Download or read book B Cell Response Regulation to Influenza Virus Infection written by Kristina Rothaeusler and published by . This book was released on 2009 with total page 300 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book Type I Interferon Directly Regulates B Cell Function During the Response to Influenza Virus Infection written by Stephen Omeade Priest and published by . This book was released on 2013 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: 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.

Download or read book The Innate Regulation of B 1 Lymphocyte Responses to Influenza Virus Infection written by Elizabeth Emlika Waffarn and published by . This book was released on 2014 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: 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.

Download or read book Janeway s Immunobiology written by Kenneth Murphy and published by Garland Science. This book was released on 2010-06-22 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: 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.

Download or read book Regulation of B Cell Response to Respiratory Viruses written by Aarthi Sundararajan and published by . This book was released on 2011 with total page 161 pages. Available in PDF, EPUB and Kindle. Book excerpt: 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.

Download or read book The Role of Il 17a in Modulating B Cell Response During Influenza Virus Infection written by Xiaohui Wang and published by . This book was released on 2017-01-27 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: 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

Download or read book Naturally Occurring Antibodies NAbs written by Hans U. Lutz and published by Springer Science & Business Media. This book was released on 2012-08-19 with total page 285 pages. Available in PDF, EPUB and Kindle. Book excerpt: 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.

Download or read book Persistent Viral Infections written by R. Ahmed and published by Wiley-Blackwell. This book was released on 1999 with total page 754 pages. Available in PDF, EPUB and Kindle. Book excerpt: 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.

Download or read book Functional Studies on Natural IgM Secreting B 1 Cells and Their Roles in Innate Anti viral IgM Immunity Against Influenza Virus Infection written by Youn Soo Choi and published by . This book was released on 2008 with total page 314 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book Human Herpesviruses written by Ann Arvin and published by Cambridge University Press. This book was released on 2007-08-16 with total page 1325 pages. Available in PDF, EPUB and Kindle. Book excerpt: This comprehensive account of the human herpesviruses provides an encyclopedic overview of their basic virology and clinical manifestations. This group of viruses includes human simplex type 1 and 2, Epstein–Barr virus, Kaposi's Sarcoma-associated herpesvirus, cytomegalovirus, HHV6A, 6B and 7, and varicella-zoster virus. The viral diseases and cancers they cause are significant and often recurrent. Their prevalence in the developed world accounts for a major burden of disease, and as a result there is a great deal of research into the pathophysiology of infection and immunobiology. Another important area covered within this volume concerns antiviral therapy and the development of vaccines. All these aspects are covered in depth, both scientifically and in terms of clinical guidelines for patient care. The text is illustrated generously throughout and is fully referenced to the latest research and developments.

