Functional Studies on Natural IgM Secreting B-1 Cells and Their Roles in Innate Anti-viral IgM Immunity Against Influenza Virus Infection PDF Download
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Author: Youn Soo Choi
Publisher:
ISBN:
Category :
Languages : en
Pages : 314
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Author: Youn Soo Choi
Publisher:
ISBN:
Category :
Languages : en
Pages : 314
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Author: Elizabeth Emlika Waffarn
Publisher:
ISBN: 9781321364187
Category :
Languages : en
Pages :
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Multiple B lymphocyte subsets contribute to immune responses to pathogens. Among these, B-1 cells are a small subset of innate-like B cells whose development, phenotype, tissue distribution, and functions are distinct from those of conventional B-2 cells, and whose responses are crucial to protection against mucosal bacterial and viral pathogens. B-1 cells contribute to protective responses even before infection, by secreting natural antibody, a polyspecific repertoire of mostly IgM antibodies produced constitutively in the absence of foreign antigens. In response to influenza virus infection, B-1 cells actively respond by accumulating locally in draining mediastinal lymph nodes (MedLN), where they differentiate to secrete both virus-binding and non virus-binding IgM. Multiple details from those earlier studies suggest that the regulation of B-1a cell responses differs from that of conventional B-2 cells and that infection-induced but antigen-independent mechanisms contribute to B-1a cell activation and function. This dissertation explores the hypothesis that B-1 cells are regulated by the quality and magnitude of local infection-induced innate immune signals, including type I interferon (IFNs) and IL-1, critical mediators of anti-viral responses and pro-inflammatory signaling. Previous studies of IL1R-/- mice showed that IL-1 signaling was required for maximal secretion of IgM and IgA after influenza infection. Because B-1 cells contribute at least half of influenza-induced IgM, we investigated the effects of IL-1 on B-1 cell redistribution and activation for IgM secretion. The studies outlined in the Second Chapter revealed that direct IL-1 stimulation did not contribute to the redistribution of B-1 cells to the lymph nodes, as it was neither directly chemotactic for B-1 cells, did not mobilize B-1 cells in vivo, nor altered the ability of B-1 cells to respond to the lymph node homing chemokines CXCL12 and CXCL13 in vitro. Instead, we found that IL-1 treatment alone modestly induced their IgM secretion in vitro. Using chimeric mice in which only B-1 cells lacked the IL-1R and which are distinguishable from B-2 cells based on Ig-allotypic differences, we investigated the ability of B-1 cells to respond to influenza virus infection. The data showed that these signals were required for maximum induction not only of CD5- B-1 cells, but also of the mostly B-2 cell-derived plasma blasts. Consistent with these findings we found IgM production both by B-1 and B-2 cells reduced. To begin to determine the mechanism by which B-1 cell IL-1 stimulation causes B-2 cell differentiation, we found that IL-1 stimulation selectively induced GM-CSF stimulation by B-1 cells. Furthermore, supernatants of IL-1-stimulated B-1 cells were able to induce IgM secretion by B-2 cells in vitro. Together, these findings suggest that activated B-1 cells play a regulatory role within lymph nodes by guiding conventional B-2 cell responses. In the Third Chapter, we took a genome-wide gene expression array approach to conduct an unbiased analysis of B-1a cell populations in the peritoneal and pleural cavity and the spleen, before and at two time points after infection. The goal was to identify all signals that affect B-1a cells following influenza infection in vivo and to identify a likely source from which lymph node B-1 cells were recruited. Somewhat surprisingly, the results revealed strong gene expression differences present before infection between B-1 cells from different tissues. Influenza virus infection further altered gene expression from all three sites, but the strongest changes occurred in pleural cavity B-1a cells within 2 days of infection, indicating that rapidly induced, locally elaborated infection signals impact B-1a cells. Based on the affected genes, type I IFN was identified as a strong early innate factor providing site-specific signaling to B-1a cells. These results suggest that B-1a cells receive site-specific signals even prior to infection and that infection-induced local signals strongly affect pleural cavity B-1a cells, likely shaping their antiviral response. The Fourth