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.

Multiple B cell subsets with phenotypes characteristic of naive, non-isotype-switched, memory (Bmem), and antibody-secreting cells (ASC), accumulate in various models of central nervous system (CNS) inflammation. However, how peripheral activation events, including germinal center (GC) formation, contribute to the dynamics of humoral immune responses in the inflamed CNS is poorly delineated. To address the role of GC formation in driving CNS humoral responses we are using a well-established model of mouse hepatitis virus (MHV) encephalomyelitis. Following MHV-induced CNS infection, T and B cell responses are initiated in cervical lymph nodes and local CNS antibody (Ab) production is crucial for control of viral persistence following initial T cell-mediated immune control. Our overall hypothesis is that antigen (Ag)-driven, peripheral GC formation is critical for development of Ag-specific B cells, as well as accumulation and maintenance in the inflamed CNS following MHV-induced encephalomyelitis. The findings of this thesis strongly support that GC reactions are critical for imprinting migration of virus-specific B cells, particularly ASC, to the CNS. They further imply that accumulation of ASC and Bmem is differentially regulated, with early GC reactions supporting preferential Bmem egress and accumulation in the CNS, and late GC reactions preferentially mediating ASC migration to the CNS during viral persistence. Our studies also do not provide any evidence for local de novo synthesis of Ag-specific B cells in the CNS, or local conversion of Bmem to ASC. Moreover, the results demonstrate that the survival factor APRIL, which maintains long-lived ASC in the bone marrow, is also important in maintaining virus-specific ASC in the CNS during MHV infection.

The microcirculation is highly responsive to, and a vital participant in, the inflammatory response. All segments of the microvasculature (arterioles, capillaries, and venules) exhibit characteristic phenotypic changes during inflammation that appear to be directed toward enhancing the delivery of inflammatory cells to the injured/infected tissue, isolating the region from healthy tissue and the systemic circulation, and setting the stage for tissue repair and regeneration. The best characterized responses of the microcirculation to inflammation include impaired vasomotor function, reduced capillary perfusion, adhesion of leukocytes and platelets, activation of the coagulation cascade, and enhanced thrombosis, increased vascular permeability, and an increase in the rate of proliferation of blood and lymphatic vessels. A variety of cells that normally circulate in blood (leukocytes, platelets) or reside within the vessel wall (endothelial cells, pericytes) or in the perivascular space (mast cells, macrophages) are activated in response to inflammation. The activation products and chemical mediators released from these cells act through different well-characterized signaling pathways to induce the phenotypic changes in microvessel function that accompany inflammation. Drugs that target a specific microvascular response to inflammation, such as leukocyte-endothelial cell adhesion or angiogenesis, have shown promise in both the preclinical and clinical studies of inflammatory disease. Future research efforts in this area will likely identify new avenues for therapeutic intervention in inflammation. Table of Contents: Introduction / Historical Perspectives / Anatomical Considerations / Impaired Vasomotor Responses / Capillary Perfusion / Angiogenesis / Leukocyte-Endothelial Cell Adhesion / Platelet-Vessel Wall Interactions / Coagulation and Thrombosis / Endothelial Barrier Dysfunction / Epilogue / References

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.

Increasing scientific evidence suggests that the majority of diseases including cancer are driven by oxidative stress and inflammation, attributed to environmental factors. These factors either drive genetic mutations or epigenetically modify expression of key regulatory genes. These changes can occur as early as gestational fetal development, and

Arrest chemokines are a small group of chemokines that promote leukocyte arrest from rolling by triggering rapid integrin activation. Arrest chemokines have been described for neutrophils, monocytes, eosinophils, naïve lymphocytes and effector memory T cells. Most arrest chemokines are immobilized on the endothelial surface by binding to heparin sulfate proteoglycans. Whether soluble chemokines can promote integrin activation and arrest is controversial (Alon-Gerszten). Many aspects of the signaling pathway from the GPCR chemokine receptor to integrin activation are the subject of active investigation. Leukocyte adhesion deficiency III is a human disease in which chemokine-triggered integrin activation is defective because of a mutation in the cytoskeletal protein kindlin-3. About 10 different such mutations have been described. The defects seen in patients with LAD-III elucidate the importance of rapid integrin activation for host defense in humans. We welcome reports that help clarifying this crucial first step in the process of leukocyte transendothelial migration.

Methods in Toxicology, Volume 2: Mitochondrial Dysfunction provides a source of methods, techniques, and experimental approaches for studying the role of abnormal mitochondrial function in cell injury. The book discusses the methods for the preparation and basic functional assessment of mitochondria from liver, kidney, muscle, and brain; the methods for assessing mitochondrial dysfunction in vivo and in intact organs; and the structural aspects of mitochondrial dysfunction are addressed. The text also describes chemical detoxification and metabolism as well as specific metabolic reactions that are especially important targets or indicators of damage. The methods for measurement of alterations in fatty acid and phospholipid metabolism and for the analysis and manipulation of oxidative injury and antioxidant systems are also considered. The book further tackles additional methods on mitochondrial energetics and transport processes; approaches for assessing impaired function of mitochondria; and genetic and developmental aspects of mitochondrial disease and toxicology. The text also looks into mitochondrial DNA synthesis, covalent binding to mitochondrial DNA, DNA repair, and mitochondrial dysfunction in the context of developing individuals and cellular differentiation. Microbiologists, toxicologists, biochemists, and molecular pharmacologists will find the book invaluable.

Liver Immunology: Principles and Practice, Second Edition begins with important information about the epidemiology and mortality of liver disease worldwide. This information is followed by chapters related to basic immunology, application of liver immunology for diagnosis, and several excellent chapters that provide a solid foundation for understanding immune-mediated liver disease, including those associated with the biliary tree. A chapter on non-hepatic manifestations of immune mediated liver disease helps provide context for how these diseases affect the patient overall. In addition, chapters discuss various discrete immunologically-mediated infectious liver disorders including those related to bacteria, parasites, and all of the classic viruses. Chapters on the traditional autoimmune liver diseases -- primary biliary cirrhosis, autoimmune hepatitis, primary sclerosing cholangitis as well as overlap syndrome – are also included. The breadth of this comprehensive second edition is highlighted by chapters on alcoholic liver disease, non-alcoholic fatty liver disease, and drug-induced liver disease, among others. This invaluable new edition ends with a forward-looking view of future directions and how the field might meet the challenge of refractory patients. Developed by a renowned group of authors, Liver Immunology: Principles and Practice, Second Edition will again serve as a comprehensive textbook by providing an excellent overview for this rapidly evolving field. It greatly adds to the understanding of the pathogenesis of these diseases, while also providing novel insights that can be harnessed into helping improve the care of patients afflicted with various immune-mediated diseases. This volume will again be a must-read for clinicians at all levels, investigators and students.