Mechanisms of Lymphocyte Activation and Immune Regulation X: Innate Immunity is the proceedings of the Xth International Conference on Mechanisms of Lymphocyte Activation and Immune Regulation: Innate Immunity, held February 6-8, 2004 in Newport Beach, California. It is the tenth volume of its kind to appear in the series Advances in Experimental Medicine and Biology. Topics include toll receptors, dendritic cells, NK cells, and complement receptors.

During the past five years major progress has been made in understanding the basic mechanisms of lymphocyte homeostasis and in the developmental relationship between different memory T subsets and their traffic patterns and functional significance. This volume highlights the current concepts of lymphocyte development, factors regulating lymphocyte trafficking and development, and specialized characteristics and functional properties of naive and memory subsets. This volume is divided into three sections. Section I deals with factors that regulate the development and maturation of T cells and B cells and lymphocyte traffic. The significance of C-kit, Bcl-6, IL-7, and Vav in the development of T and B lymphocytes is discussed. A role of lymphotoxins and VAP-I in trafficking of leucocytes is reviewed. Finally, the trafficking and homing characteristics of T cell and B cell subsets, and the regulation of these processes during the immune response, is presented. Section II discusses various aspects of naive and memory T cell biology, including clonal expansion, reprogramming of genes including those encoding cytokines and cytotoxic granules, changes in the expression of cell surface proteins involved in cell-cell adhesion, homing of naive and memory T cells, the role of MHC and cytokines in the maintenance of naive and memory T cells, and the characterization and differentiation of virus-specific memory T cell heterogeneity in mice and humans. Novel methods of visualization of immune cells and immune systems are reviewed in Section III. This includes tracking of dendritic cells in vivo, monitoring arterial smooth muscle-specific T cells in the inflamed vasculature, imaging of molecular migrations in immune synapses, and visualization of various immune cells in intact lymphoid tissues by two photon confocal imaging. This volume should be of interest to immunologists, molecular biologists, microbiologists, pathologists, academic physicians, cell bio

Signaling through antigen receptor initiates a complex series of events resulting in the activation of genes that regulate the development, proliferation and differentiation of lymphocytes. During the past few years, rapid progress has been made in understanding the molecular basis of signaling pathways mediated by antigen and cytokine receptors. These pathways involve protein tyrosine kinases which are coupled to downstream regulatory molecules, including small guanine nucleotide binding proteins (e. g. p21'OS), serine threonine kinases (e. g. , members of the ERK family), and a large group of transcription factors. More recently, there have been breakthroughs in elucidating the genetic defects underlying three X-linked primary immunodeficiency diseases in humans. This volume surveys aspects of these rapidly developing areas of research. The book is divided into 5 different sections. Section I deals with signaling pathways in B lymphocytes. It includes a contemporary assessment of B cell antigen receptor structures, and discussion of the role of Ig-a/lg-B polypeptides in linking the antigen receptor to intracellular signal transduction pathways. The role of accessory molecules in the regulation of signaling by the B cell antigen receptor is also considered. Section II adopts a similar approach to the analysis of the antigen receptor on T lymphocytes. The importance of specialized signaling motifs in the CD3 polypeptides, mechanisms whereby these motifs may interact with the lymphocyte-specific protein tyrosine kinases, and the downstream consequences of these interactions are reviewed. In addition, the role of antigen-induced apoptosis in the generation of immunological tolerance is discussed.

Since programmed cell death was first described in insects in 1964 and apoptosis was described in 1972, rapid progress has been made in understanding the basic mechanisms and genes regulating programmed cell death and apoptosis. In addition, defects in various genes regulating programmed cell death have been delineated in several experimental models of human diseases. This volume surveys various aspects of these rapidly developing areas of research in programmed cell death/apoptosis. This volume should be of interest to basic immunologists and molecular biologists. The volume begins with a historical perspective of cell death. The remainder of the volume is divided into four different parts. Part I deals with the signaling pathways in apoptosis, including cell cycle control of apoptosis, role of ceramide in apoptosis, role of antibody signaling, and biochemical regulation of apoptosis. The mechanisms for recognition of apoptotic lymphocytes by macrophages are also reviewed. Part II examines the role of various genes that regulate apoptosis, including the role ofFas, FasL, and other TNF family members in apoptosis and homeostatic regulation of immune response. Recently described splice variants and their influence on apoptosis are also reviewed, and the role of the members of the Bcl-2 family in apoptosis is discussed in detail. Part III reviews various aspects of apoptosis in B lymphocytes, including mechanisms that regulate apoptosis/survival of B lymphocytes and the regulation of Fas-mediated apoptosis in B lymphocytes.