Download or read book TRANSCRIPTIONAL REGULATION OF B CELL RESPONSES IN PROTECTION AND AUTOIMMUNITY written by Adam James Fike and published by . This book was released on 2022 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Humoral immunity plays a pivotal role in both protective and autoimmune responses. Following a vaccination or pathogenic challenge, B lymphocytes respond by differentiating through germinal center (GC) or extrafollicular (EF) pathways to ultimately become antibody forming cells, which produce antibodies to protect the host. In autoimmune diseases, like systemic lupus erythematosus (SLE), these pathways become dysregulated which allows autoreactive B cells to produce antibodies against self-antigen. Thus, deciphering the transcriptional networks that regulate protective and aberrant responses in autoimmune diseases is paramount to guiding insights for new vaccines or therapeutics for autoimmune conditions. The GC is a site of B cell evolution and is the dominant source of high-affinity long lived plasma cells (LLPCs). GCs are canonically organized into two distinct niches, the dark (DZ) and light (LZ) zone. A bottle neck for the selection of high-affinity B cells within the GC is at the T cell-mediated selection stage in the light zone (LZ) of the GC. STAT3 is a transcription factor activated by several cytokines and signals critical to B cell biology and has a known role in plasma cell maturation. How STAT3 influences the GC reaction remains incompletely understood. Using numerous stage-specific and inducible B cell intrinsic systems, we determined that STAT3 is not required for the initiation or maintenance of a GC reaction, but rather is required for the zonal organization of the GC. STAT3-deficient GCs have an expansion of the LZ and reduction of the DZ. STAT3 exerts its functions independent of any effects on proliferation, cell cycle progression, DNA damage, or apoptosis. Further, we identified that STAT3 is not required for memory B cell (MBC) formation or the initial progression towards a plasma cell but is required for post-GC PC maturation. We discovered that STAT3 is activated in the LZ of the GC in a T-dependent manner, which permits STAT3 to orchestrate the transcriptional program required for LZ GC B cells to progress into DZ GC B cells. We next sought to delineate the functions of another STAT transcription factor, STAT4, in regulating SLE and Th1-mediated B cell responses. STAT4 has been suggested to be involved in autoimmune and protective B cell responses, but its exact contribution remains undefined. Further, numerous GWAS identified polymorphisms in or near the Stat4 locus in SLE patients. To examine the role of STAT4 in the regulation of B cell responses in SLE-like autoimmunity, we investigated the effects of STAT4 deficiency in three autoimmune- or lupus-prone mouse models: Fc[gamma]RIIB-/-, B6.Sle1b, and imiquimod treated B6.Sle1b.We found no significant effects of STAT4 on autoimmune B and T cell responses, and SLE-like autoimmunity. We next investigated if STAT4 deficiency impacted B cell responses to immunization or influenza viral infection. Again, we identified no significant impact on B or T cell responses in the absence of STAT4. From these results, we conclude that STAT4 is not required for autoimmune or protective B cell responses. Finally, B cell responses in SLE are heavily dependent upon Toll-like receptor 7 (TLR7) signaling. TLR7 activation results in the activation of several transcription factors, including interferon regulatory factor 7 (IRF7). IRF7 has been generally suspected to be involved in promoting autoimmunity, but its functions in various immune cells remain unexplored. We utilized mouse models of SLE autoimmunity and scRNAseq to delineate the mechanisms by which IRF7 in B cells drives autoimmune B cell differentiation into GC B cells and autoantibody producing antibody forming cells (AFC). Specifically, IRF7 regulates activated B cell differentiation into GC and antibody forming cell (AFC) pathways during an autoimmune response by controlling the metabolic and transcriptional program required for differentiation. These findings highlight the critical involvement of IRF7 as a primary driver of dysregulated B cell responses in systemic autoimmunity. Collectively, the findings presented in this body of work advance in our understanding of the transcriptional control of protective and autoimmune B cell responses.

Download or read book Quantitative Analysis of Influenza Virus specific B Cell Responses Generated by Infection and Vaccination written by Hye Mee Joo and published by . This book was released on 2009 with total page 140 pages. Available in PDF, EPUB and Kindle. Book excerpt: The two cellular components of B cell memory are antibody (Ab)-secreting cells (ASCs) and memory B cells (BMem). BMem are quiescent cells that respond to "recall" antigen and contribute substantially to vaccine effectiveness. The rational evaluation of vaccination strategies is dependent on quantitative information on the state of B cell memory. Despite the importance of BMem in resistance to infection, there is little information on the nature of BMem populations generated by influenza infection or vaccination. The major goal of this dissertation was a comprehensive quantitative analysis of the frequency and distribution of influenza-specific BMem generated by influenza infection of the respiratory tract, or by vaccination with inactivated virus. To achieve this, a prerequisite was the development of a sensitive and reproducible limiting dilution assay (LDA) for determining influenza-specific BMem frequencies. The results in Chapter 2 demonstrated that a strategy utilizing BPL-inactivated virus particles was effective for the in vitro activation of virus-specific BMem. This strategy selectively activates virus-specific BMem and, importantly, achieves this without a requirement for CD4+ T cell associated factors. Using this strategy, the frequency of Influenza specific BMem in different anatomical sites was measured and we also tested three different forms of influenza virus immunization strategy; (i) intranasal (i.n.) infection, (ii) i.n. vaccination, (iii) intramuscular (i.m.) vaccination. The results in Chapter III, IV showed that following different forms of immunization, BMem dispersed broadly to organized lymphoid tissues throughout the body, and a population of ASCs was established in the bone marrow. ASC and BMem frequencies in these locations reflected the magnitude of the primary B cell response to the form of immunization. Thus, the frequencies were higher following i.n. infection. Interestingly, the state of B cell memory in the lung was profoundly influenced by the form of immunization. The lung was a preferential site of BMem localization after i.n. infection. However, this was not the case after i.m. immunization when BMem frequencies in the lung were considerably lower than in other sites. Our findings point to an effect of influenza infection on the lung environment that profoundly influences ASC and BMem trafficking to this site.