Chapter investigates the tissue origins of B-1a cells accumulating at the site of influenza infection and the role of type I IFN in their migration and differentiation. Labeled B-1a cells preferentially redistributed from pleural cavity sites to the draining MedLN after influenza infection, consistent with the results of our microarray analyses. However, in mice in which only B cells, or only B-1 cells lacked IFNR-expression, this enhanced accumulation was absent suggesting a role for type I IFN signaling B-1 cell redistribution. An in vitro vascular mimetic chamber model was used to evaluate the adherence of B-1 cells to a substrate consisting of ICAM-1 and CXCL13. Strikingly, type I IFN treatment or in vivo influenza infection stimulated B-1 cells to arrest on the substrate. Antibody-blocking studies showed that this was due to the increased integrin-mediated binding to ICAM-1. In vivo competition experiments designed to measure the ability of B-1 cells, from wildtype and CD11b or CD11a integrin-deficient mice, to accumulate in the MedLN in response to influenza infection after transfer into the pleural cavity of recipient mice, demonstrated the importance of CD11b in the B-1 cell redistribution process. Further studies suggested that type I IFN acts to enhance CD11b-mediated lymph node accumulation by activating the conformation state of CD11b. These studies identify a novel axis of type I IFN mediated integrin activation for rapid regulation of innate lymphocyte redirection. Together, these studies provide two examples of innate-signaling mediated regulation of B-1 cell responses during influenza infection. The results indicate that B-1 cells in the body cavities are optimally positioned to rapidly respond to an infection and that their characteristic expression of CD11b aids in rapid migration and accumulation in regional lymphoid tissues. Finally, the results of this study also suggest that B-1a cells broadly regulate the adaptive antiviral response by providing non-redundant signals to conventional B-2 cells for maximal induction of virus-specific antibody responses.
Author: Kenneth Murphy
Publisher: Garland Science
ISBN: 9780815344575
Category : Medical
Languages : en
Pages :
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The Janeway's Immunobiology CD-ROM, Immunobiology Interactive, is included with each book, and can be purchased separately. It contains animations and videos with voiceover narration, as well as the figures from the text for presentation purposes.
Author: Xiaohui Wang
Publisher:
ISBN: 9781361366912
Category :
Languages : en
Pages :
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This dissertation, "The Role of IL-17A in Modulating B Cell Response During Influenza Virus Infection" by Xiaohui, Wang, 王晓辉, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Interleukin-17A (IL-17A)is an important pro-inflammatory cytokine that plays a critical role in host defenses against diverse pathogens. Studies have shown that IL-17Aplays protective role against sub-lethal H1 and H3 subtypes influenza infections, but it is unclear about the role of IL-17A in the highly pathogenic H5N1 and lethal H1N1 influenza virus infection. B cell is an important effector cell type in anti-influenza immunity. Although roles of B cell in influenza infection have been extensively investigated, it is unclear whether and how IL-17AregulatesB cell response during influenza infection. I examined the role of IL-17A against influenza infection by challengingIL-17A knockout (KO) and wild-type (WT) mice with highly pathogenic H5N1 and lethal H1N1 influenza viruses. Following challenge, IL-17AKO mice exhibited significantly lower survival rate, profoundly reduced body weight, more severe tissue damage and higher viral burden in the lung tissues. These evidences suggest that IL-17Aplays a protective role in lethal influenza infection. To study whether IL-17Amodulates B cell response against influenza, I found that both B-1a and B-2 cells were detected in the lung tissue and pulmonary draining lymph node, Mediastinal lymph node (MedLN), as early as 2days post-infection. Meanwhile, B-1a cells predominantly contributed to the early virus-specific IgM in the respiratory tract. However, virus-specific IgM markedly reduced in IL-17A KO mice when compared with WT controls. Adoptive transfer of B-1a cells or B-1a cell-derived antibodies conferred protection in IL-17A KO mice. These results demonstrate that IL-17A plays a critical role in modulating early antibody production of B-1a cells against lethal influenza infection. To further elucidate how IL-17A regulates B-1a cell response, I observed that B-1a cells migrated into MedLN and lung tissues during infection and underwent plasmacytic