Advances in biochemistry, cell biology, genome-wide mutagenesis - coupled with molecular technology, including gene microarray and transgenic and knock-out animals - have been instrumental in understanding the cellular processes and molecular pathways of self-tolerance and autoimmune diseases. The molecular definition of these pathways and processes has led to novel treatments for certain auto-immune diseases that are based on the pathogenesis of diseases rather than on broad-spectrum immunosuppression. This book reviews many of these current developments and proposes future novel approaches for understanding the pathogenesis of auto-immune diseases and designing novel therapy. This book covers three major areas of auto-immunity: the basic mechanisms of immunological tolerance, pathogenesis of auto-immune diseases, and some novel therapies. This book should be useful for immunologists, molecular biologists, rheumatologists, and clinical scientists.

Innate Defense Mechanisms: Development of Self-Recognition Systems in Natural Killer Cells; P.V. Sivakumar, et al. Activating and Inhibitory NK Cell Receptors; L.L. Lanier. Regulation of Immune Responses by Inhibitory Receptors; E.O. Long. Effector Choice: Interleukin-4 Receptor Signaling Mechanisms and Their Biological Significance; K. Nelms, et al. Development of CD4 + Effector T Cells and Susceptibility to Infectious Diseases; R.M. Locksley, et al. Regulation of Host Resistance to Intracellular Pathogens: Interleukin-4 Production in Response to Infection with Intracellular Bacteria; H. Collins, et al. Cytotoxic T Lymphocytes in Resistance to Tuberculosis; R.J. Mazzaccaro, et al. Immunopathogenesis of HIV-1 Infection: HIV Entry and Tropism: When One Receptor is Not Enough; E.A. Berger. Immune Control of HIV-1 Replication; B.D. Walker, et al. New Approaches to Vaccine Development: Non-Structural Determinants of Immunogenecity and the B Cell Co-Receptors, CD19, CD21, and CD22; D.T. Fearon. DNA Vaccines: Mechanisms for Generation of Immune Responses; M.A. Liu, et al. 12 Additional Chapters. Index.

Leading experts provide the only comprehensive book examining all aspects of immune response and immune-based treatments for HIV infection. Contributions, divided into three sections, discuss basic mechanisms, immunopathogenesis of HIV infection, and immune-based therapies. Researchers thoroughly review vaccine-including prospects of T cell vaccine-and gene therapy for HIV infection. Additional topics include organization of HIV genes, the role of co-receptors in signaling of lymphocytes, and biological response modifiers. This reference is designed for basic and clinical researchers, internists, pediatricians, infectious disease specialists, neuropathologists, oncologists, and rheumatologists.

In recent years, major developments have increased understanding of various genetic and epigenetic regulatory processes that are critical for the generation of B cell repertoires. These include the role of chromatin regulation and nuclear organization in understating the IgH gene regulation. These proceedings highlight recent developments in lymphocyte development, Ig gene rearrangements and somatic hypermutation, chromatin structure modification, B lymphocyte signaling and fate, receptor editing, and autoimmunity.

