Alterations in B cell homeostasis drive pathogenesis of various immune mediated diseases. Breaks in peripheral tolerance allow autoreactive B cells to differentiate in to pathogenic auto-antibody secreting cells. B cells themselves may directly drive pathogenesis through antigen-presentation capabilities and secretion of pro-fibrotic factors. Lastly, the inability of B cells to mount effective responses against pathogens may trigger subsequent inflammatory or autoimmune reactions. In this work, we dissect various ways in which B cells contribute to pathogenesis of inflammatory disease by evaluating their role in three different immune mediated diseases. In chapter 2 we identify a potential regulatory role for B cells in the context of Systemic Lupus Erythematosus (SLE), an autoimmune disease characterized by the pathogenic secretion of anti-nuclear antibodies. We found that CD52 is a B cell regulatory glycoprotein elevated on the surface of B cells in patients and acts to suppress B cell hyperactivity both through its surface expression and through the secretion of a soluble form that can bind receptor Siglec-10. In chapter 3 we describe a population of B cells that is significantly expanded in IgG4-RD, a fibroinflammatory condition characterized by infiltration of IgG4+ plasma cells into tumefactive lesions and the development of storiform fibrosis. The expanded population of B cells was CD21-- and CXCR5+, expressing high levels of pathogenic B cell marker CD11c. Moreover, the frequency of this expanded population correlated with clinical parameters such as IgG4 titers. We observed a tremendous elevation of CXCL13, the ligand for CXCR5, strongly implicating the CXCR5-CXCL13 axis in recruiting B cells to affected tissue, making it a viable therapeutic target. Lastly, in chapter 4 we performed high-dimensional sequencing on B cells from sarcoidosis patients, a disease characterized by spontaneous granuloma formation. Although B cells have not been directly implicated in the inflammation, we observed a less diverse and less mutated B cell receptor repertoire; together, our findings point to the initiation of sarcoidosis after ineffective antibody mediated clearance of pathogen from affected organs. In total, this work sheds novel insights on the role of B cells-- from the initial stages of activation and germinal center recruitment, to the development of a diverse antibody repertoire-- in the context of poorly understood immune mediated conditions and contributes important knowledge for the advancement of better treatments for affected patients.

B cells play a central role not only in adaptive immunity, but also in autoimmunity. To understand how B cells are normally prevented from reacting to self-tissue, what goes wrong in autoimmunity, and how B cells contribute to it is the aim of this book. This volume includes more than a dozen in-depth reviews by researchers specializing in various aspects of basic B cell biology that have relevance to autoimmune diseases. These up-to-date chapters present the latest information on B cell signal transduction, apoptosis, genetics and molecular biology. Also featured are chapters with special reference to particular autoimmune diseases in which B cells have been shown to play a critical role, such as type 1 diabetes, chronic graft-versus-host disease and lupus erythematosus. Further topics covered include the role of the complement system, rheumatoid factors, and anti-DNA autoantibodies as well as important related areas such as natural autoantibodies, B cell immune tolerance, Toll receptor signaling, and the immunobiology of BAFF/BLyS. Both basic researchers and clinician scientists who wish to understand the role of B lymphocytes in immune tolerance and autoimmunity will benefit from this timely publication.

The understanding of B cell biology has increased and expanded enormously in the last three decades. It is now known that B cells, in addition to just differentiating into antibody-secreting cells, serve many other vital functions. For example, their roles as antigen-presenting cells and cytokine-producing cells as well as effector cells and regulatory cells are well appreciated now. Indeed, the pathologic role of B cells in many autoimmune disorders may be largely autoantibody-independent. Today, the B cell is of considerable interest not only to immunologists but also to mainstream clinicians and scientists. The current volume covers the latest information on the functions of B cells in normal and disease states, and their therapeutic antagonism. Chapters cover cutting-edge topics from the basic to the clinical, including B cells in infection and autoimmunity, CD19-CD21 signal transduction complex, marginal zone B cell physiology and disease, B cell growth and differentiation, their role in rheumatoid arthritis, SLE treatment, the BAFF/APRIL system and B lymphocyte malignancies. This book is recommended reading for cellular and molecular immunologists as well as for rheumatologists, hematologists and clinical immunologists, and all those interested in human diseases in which B cells play an important contributory role.

This book contains twelve chapters contributed by prestigious international experts who are at the forefront of B cell research, and aims to provide a cutting-edge and comprehensive overview of all aspects of B cells, including B cell development, maturation and activation, germinal center reaction, memory and plasma cell differentiation, and antibody-mediated positive and negative regulation of humoral immune responses. There are also three chapters describing human diseases caused by B cell abnormalities, including primary antibody deficiencies, autoimmune diseases, and B cell malignancies. We hope that this book will become a standard and routine reference for both basic researchers and clinicians.

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.

This volume details our current understanding of the architecture and signaling capabilities of the B cell antigen receptor (BCR) in health and disease. The first chapters review new insights into the assembly of BCR components and their organization on the cell surface. Subsequent contributions focus on the molecular interactions that connect the BCR with major intracellular signaling pathways such as Ca2+ mobilization, membrane phospholipid metabolism, nuclear translocation of NF-kB or the activation of Bruton’s Tyrosine Kinase and MAP kinases. These elements orchestrate cytoplasmic and nuclear responses as well as cytoskeleton dynamics for antigen internalization. Furthermore, a key mechanism of how B cells remember their cognate antigen is discussed in detail. Altogether, the discoveries presented provide a better understanding of B cell biology and help to explain some B cell-mediated pathogenicities, like autoimmune phenomena or the formation of B cell tumors, while also paving the way for eventually combating these diseases.

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.

Molecular Biology of B Cells, Second Edition is a comprehensive reference to how B cells are generated, selected, activated and engaged in antibody production. All of these developmental and stimulatory processes are described in molecular, immunological, and genetic terms to give a clear understanding of complex phenotypes. Molecular Biology of B Cells, Second Edition offers an integrated view of all aspects of B cells to produce a normal immune response as a constant, and the molecular basis of numerous diseases due to B cell abnormality. The new edition continues its success with updated research on microRNAs in B cell development and immunity, new developments in understanding lymphoma biology, and therapeutic targeting of B cells for clinical application. With updated research and continued comprehensive coverage of all aspects of B cell biology, Molecular Biology of B Cells, Second Edition is the definitive resource, vital for researchers across molecular biology, immunology and genetics. - Covers signaling mechanisms regulating B cell differentiation - Provides information on the development of therapeutics using monoclonal antibodies and clinical application of Ab - Contains studies on B cell tumors from various stages of B lymphocytes - Offers an integrated view of all aspects of B cells to produce a normal immune response