differentiation with increased antibody production in airways. IL-17A deficiency impaired these processes of B-1a cells, while intra-nasally instillation of IL-17A restored B-1a cell response by promoting both B-1a cell migration and plasmacytic differentiation. By inducing blimp-1 expression in B-1a cells in an NF-κB dependent pathway, IL-17A directly promoted plasmacytic differentiation of B-1a cells both in vivo and in vitro. Furthermore, chromatin immuno-precipitation analysis confirmed that NF-κB directly bound to the promoter of blimp-1 gene and promoted blimp-1 expression in B-1a cells following IL-17A stimulation. To determine the functional significance of IL-17A signaling in modulating B cell response against influenza infection, I first uncovered markedly reduced B cell response, predominantly B-1a cell response in IL-17A KO mice, showing reduced local migration and impaired plasmacytic differentiation in the early stage of infection. Next, intra-nasal administration of IL-17A into IL-17A KO mice significantly restored this B-1a cell response. Moreover, I detected expression of IL-17A receptor in B-1a cells. IL-17A treatment could promote antibody production from B-1a cells by inducing blimp-1 expression in an NF-κB dependent pathway. Taken together, these findings identify a novel role of IL-17A in actingas an immune modulator of B cell response against influenza infection, which will contribute to a fuller understanding of B cell biology and anti-vi
Author: Stephen Omeade Priest
Publisher:
ISBN: 9781303154423
Category :
Languages : en
Pages :
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Type I interferon (IFN-I) is a potent antiviral cytokine, whose pleotropic effects makes it a key signal in the regulation of both the innate and adaptive arms of the immune response to virus infection. Its innate effects, which include antiproliferative and pro-apoptotic effects, have been characterized in extensive studies, as has its immunomodulatory role enhancing NK cell, macrophage, and dendritic cell fuction. Recent findings indicate type I IFN also directly stimulates B cells during virus infection, affecting the subsequent antibody response. The mechanisms by which it regulates B cells are unclear. Here I began by exploring two potential direct effects of IFN-I on B cells and their responses to influenza virus infection. Following a summary in Chapter 1 of existing literature linking innate signals in the regulation of B cell responses to influenza virus infection, I define in Chapter 2 the effects of Type I IFN-signaling on B cell proliferation and survival. I examine these effects both in vitro with and without BCR stimulation, and in vivo in the context of homeostatic expansion and influenza virus infection. The study shows that the balance of IFN-I's effects on apoptosis and cell cycle regulation determine the outcome of B cell proliferative responses, with the net effect dependent on the context of the mitogenic stimuliation. Specifically, IFN-enhanced survival was reversed in proliferating B cells, enhancing apoptosis following both in vitro and in vivo stimulation. In BCR-stimulated B cell in vitro, the net effect was negative as cell cycle entry and proliferation was reduced by IFN-I. However the net effect was neutral in vivo during homeostatic expansion and influenza virus infection, as cell cycle entry was enhanced by IFN-I signaling, suggesting the involvement of additional IFN-I-mediated signals in regulating B cell proliferation. In Chapter 3 the role of type I IFN-mediated induction of TLR7 by B cells is considered in the context of influenza virus infection. We show that B cell functional responses to influenza virus infection are enhanced by locally generated IFN-I, corresponding with its ability to directly increase TLR7 expression in B cells. Furthermore, we show close correllations between IFN-I and TLR7 signaling in regulating B cell proliferation and antibody responses to influenza virus infection. Together, these findings establish IFN-I's key role in promoting B cell clonal expansion during virus infection, likely through enhanced sensitivity to TLR7-mediate stimulation. Notably, studies in BXSB mice, a strain in which male mice overexpress TLR7 due to an additional copy of the gene on the Y-chromosome, demonstrate the aparent presence of a threshold of TLR7 expression that cannot be overcome by IFN-I signaling, and thereby indicate the tight regulation of this innate receptor in B cells. Overall, this study demonstrates that type I IFN directly regulates B cell function during steady-state, homeostatic expansion, and influenza virus infection, through its combined effects on apoptosis, cell cycle progression, and TLR7 expression.