Section I: T Cell Receptors and T Cell Activation.- T Cell Receptor Structure and Function: Analysis by Expression of Portions of Isolated Subunits.- The T Cell Antigen Receptor Tyrosine Kinase Pathway.- Dissection of the Hb(64-76) Determinant Reveals That the T Cell Receptor May Have the Capacity to Differentially Signal.- CD28 Receptor Crosslinking Induces Tyrosine Phosphorylation of PLC?1.- Structure and Function of CD45: A Leukocyte-Specific Protein Tyrosine Phosphatase.- Multidrug Resistant Gene 1 Product in Human T Cell Subsets: Role of Protein Kinase C Isoforms and Regulation by Cyclosporin A.- Integrins, T Cells, and Autoimmunity.- The Interleukin-2 Receptor: A Target for Immunotherapy.- Section II: T Cell Development.- Lymphocyte Development in Mice Deficient for MHC Class I Expression.- Generation of Mutant Mice Lacking Surface Expression of CD4 or CD8 Gene Targeting.- Alteration of T Cell Lineage Commitment by Expression of a Hybrid CD8/CD4 Transgene.- Differential Involvement of Protein Tyrosine Kinases p56lck and p59fyn in T Cell Development.- Mechanism of Tolerance Induction.- Section III: B Cell Development, Activation, Proliferation, And Differentiation.- B-Lymphocyte Lineage-Committed, IL-7 and Stroma Cell-Reactive Progenitors and Precursors, and Their Differentiation to B Cells.- Regulatory Cells and Cytokines Involved in Primary B Lymphocyte Production.- The Role of IL-7 and Its Receptor in B-Cell Ontogeny.- Role of Contact and Soluble Factors in the Growth and Differentiation of B Cells by Helper T Cell.- B-Cell Activation Mediated by Interactions with Membranes from Helper T Cells.- The Low Affinity IgE Fc Receptor (CD23) Participates in B Cell Activation.- Section IV: Adhesion Molecules: Structure, Regulation and Functions.- T Cell Adhesion Cascades: General Considerations and Illustration with CD31.- Analyses of VLA-4 Structure and Function.- On the Regulation of ?2 Integrins.- Leukocyte-Endothelial Cell Adhesion as an Active, Multi-Step Process: A Combinatorial Mechanism for Specificity and Diversity in Leukocyte Targeting.- Contributors.

Leading experts provide the only comprehensive book examining all aspects of immune response and immune-based treatments for HIV infection. Contributions, divided into three sections, discuss basic mechanisms, immunopathogenesis of HIV infection, and immune-based therapies. Researchers thoroughly review vaccine-including prospects of T cell vaccine-and gene therapy for HIV infection. Additional topics include organization of HIV genes, the role of co-receptors in signaling of lymphocytes, and biological response modifiers. This reference is designed for basic and clinical researchers, internists, pediatricians, infectious disease specialists, neuropathologists, oncologists, and rheumatologists.

Signaling through antigen receptor initiates a complex series of events resulting in the activation of genes that regulate the development, proliferation and differentiation of lymphocytes. During the past few years, rapid progress has been made in understanding the molecular basis of signaling pathways mediated by antigen and cytokine receptors. These pathways involve protein tyrosine kinases which are coupled to downstream regulatory molecules, including small guanine nucleotide binding proteins (e. g. p21'OS), serine threonine kinases (e. g. , members of the ERK family), and a large group of transcription factors. More recently, there have been breakthroughs in elucidating the genetic defects underlying three X-linked primary immunodeficiency diseases in humans. This volume surveys aspects of these rapidly developing areas of research. The book is divided into 5 different sections. Section I deals with signaling pathways in B lymphocytes. It includes a contemporary assessment of B cell antigen receptor structures, and discussion of the role of Ig-a/lg-B polypeptides in linking the antigen receptor to intracellular signal transduction pathways. The role of accessory molecules in the regulation of signaling by the B cell antigen receptor is also considered. Section II adopts a similar approach to the analysis of the antigen receptor on T lymphocytes. The importance of specialized signaling motifs in the CD3 polypeptides, mechanisms whereby these motifs may interact with the lymphocyte-specific protein tyrosine kinases, and the downstream consequences of these interactions are reviewed. In addition, the role of antigen-induced apoptosis in the generation of immunological tolerance is discussed.

Since programmed cell death was first described in insects in 1964 and apoptosis was described in 1972, rapid progress has been made in understanding the basic mechanisms and genes regulating programmed cell death and apoptosis. In addition, defects in various genes regulating programmed cell death have been delineated in several experimental models of human diseases. This volume surveys various aspects of these rapidly developing areas of research in programmed cell death/apoptosis. This volume should be of interest to basic immunologists and molecular biologists. The volume begins with a historical perspective of cell death. The remainder of the volume is divided into four different parts. Part I deals with the signaling pathways in apoptosis, including cell cycle control of apoptosis, role of ceramide in apoptosis, role of antibody signaling, and biochemical regulation of apoptosis. The mechanisms for recognition of apoptotic lymphocytes by macrophages are also reviewed. Part II examines the role of various genes that regulate apoptosis, including the role ofFas, FasL, and other TNF family members in apoptosis and homeostatic regulation of immune response. Recently described splice variants and their influence on apoptosis are also reviewed, and the role of the members of the Bcl-2 family in apoptosis is discussed in detail. Part III reviews various aspects of apoptosis in B lymphocytes, including mechanisms that regulate apoptosis/survival of B lymphocytes and the regulation of Fas-mediated apoptosis in B lymphocytes.

