Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) mediated by autoreactive T cells specific for myelin proteins. A recent development in MS treatment is the discovery that B cell depletion with Rituximab reduced the numbers of lesions and new relapses in MS patients. The role of B cells has been studied in the animal model of MS, experimental autoimmune encephalomyelitis (EAE), but results from these studies have been variable and contradictory, and the contribution of B cells to CNS autoimmune disease is still unclear. We examined the role of B cells in C3H mice and found that both C3HeB/Fej and C3H.SW [omega]MT mice had a reduced incidence of EAE, suggesting an important role for B cells in the initiation of disease. B cells were the predominant MHC class II+ cells in the healthy CNS and were able to secrete cytokines, indicating that they could be influencing T cell responses before inflammation is initiated. Myelin-specific T cells were able to migrate to the CNS in the absence of B cells, but were unable to initiate immune responses. The ability of the early infiltrating T cells to secrete cytokines and initiate the recruitment of additional T cells to the CNS from the periphery before onset of EAE was defective in B cell deficient mice. Recruitment of T cells from the periphery constituted the majority of the increase in T cell number in the CNS of wildtype mice prior to onset. In vitro, B cells preferentially reactivated effector Th1 cells and not Th17 cells in the absence of IL-1[beta]. Induction of EAE with Th1- or Th17-skewed cells led to reduced numbers of IFN-[gamma]- and IL-17-producing cells in the brains of B cell deficient mice after onset of EAE. However, there was a greater effect on the numbers of IFN-[gamma]-producing cells, and in B cell deficient recipients of Th1-skewed cells, the localization of inflammation changed to permit inflammation in the brain. These studies indicate that B cells are important for T cell responses in the initiation of CNS autoimmunity, and can influence the localization of inflammation in EAE.

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.

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 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.

Central nervous system (CNS) inflammation results in the accumulation of various B cell subsets, including naive, activated, memory B cells (Bmem), and antibody secreting cells (ASC). While ASC are well studied, signals driving recruitment of B cells, their relationship to peripheral activation, and role within the CNS remain largely unknown. Using the murine neurotropic coronavirus JHMV infection model, our studies established a critical role for draining lymph node germinal center formation in driving accumulation of isotype-switched ASC/Bmem in the CNS. Divergent accumulation of isotype-unswitched B cells to perivascular/meningeal space and isotype-switched B cells to the CNS parenchyma indicated B cell differentiation state regulates localization. Multiple lymphoid chemokines guiding B cell migration are induced following CNS infection. Differing chemokine receptor expression profiles on infiltrating B cell subsets implied receptors in combination or alone regulate their migration to and within the CNS. Interestingly, B cell accumulation occurred independent of ectopic follicles during JHMV infection. A sustained CD4 T cell "helped" phenotype during both JHMV infection and autoimmune mediated inflammation indicated B cell activation in the CNS occurred independent of follicle formation. Moreover, isotype-switched B cell accumulation and activation was unaltered in the absence of CXCL13, a chemokine critical in organizing follicles. CD4 T cells supported isotype-unswitched B cell CNS accumulation, indicating a role in facilitating B cell survival and undefined effector functions in the CNS. The identification of virus-specific Bmem during persistent JHMV infection implied Bmem contribute to local Ab production. In contrast, early accumulating B cells were not virus specific, implying non-specific bystander recruitment and functions not related to antigen presentation. Nonetheless, the recruitment of isotype-unswitched B cells in multiple CNS inflammation models suggests an important, yet to be defined role in the inflamed CNS.

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 nervous system plays an important role in the regulation of immunity and inflammation. On the other hand unbalanced immune responses in inflammatory and autoimmune conditions may have a deleterious impact on neuronal integrity and brain function. Recent studies have characterized neural pathways communicating peripheral inflammatory signals to the CNS, and brain- and spinal cord-derived circuitries controlling various innate and adaptive immune responses and inflammation. A prototypical neural reflex circuit that regulates immunity and inflammation is the vagus nerve-based “inflammatory reflex”. Ongoing research has revealed cellular and molecular mechanisms underlying these neural circuits and indicated new therapeutic approaches in inflammatory and autoimmune disorders. Pharmacological and bioelectronic modulation of neural circuitry has been successfully explored in preclinical settings of sepsis, arthritis, inflammatory bowel disease, obesity-driven disorders, diabetes and other diseases. These studies paved the way to successful clinical trials with bioelectronic neuronal modulation in rheumatoid arthritis and inflammatory bowel disease. Dysregulated release of cytokines and other inflammatory molecules may have a severe impact on brain function. Brain inflammation (neuroinflammation), imbalances in brain neuronal integrity and neurotransmitter systems, and cognitive impairment are characteristic features of post-operative conditions, sepsis, liver diseases, diabetes and other disorders characterized by immune and metabolic dysregulation. Derangements in cytokine release also play a pivotal role in depression. Characteristic brain reactive antibodies in autoimmune conditions, including systemic lupus erythematosus and neuromyelitis optica, significantly contribute to brain pathology and cognitive impairment. These studies, and the simultaneous characterization of neuro-protective cytokines, identified new therapeutic approaches for treating neurological complications in inflammatory and autoimmune disorders. This Frontiers Research Topic is a forum for publishing research findings and methodological and conceptual advances at the intersection of immunology and neuroscience. We hope that presenting new insight into bi-directional neuro-immune communication in inflammation and autoimmunity will foster further collaborations and facilitate the development of new efficient therapeutic strategies.

Inflammation of the CNS can have devastating, long-lived, and in some cases fatal consequences for patients. The stimuli that can induce CNS inflammation are diverse, and include infectious agents, autoimmune responses against CNS-expressed antigens, and sterile inflammation following ischemia or traumatic injury. In these conditions, cells of the immune system play central roles in promulgation and resolution of the inflammatory response. However, the immunological mechanisms at work in these diverse responses differ according to the nature of the response. Our understanding of the actions of immune cells in the CNS has been restricted by the difficulty in visualising leukocytes as they undergo recruitment from the cerebral microvasculature and following their entry into the CNS parenchyma. However, advances in in vivo microscopy over the last 10-15 years have overcome many of these difficulties, and studies using these forms of microscopy have revealed a wealth of new information regarding the cellular and molecular mechanisms of CNS inflammation. This Research Topic brings together state of the art reviews examining the use of in vivo imaging in investigating inflammation and leukocyte behaviour in the CNS. Papers in this Research Topic describe how in vivo microscopy has increased our understanding of the actions of immune cells in the inflamed CNS, following various stimuli including autoimmunity, infection and sterile inflammation.