following LV-mediated gene transfer into progenitor cells from perforin-deficient mice, we observed perforin expression in mature T and NK cells, and there was no evidence of progenitor cell toxicity when transplanted into irradiated recipients. The resulting perforin-reconstituted NK cells showed partial recovery of cytotoxicity, and we observed full recovery of cytotoxicity in polyclonal CD8(+) T cells. Furthermore, reconstituted T cells with defined antigen specificity displayed normal cytotoxic function against peptide-loaded targets. Reconstituted CD8(+) lymphoblasts had reduced interferon-γ secretion following stimulation in vitro, suggesting restoration of normal immune regulation. Finally, upon viral challenge, mice with >30% engraftment of gene-modified cells exhibited reduction of cytokine hypersecretion and cytopenias. This study demonstrates the potential of hematopoietic stem cell gene therapy as a curative treatment for perforin-deficient FHL. PMID:25523759

  5. Molecular surveillance of antimalarial drug resistance related genes in Plasmodium falciparum isolates from Eritrea.

    PubMed

    Menegon, Michela; Nurahmed, Abduselam M; Talha, Albadawi A; Nour, Bakri Y M; Severini, Carlo

    2016-05-01

    The introduction of artemisinin-based combination therapy has led to extraordinary results in malaria control, however the recent emergence of partial resistance to artemisinin therapy in Southeast Asia jeopardizes these successes. This study aimed at investigating resistance to the antimalarial drugs by evaluating the polymorphisms in the PfK13, Pfcrt and Pfmdr1 genes in Plasmodium falciparum isolates obtained from patients in Eritrea. PMID:26875763

  6. IL-10 Gene Polymorphisms and Their Association with Immune Traits in Four Rabbit Populations

    PubMed Central

    WAN, Xiaoying; MAO, Liuliu; LI, Ting; QIN, Lizhi; PAN, Yulai; LI, Bichun; WU, Xinsheng

    2013-01-01

    ABSTRACT Interleukin-10 (IL-10) has been recently identified as a multifunctional cytokine, because of its close link with immunoregulation and anti-inflammatory responses. This study investigated the association of IL-10 genetic polymorphisms with the immune traits of New Zealand white rabbits (N-W), Fujian yellow rabbits (F-Y) and their reciprocal crosses (N-Y and Y-N, respectively). SNPs on five exons of the IL-10 gene were genotyped in 204 healthy rabbits via PCR-SSCP and DNA sequencing. Two SNPs (A1435G and G1519A, both were synonymous mutations) and six genotypes (AA, BB, CC, AB, AC and BC) were found on exon 3 and one SNP (T base insertion between loci 2532 and 2533, which caused a frameshift mutation), and three genotypes (OO, TT and TO) were present on exon 4. Allele A was the most frequent allele on exon 3 (from 0.548 to 0.771), whereas O was the most frequent on exon 4 (from 0.808 to 0.968). These four populations were all in Hardy-Weinberg equilibrium on both exon3 and exon4. Association analysis between polymorphisms and immune parameters showed that SNPs on exon 3 were significantly associated with immune traits, while SNP on exon 4 may not significantly affect immune traits, but the mechanism is yet to be further studied. PMID:24240540

  7. Expression of Immune-Related Genes of Ducks Infected with Avian Pathogenic Escherichia coli (APEC)

    PubMed Central

    Li, Rong; Li, Ning; Zhang, Jinzhou; Wang, Yao; Liu, Jiyuan; Cai, Yumei; Chai, Tongjie; Wei, Liangmeng

    2016-01-01

    Avian pathogenic Escherichia coli (APEC) can cause severe disease in ducks, characterized by perihepatitis, pericarditis, and airsacculitis. Although the studies of bacteria isolation and methods of detection have been reported, host immune responses to APEC infection remain unclear. In response, we systemically examined the expression of immune-related genes and bacteria distribution in APEC-infected ducks. Results demonstrated that APEC can quickly replicate in the liver, spleen, and brain, with the highest bacteria content at 2 days post infection. The expression of toll-like receptors (TLRs), avian β-defensins (AvBDs) and major histocompatibility complex (MHC) were tested in the liver, spleen, and brain of infected ducks. TLR2, TLR4, TLR5, and TLR15 showed different expression patterns, which indicated that they all responded to APEC infection. The expression of AvBD2 was upregulated in all tested tissues during the 3 days of testing, whereas the expression of AvBD4, AvBD5, AvBD7, and AvBD9 were downregulated, and though MHC-I was upregulated on all test days, MHC-II was dramatically downregulated. Overall, our results suggest that APEC can replicate in various tissues in a short time, and the activation of host immune responses begins at onset of infection. These findings thus clarify duck immune responses to APEC infection and offer insights into its pathogenesis. PMID:27199963