Impressive progress has been made in the general field of immunology which has made possible new understanding and pragmatic approaches to the patient with allergic disease. Indeed, one working in the field of immunology senses a major revolution of immunobiologic thinking, much of which has relevance to the clinical practice of allergy. To the practicing allergist, pediatrician, or internist who must deal with allergic patients, the surging new information may seem confusing and bewildering. As part of our comprehensive series on modern immunobiology which aims to digest this progress, we believe it is appropriate to devote an entire volume to the fundamental principles, new knowledge, and clinical lore on which the modern practice of allergy must be based. In the present volume we strive to bring together relevant contributions from leaders in the field of immunobiology with those whose work stands at the forefront of clinical practice. The advancing understanding has in numerous instances reached the point of clinical application, and we have tried to encompass in this volume the entire scope of modern allergy.

This is the proceedings of the International Conference on AIDS Associated Syndromes held at Irvine on December 7-8, 1984. The purpose of this conference was to bring together investigators who are actively engaged in AIDS research to present their most recent data with regard to etiological agent(s) of AIDS, immunological characteristics of some of the patients in early stages of AIDS and various therapeutical modalities that are available for the treatment of AIDS, early AIDS (persistent generalized lymphadnopathy) or for those who demonstrate asymptomatic acquired immunodeficiency. In the area of etiological agents, the discussions are presented dealing with the questions of whether HTLV III/LAV alone or with other co-factor(s) like EBV or CMV are responsible for AIDS. What is the relationship of these viruses to Kaposi's sarcoma, since Kaposi's sarcoma in AIDS cannot be simply explained on the basis of the underlying immune deficiency? Data are presented for HTLV III/LAV interactions with the T4 molecule on the surface of helper T cells. A paper is presented with epidemiologicai evidence for AIDS being an African disease which perhaps was brought to the United States and then to Haiti."

In recent years rapid progress has been made in the areas of T cell and B cell biology, cell-cell and cell-matrix/stroma interactions. The use of isolated subunits of the T cell receptor invariant chains has been instrumental in defining their role in signal transduction and tyrosine phosphorylation. A role of src family phosphotyrosine kinases in T cell activation has been demonstrated and several phosphotyrosine kinase substrates have been identified and their functions characterized. Homologous recombinant techniques have led to the development of murine strains that lack CD4 or CD8 expression. These models are likely to be instrumental in studying the role of T cell subsets in autoimmune disorders, tissue transplant rejection and tumor rejection. A role of major histocompatibility complex I in the development of T cell subsets and NK cells has been defined. Recent data suggest a role of interaction between plasma membrane molecules of activated T helper cells and B cells, B cells primed with plasma membrane of activated T helper cells and cytokines, and interaction between bone marrow stromal cells and B cell progenitors and precursors, in the B cell development, proliferation, and differentiation. The structure and functions of adhesion molecules, especially with regard to signal transduction and homing events, are better defined.

During the last decade, rapid progress has been made in the area of microbial immu- nity. New conceptual frameworks have emerged with regard to the processing and presen- tation of peptides and nonpeptide antigens from microbes, especially bacteria, to T cells in the context of classical MHC class I and nonconventional MHC I molecules. Experimen- tal models have been instrumental in defining some of these pathways for generating pro- tective immune responses against microbes, which form the basis for the design of new vaccines. New evidence has stressed the importance of innate immunity in microbial in- fections. The concept of dichotomy within T helper cells has revealed the role of these cell types in resistance and susceptibility to microbial-mediated pathology. These latest devel- opments in microbial immunity are discussed in this volume. Natural killer cell development is known to be regulated by the presence of MHC class I antigens. Receptors for MHC class I molecules on NK cells have been discovered. Interaction of these receptors with their specific ligands leads to inhibition of cytotoxicity. Vinay Kumar and colleagues review NK cell differentiation and ontogeny, and functions of NK cells in experimental animals. Lewis Lanier discusses the role of a newly discov- ered molecule, DAP 12, in KIR and other receptor-mediated signal transduction in NK cells. Eric Long describes the regulation of immune response by inhibitory receptors.