Author: Trang Thi Thuy Nguyen
Publisher:
ISBN: 9780355150360
Category :
Languages : en
Pages :
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The immunoglobulin (Ig) isotype IgM is present on the surface of all developing B lymphocytes, as membrane-bound antigen-receptor (BCR). Like all Ig, it is present also in secreted form (sIgM). sIgM is generated by activated B cells following foreign antigen exposure, such as following infections, as well as spontaneously by the B-1 cell subset as “natural” sIgM, via stimulation by self-antigens. The absence of sIgM was shown previously to diminish the ability of a host to control infections with various bacterial and viral pathogens. This appeared to be due at least in part to an effect of sIgM on IgG response enhancement. Furthermore, selective deficiency of sIgM in humans and mice has been associated with antibody-mediated autoimmunity. Thus, sIgM has multiple immune-regulatory and immune-defense functions, but the mechanisms underlying these different functions are incompletely understood. The objective of this dissertation was to explore how sIgM and its receptors regulate B cell immunity. In Chapter 2, I outline studies that characterized the B cell developmental changes in mice lacking all sIgM ([mu]s[superscript –/–]). The data demonstrated that the absence of sIgM resulted in altered B cell selection during bone marrow B cell development. The resulting changes in the BCR repertoire caused the accumulation of autoreactive B cells and autoantibodies in these mice. The absence of sIgM affected all subsets of B cells. It increased marginal zone B cells and decreased follicular B cells as well as body cavity B-1 cells, and resulted in the appearance of a large population of CD5+ anergic B cells. A causal relationship between the absence of natural sIgM and these developmental defects was established by demonstrating that polyclonal IgM rescued B cell development and returned autoantibody levels to near normal. Thus, sIgM deficiency causes primary autoimmune disease by altering B cell development and selection. Chapter 3 explores how sIgM-deficiency reduces IgG responses. Adoptive transfer systems were used to distinguish effects of sIgM on B cell development and B cell activation. The studies showed that development of sIgM-deficient B cells in a sIgM-sufficient environment did not rescue normal anti-viral IgG responses to influenza virus infection and suggested a direct effect of sIgM on B cell activation. Complement receptor and Fc[alpha]/[mu]R interaction with sIgM were shown to be unlikely responsible. Instead, B cell-specific deletion of the Fc[mu]R resulted in similar reductions in virus-specific serum IgG titers as seen in [mu]s[superscript -/-] mice, as well as strongly reduced hemagglutination inhibition titers, and passive protective capacity of immune sera. Reduced IgG responses correlated with reduced antigen-specific B cell numbers early after infection and reduced short- and long-lived plasma cells and memory B cells. Provision of sIgM rescued plasma cell differentiation in [mu]s[superscript –/–] B cells, but not Fc[mu]R[superscript –/–] mice. The data identify sIgM-Fc[mu]R direct interaction on B cells as a non-redundant signal required for full B cell activation and differentiation after influenza virus infection.Chapter 4 determines how the interaction of IgM and Fc[mu]R affects B cell development and peripheral B cell homeostasis. Transfection experiments, STED microscopy and proximal ligation assays demonstrated that the Fc[mu]R receptor interacted with IgM in two distinct B cell compartments: The cell surface and the trans-Golgi network. Expression in the trans-Golgi network in developing immature B cells constrained mIgM, i.e. BCR transport and surface expression. By controlling the levels of IgM-BCR expression, the Fc[mu]R regulated the peripheral B cell pool size, the development of natural IgM-secreting B-1 cells, and prevented the formation of spontaneous germinal centers, and IgG autoantibody producing B cells. Thus, the Fc[mu]R is a critical regulator of B cell homeostasis and late B cell development.