  8. Improved Induction of Immune Tolerance to Factor IX by Hepatic AAV-8 Gene Transfer

    PubMed Central

    Cooper, Mario; Nayak, Sushrusha; Hoffman, Brad E.; Terhorst, Cox; Cao, Ou

    2009-01-01

    Abstract Gene therapy for hemophilia B has been shown to result in long-term expression and immune tolerance to factor IX (F.IX) after in vivo transduction of hepatocytes with adeno-associated viral (AAV-2) vectors in experimental animals. An optimized protocol was effective in several strains of mice with a factor 9 gene deletion (F9−/−). However, immune responses against F.IX were repeatedly observed in C3H/HeJ F9−/− mice. We sought to establish a gene transfer protocol that results in sustained expression without a requirement for additional manipulation of the immune system. Compared with AAV-2, AAV-8 was more efficient in transgene expression and induction of tolerance to F.IX in three different strains of wild-type mice. At equal vector doses, AAV-8 induced transgene product-specific regulatory CD4+CD25+FoxP3+ T cells at significantly higher frequency. Moreover, sustained correction of hemophilia B in C3H/HeJ F9−/− mice without antibody formation was documented in all animals treated with ≥4 × 1011 vector genomes (VG)/kg and in 80% of mice treated with 8 × 1010 VG/kg. Therefore, it is possible to develop a gene transfer protocol that reliably induces tolerance to F.IX largely independent of genetic factors. A comparison with other studies suggests that additional parameters besides plateau levels of F.IX expression contributed to the improved success rate of tolerance induction. PMID:19309290

  9. Evolution of a Novel Antiviral Immune-Signaling Interaction by Partial-Gene Duplication

    PubMed Central

    Korithoski, Bryan; Kolaczkowski, Oralia; Mukherjee, Krishanu; Kola, Reema; Earl, Chandra; Kolaczkowski, Bryan

    2015-01-01

    The RIG-like receptors (RLRs) are related proteins that identify viral RNA in the cytoplasm and activate cellular immune responses, primarily through direct protein-protein interactions with the signal transducer, IPS1. Although it has been well established that the RLRs, RIG-I and MDA5, activate IPS1 through binding between the twin caspase activation and recruitment domains (CARDs) on the RLR and a homologous CARD on IPS1, it is less clear which specific RLR CARD(s) are required for this interaction, and almost nothing is known about how the RLR-IPS1 interaction evolved. In contrast to what has been observed in the presence of immune-modulating K63-linked polyubiquitin, here we show that—in the absence of ubiquitin—it is the first CARD domain of human RIG-I and MDA5 (CARD1) that binds directly to IPS1 CARD, and not the second (CARD2). Although the RLRs originated in the earliest animals, both the IPS1 gene and the twin-CARD domain architecture of RIG-I and MDA5 arose much later in the deuterostome lineage, probably through a series of tandem partial-gene duplication events facilitated by tight clustering of RLRs and IPS1 in the ancestral deuterostome genome. Functional differentiation of RIG-I CARD1 and CARD2 appears to have occurred early during this proliferation of RLR and related CARDs, potentially driven by adaptive coevolution between RIG-I CARD domains and IPS1 CARD. However, functional differentiation of MDA5 CARD1 and CARD2 occurred later. These results fit a general model in which duplications of protein-protein interaction domains into novel gene contexts could facilitate the expansion of signaling networks and suggest a potentially important role for functionally-linked gene clusters in generating novel immune-signaling pathways. PMID:26356745

  10. Tamoxifen Induces Expression of Immune Response-Related Genes in Cultured Normal Human Mammary Epithelial Cells

    PubMed Central

    Schild-Hay, Laura J.; Leil, Tarek A.; Divi, Rao L.; Olivero, Ofelia, A.; Weston, Ainsley; Poirier, Miriam C.

    2008-01-01

    Use of tamoxifen (TAM) is associated with a 50% reduction in breast cancer incidence and an increase in endometrial cancer incidence. Here, we documented TAM-induced gene expression changes in cultured normal human mammary epithelial cells (NHMEC strains numbered 5, 16 and 40), established from tissue taken at reduction mammoplasty from 3 individuals. Cells exposed to 0, 10 or 50 μM TAM for 48 hours were evaluated for (E)-α-(deoxyguanosin-N2-yl)-tamoxifen (dG-N2-TAM) adduct formation by TAM-DNA (DNA modified with dG-N2-TAM) chemiluminescence immunoassay (CIA), gene expression changes using NCI DNA-oligonucleotide microarray, and real time (RT)-PCR. At 48 hr, cells exposed to 10 μM and 50 μM TAM were 85.6% and 48.4% viable, respectively, and there were no measurable dG-N2-TAM adducts. For microarray, cells were exposed to 10 μM TAM and genes with expression changes of ≥ 3-fold were as follows: thirteen genes up-regulated and one down-related for strain 16; seventeen genes up-regulated for strain 5; and eleven genes up-regulated for strain 40. Interferon-inducible genes (IFITM1, IFIT1, IFNA1, MXI and GIP3), and a potassium ion channel (KCNJ1) were up-regulated in all 3 strains. No significant expression changes were found for genes related to estrogen or xenobiotic metabolism. RT-PCR revealed up-regulation of interferon α (IFNA1) and confirmed the TAM-induced up-regulation of the genes identified by microarray, with the exception of GIP3 and MX1, which were not up-regulated in strain 40. Induction of interferon-related genes in the three NHMEC strains suggests that, in addition to hormonal effects, TAM exposure may enhance immune response in normal breast tissue. PMID:19155303