Download or read book Handbook on Immunosenescence written by Tamas Fulop and published by Springer Science & Business Media. This book was released on 2009-02-27 with total page 1693 pages. Available in PDF, EPUB and Kindle. Book excerpt: This authoritative handbook covers all aspects of immunosenescence, with contributions from experts in the research and clinical areas. It examines methods and models for studying immunosenescence; genetics; mechanisms including receptors and signal transduction; clinical relevance in disease states including infections, autoimmunity, cancer, metabolic syndrome, neurodegenerative diseases, frailty and osteoporosis; and much more.

Download or read book The Functions of B 1 Cells in Health and Disease written by Hannah Pritikin Savage and published by . This book was released on 2018 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: B-1 cells are a small subset of B lymphocytes that contribute to both the maintenance of a normal, healthy state and to the immune response during infections. B-1 cells have a distinct developmental pathway, maintenance, and function compared to conventional B cells (B-2 cells). They secrete a constant level of IgM, called natural IgM, even in the absence of any microbes, which can bind to epitopes expressed by both altered host antigens and pathogens. IgM is required for the normal development of B-2 cells, as it prevents the development of auto-reactive B-2 cells. Natural IgM also contributes to early control of pathogens through its ability to bind common antigens found on many pathogens. This dissertation aims to further understand these two distinct functions performed by B-1 cells: natural IgM secretion and the response to infection. In Chapter 1, I review our current understanding of the development and function of B-1 cells and identified areas in which additional studies were needed to further our understanding. In particular, I found that the identity of major populations of natural IgM-secreting B-1 cells and their relative contributions to the pool of natural IgM-secreting cells had not been clearly demonstrated. Additionally, although a “Division of Labor” between two subsets of B-1 cells, CD5+ B-1a cells and CD5- B-1b cells has been proposed, studies on the functions of these two populations have yielded seemingly contradictory results, and so their contributions to both natural IgM and the B-1 cell response to infection remain unclear. In Chapter 2, I describe the identification of the major tissues and cellular sources of natural antibody and examined the dependence of natural antibody secreting cells on the transcriptional regulator of plasma cell differentiation, Blimp-1. My studies identified three B-1 cell populations in spleen and bone marrow contributing IgM: Blimp-1-dependent B-1 cells, Blimp-1-independent B-1 cells, and a new population, B-1-derived plasma cells (B-1PC). Furthermore, I found that the Blimp-1 independent B-1 cells in the bone marrow were able to increase their frequency of IgM antibody secreting cell formation when serum IgM was low. Taken together, my findings demonstrated that the population of natural antibody secreting cells is heterogeneous in phenotype and differentiation requirements and in their ability to respond to changes in IgM levels. Chapter 3 examines the development of the newly-identified terminally-differentiated B-1 plasma cells (B-1PC). In contrast to B-1 cells, which develop in a T-independent manner from before birth to a few weeks after birth, B-1PC development began about 3 weeks after birth and required [alpha]/[beta] CD4 T cells. Non-terminally differentiated B-1 cells increased IgM production in the absence of B-1PC such that no overall change in serum IgM was measurable, explaining previous studies that failed to show an effect of T-cell deficiency on serum IgM levels. I also identified a difference in the antigen binding capabilities of B-1 cells and B-1PC, suggesting distinct repertoires. Overall, I demonstrated that B-1PC develop over time through interactions with CD4 T cells. Their distinct developmental requirements may lead to a unique repertoire of natural IgM. Chapter 4 examines the response of CD5+ B-1a and CD5- B-1b cells to infection and the role of the B cell receptor inhibitor CD5 in their regulation. Our laboratory previously showed that CD5+ but not CD5- B-1 cells respond to influenza infection. However, others have identified CD5- B-1 cells as the main source of B-1-derived IgM after infection. Explaining these difficult to reconcile findings, I found that CD5+ B-1 cells lose CD5 expression, after TLR stimulation in vitro and in vivo in the local lymphoid tissues of mice infected with Influenza virus or with Salmonella enterica serovar Typhimurium (S. Typhimurium). Overall my data demonstrate that some CD5+ B-1a cells can become CD5- B-1b cells, and thus B-1a and B-1b cells are not two distinct populations. Taken together, this dissertation expands our understanding of the diverse subsets of B-1 cells and their functions. I demonstrate for the first time the presence of a population of B-1-derived plasma cells that contribute T-dependent IgM to the pool of natural antibodies. I also describe a population of non-differentiated B-1 cells that are adjusting IgM responses to circulating levels serum IgM. Finally, I demonstrated that CD5 expression appears to be an indicator of activation state for B-1 cells, rather than a marker of distinct subsets.

