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Author: Kristina Rothaeusler
Publisher:
ISBN:
Category :
Languages : en
Pages : 300
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Author: Kristina Rothaeusler
Publisher:
ISBN:
Category :
Languages : en
Pages : 300
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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: 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: Aarthi Sundararajan
Publisher:
ISBN:
Category :
Languages : en
Pages : 161
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Viruses replicating in the respiratory tract (RT) trigger a wide range of cytokines and chemokines that have antiviral and pro-inflammatory features, instigating an efficient virus- specific B and T cell response that aids in virus- clearance. The majority of antibody secreting cells (ASCs) localizing in the upper RT secrete IgA that can effectively neutralize viruses. In addition, elements of B cell memory are generated that can provide protection from re-infection. Studies examining these aspects, following murine gammaherpesvirus 68 (MHV-68) infection comprise chapter 2 of the dissertation work. Our studies demonstrate that following MHV-68 infection, unlike influenza infection, resulted in a generalized deficiency of virus-specific IgA induction and deficient B cell memory establishment in the respiratory tract. Our studies indicate that features of virus- replication in the RT regulate these aspects of B cell response. These studies lead to the speculation that these features of B cell response may represent an evolutionary adaptation of viruses that establish long-term latency and are transmitted periodically after reactivation and shedding in secretions. Following cognate interactions with CD4+ T cells, the B cells undergo proliferation, isotype-switching and differentiate towards extrafollicular (low affinity, rapid) or towards germinal center pathway (high affinity). It is not clear what factors regulate these pathways of B cell differentiation, especially in the context of virus infection in the RT. Studies examining these aspects following influenza infection comprise chapter 3 of the dissertation work. Our studies establish a model for the investigation of host and viral factors that modulate the quality and effectiveness of the B cell response to influenza infection. The findings indicate that the quality/nature of the extrafollicular B cell response depends on the nature of the infecting virus. We present evidence that this pathway of rapid antiviral antibody production relates to the production of non-specifically acting factors in the lung and correlates with the cytokine profile of virus-specific CD4+T cells. In summary, the current dissertation findings point to an influence of virus and host associated factors in regulating features of B cell response in the RT.
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: R. Ahmed
Publisher: Wiley-Blackwell
ISBN:
Category : Medical
Languages : en
Pages : 754
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Book Description
Persistent Viral Infections Edited by Rafi Ahmed Emory Vaccine Center, Atlanta, USA and Irvin S. Y. Chen UCLA School of Medicine, Los Angeles, USA During the past decade much of our attention has focused on diseases associated with viral persistence. Major breakthroughs in immunology, and the advent of molecular approaches to study pathogenesis have increased our understanding of the complex virus-host interactions that occur during viral persistence. Persistent Viral Infections focuses on: * The pathogenesis and immunology of chronic infections * Animal models that provide, or have the potential to provide, major insights This volume will be essential reading for virologists, immunologists, oncologists and neurologists.
Author: Hans U. Lutz
Publisher: Springer Science & Business Media
ISBN: 1461434610
Category : Medical
Languages : en
Pages : 285
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Book Description
This volume illustrates the functional properties of NAbs. Authors from pioneering groups report in their chapters on the tissue homeostatic, tissue regenerating and regulatory properties of NAbs and NAbs in pooled human IgG. Scientists interested in the regulation and modulation of components of the immune system found a whole variety of NAbs to cytokines with regulatory and protective functions and NAbs that modulate, e.g., dendritic cells, regulatory T cells, B cells and granulocytes. Considering the large plasma pools and initial difficulties in preparing IVIG that does not induce adverse effects upon infusion into recipients, this volume ends with a historical chapter on how pooled human plasma was fractionated and the IgG component pretreated for a safe intravenous application.
Author: Marta L. DeDiego
Publisher: MDPI
ISBN: 3039288172
Category : Science
Languages : en
Pages : 130
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Book Description
The influenza virus poses a threat to human health and is responsible for global epidemics every year. In addition to seasonal infections, influenza can cause occasional pandemics of great consequence when novel viruses are introduced into humans. Despite the implementation of comprehensive vaccination programs, influenza viruses continue to pose an important and unpredictable global public health threat. They are one of the most significant causes of morbidity and mortality each year and have a significant economic impact. In recent years, research has been conducted to find alternative approaches to influenza vaccine development, including the generation of universal vaccines. Notably, significant progress in the field of influenza infection, transmission, and immunity have contributed to our understanding of influenza biology, and to expanding the technological approaches for the generation of more efficient strategies against influenza infections. Moreover, highly remarkable developments have been made in the implementation of new methodologies to evaluate the efficiency of vaccines and improve them for use on domestic animals such as poultry, horses, dogs or pigs. This enables us to decrease the exposure of humans to potentially pandemic viruses. The articles in this Special Issue will address the importance of influenza to human health and the advances in influenza research that have led to the development of better therapeutics and vaccination strategies.
Author: Youn Soo Choi
Publisher:
ISBN:
Category :
Languages : en
Pages : 314
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