Author: Peter D. Katsikis
Publisher: Springer Science & Business Media
ISBN: 1461462177
Category : Medical
Languages : en
Pages : 144
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This volume presents a collection of reviews derived from work presented at the Aegean Conference: “4th Crossroads between innate and adaptive immunity”. This meeting was the fourth in a series, and assembled a team of scientists working on mechanisms by which the innate immune system of the host senses pathogens, the cellular and signaling networks that orchestrate the innate response and antigen presentation and adaptive immunity. The importance of the crosstalk between innate immunity and the adaptive immune response has only recently started to be appreciated. Although it is well recognized that dendritic cells, NK cells, NK-T cells and T cells are all critical for the host response to pathogens, the respective fields that study the biology of these immune cells tend to exist in parallel worlds with minimum exchange of information and ideas. This fragmentation hinders the integration of these fields towards a unified theory of host response. The Aegean Conference “Crossroads between Innate and Adaptive Immunity” brought together leading international scientists and experts to address critical areas of Innate and Adaptive immunity something necessary for the development of more efficient scientific exchange and crosspollination between these fields. This conference attracted scientists from all over the world to discuss their latest findings on the various aspects of Innate and Adaptive immunity. The conference had limited participation and a scientific and social program that maximized scientific interchange through lecture presentations, poster sessions and informal discussions.
Author: Hiroshi Kiyono
Publisher: Elsevier
ISBN: 0080537057
Category : Medical
Languages : en
Pages : 501
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Book Description
This comprehensive, authoritative treatise covers all aspects of mucosal vaccines including their development, mechanisms of action, molecular/cellular aspects, and practical applications. The contributing authors and editors of this one-of-a-kind book are very well known in their respective fields. Mucosal Vaccines is organized in a unique format in which basic, clinical, and practical aspects of the mucosal immune system for vaccine development are described and discussed. This project is endorsed by the Society for Mucosal Immunology. Provides the latest views on mucosal vaccines Applies basic principles to the development of new vaccines Links basic, clinical, and practical aspects of mucosal vaccines to different infectious diseases Unique and user-friendly organization
Author: Thomas Howard Oguin
Publisher:
ISBN:
Category :
Languages : en
Pages :
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Influenza virus is a threat to public health on a global scale. Each year, millions of people are infected with influenza virus leading to hundreds of thousands of deaths. Despite progress in developing anti-influenza drugs, every antiviral compound used has caused influenza strains to mutate and become resistant to the drug. In order to improve our defenses against influenza virus, novel research strategies are needed. The innate immune system is the first line of defense against incoming pathogens. Many signaling networks are involved in coordinating an efficacious response to viral insult. We have found that lipid signaling through phospholipase D is critical to influenza pathogenesis. Influenza virus exploits this signaling to quickly infect human lung cells and evade the host antiviral response. By inhibiting this process, we observed a marked protection from infection. One of the critical molecules of the protective innate immune response after phospholipase D inhibition is interferon regulatory factor 3. Surprisingly, we found that mice missing this protein are more likely to survive a lethal influenza infection. This survival advantage depends on an amplified adaptive immune response. We are currently investigating this crosstalk between the innate and adaptive immune systems. One of the most potent direct antiviral effector molecules in the innate arsenal is myxovirus resistance gene 1. While this protein is generally considered to function by binding directly to viral proteins and inhibiting their functions, we have uncovered an unrecognized activity of this protein. We show that basal expression of this protein is critical in the induction of the innate immune response, and it is potentially involved in the signaling network that is constructed in response to influenza infection. These results help define the critical events mediating the host-virus interaction in infected epithelial cells. Future research for new antiviral strategies can exploit these novel pathways to enhance host responses and limit viral replication efficiency.
Author: Manlio Ferrarini
Publisher: Karger Medical and Scientific Publishers
ISBN: 9783805564601
Category : Medical
Languages : en
Pages : 152
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Book Description
B cells used to be considered as a homogeneous population of cells destined to produce antibodies of increasing affinity and to maintain an immunological memory. In recent years, it has been determined that B cells can be subdivided into different subsets characterized by distinct morphologic, phenotypic, and functional features. Presenting results of research work on the definition of B cell subset populations, this book explains the basic mechanisms that control B cell activation, stimulation and regulation. Articles include studies on both normal and malignant B cells and describe the mechanisms underlying T-B cell interactions during the immune response. The most important advances in the field of immunodeficiency are also reported. This volume will be essential not only for basic and clinical immunologists, but also for hematologists, pathologists and rheumatologists with a special interest in the pathogenesis of lymphoproliferative or autoimmune disorders.