Download or read book Regulation of Macrophage mediated Immunity to Influenza Virus Infection written by François Coulombe and published by . This book was released on 2015 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: "Influenza virus infection causes a complex respiratory disease inflicting a persistent threat to human health worldwide and presenting challenges to clinicians who are left with no available therapeutic interventions. The broad complexity of the disease is the consequence of host-pathogen interactions, which may result in severe influenza- associated illness and death. Severity of influenza infections correlates with the ability of the virus to reach and replicate within the lower respiratory tract, where it encounters alveolar macrophages. These cells reside in close contact with the respiratory epithelium of the lower airways and are the first immune cells to make contact with the influenza virus. Despite evidence showing their critical role in anti-viral immunity and in the maintenance of pulmonary homeostasis, the regulatory mechanisms that drive macrophage function during severe influenza virus infection are poorly defined.The first part of the work presented herein focuses on the function of host-derived lipid mediators, known as eicosanoids, in the regulation of macrophage function during influenza virus infection. Using mice deficient in various components of the eicosanoid biosynthesis pathways, we first established that influenza virus specifically hijacks the prostaglandin E2 pathway to subvert macrophage function and suppress both innate and adaptive immune responses. We identified two distinct pathways through which prostaglandin E2 paralyzed macrophage anti-viral immunity: type I interferon and apoptosis. The impairment of these two pathways severely hinders the innate immune response as type I interferon directly counteracts viral replication, while apoptosis blocks the cellular machinery crucial for viral amplification/dissemination. In addition, we found that prostaglandin E2 suppresses adaptive immunity to influenza virus infection. Importantly, prostaglandin E2-deficient mice were more protected against influenza and pharmacological inhibition of prostaglandin E2 recapitulated this protective effect against the virus.Next, we demonstrated that mice deficient in the 5-lipoxygenase pathway showed remarkable protection against influenza infection. This protection was associated with a concomitant lack of lipoxin A4 up-regulation in infected mice, as well as early expansion of granulocyte macrophage-colony stimulating factor (GM-CSF)-secreting alveolar macrophages in the airways. GM-CSF has a well-established protective role against pulmonary viral infection and specific inhibition of GM-CSF in 5-lipoxygenase deficient mice abrogated their protection against influenza.The second part of this thesis focuses on the consequences of macrophage death modality during the course of influenza virus infection. While host-induced apoptosis of infected cells is a mechanism to restrict viral replication, influenza virus paradoxically has been shown to induce early apoptosis in immune cells, especially in monocytes/macrophages, via its PB1-F2 accessory protein. Here, we demonstrate that the host NLRX1 receptor can effectively interact with the influenza virus pro-apoptotic protein PB1-F2 in macrophage mitochondria, thereby preventing PB1-F2-induced apoptosis and leading to increased type I interferon production by macrophages. The interaction between host NLRX1 and viral PB1-F2 in macrophages was furthermore critical for the control of influenza virus replication.Taken together, our results suggest that eicosanoids and apoptosis act in concert as critical regulators of macrophage-mediated immunity against severe influenza virus infection. We propose that macrophages act as the cellular switch initiating the pulmonary anti-viral responses by monitoring the balance between virus-triggered or host-triggered production of eicosanoids and induction of apoptosis. We further envision that immunotherapies targeting specific eicosanoids offer promising avenues for treatment of influenza and potentially other viral infections." --

Download or read book Immunology and Evolution of Infectious Disease written by Steven A. Frank and published by Princeton University Press. This book was released on 2002-07-21 with total page 364 pages. Available in PDF, EPUB and Kindle. Book excerpt: Publisher Description

Download or read book Influenza Pathogenesis and Control Volume II written by Michael B. A. Oldstone and published by Springer. This book was released on 2014-11-06 with total page 478 pages. Available in PDF, EPUB and Kindle. Book excerpt: This two-volume work covers the molecular and cell biology, genetics and evolution of influenza viruses, the pathogenesis of infection, resultant host innate and adaptive immune response, prevention of infection through vaccination and approaches to the therapeutic control of infection.. Experts at the forefront of these areas provide critical assessments with regard to influenza virology, immunology, cell and molecular biology, and pathogenesis. Volume I provides overviews of the latest findings on molecular determinants of viral pathogenicity, virus entry and cell tropism, pandemic risk assessment, transmission and pathogenesis in animal species, viral evolution, ecology and antigenic variation, while Volume II focuses on the role of innate and adaptive immunity in pathogenesis, development of vaccines and antivirals.