Advances in biochemistry, cell biology, genome-wide mutagenesis - coupled with molecular technology, including gene microarray and transgenic and knock-out animals - have been instrumental in understanding the cellular processes and molecular pathways of self-tolerance and autoimmune diseases. The molecular definition of these pathways and processes has led to novel treatments for certain auto-immune diseases that are based on the pathogenesis of diseases rather than on broad-spectrum immunosuppression. This book reviews many of these current developments and proposes future novel approaches for understanding the pathogenesis of auto-immune diseases and designing novel therapy. This book covers three major areas of auto-immunity: the basic mechanisms of immunological tolerance, pathogenesis of auto-immune diseases, and some novel therapies. This book should be useful for immunologists, molecular biologists, rheumatologists, and clinical scientists.

This volume is divided into three sections. Section I deals with factors that regulate the development and maturation of T cells and B cells and lymphocyte traffic. The significance of C-kit, Bcl-6, IL-7, and Vav in the development of T and B lymphocytes is discussed. A role of lymphotoxins and VAP-I in trafficking of leucocytes is reviewed. Finally, the trafficking and homing characteristics of T cell and B cell subsets, and the regulation of these processes during the immune response, is presented. Section II discusses various aspects of naive and memory T cell biology, including clonal expansion, reprogramming of genes including those encoding cytokines and cytotoxic granules, changes in the expression of cell surface proteins involved in cell-cell adhesion, homing of naive and memory T cells, the role of MHC and cytokines in the maintenance of naive and memory T cells, and the characterization and differentiation of virus-specific memory T cell heterogeneity in mice and humans. Novel methods of visualization of immune cells and immune systems are reviewed in Section III.

During the past 5 years, impressive progress has been made in understanding the etiopathogenesis of expeiimental and clinical diabetes. The rapid progress that has been made in the general field of immunology has made possible new understanding regarding the role of the immune system in the pathogenesis of diabetes. The other two areas in which recent progress has been made in the field of diabetes include genetics and the role of infectious agent(s) in the etiopathogenesis of diabetes. Because of these recent developments, a vast amount of data has been accumulated and published in a number of metabolic, endocrine, immunological, and general medicine journals. The purpose of this book is to consolidate all the available information and present it in its current state. In the present volume, I strive to bring together relevant contributions from leaders in the fields of immunopathology, immunobiology, and genetics. The advancing understanding has in several instances reached the point of clinical applica tion. This volume encompasses the entire scope of modem immunology of diabetes mellitus. This volume has been divided into two major parts, Experimental Diabetes and Clinical Diabetes. In the Experimental part are included chapters dealing with the structure and functions of insulin and the immune response to insulin. Spontaneous and experimentally induced models of type I diabetes mellitus are presented. The role of virus(es) in the etiology of experimental diabetes and the influence of sex on experi mental diabetes are discussed. The transplantation of pancreas and islets is reviewed in detail."

Recent advances in the understanding of the major events that shape the immune recog nition system have been remarkable. The analysis of immunoglobulin (Ig) gene organization and Ig repertoire diversification in lower vertebrates has provided new insight into this process in mammals. Similarly, the understanding of the early development of lymphocytes and of the acquisition of immunological tolerance has been aided by elegant studies in quail/chicken chimeras, using the power of the distinctive markers of the constitutive cells of these birds. Great strides have been made in understanding the role played by major histocompatibility complex (MHC) molecules in antigen presentation and in repertoire selec tion within the thymus. The use of transgenic mice expressing specific T-cell receptor (TCR) genes has elucidated the process of both positive and negative selection. In parallel, there has been considerable progress in our understanding of tolerance, based in part on the use of markers for the V fJ genes of T-cell receptors and in part on the analysis of the behavior of long term T-cell lines. This has led to the realization that both clonal deletion and clonal anergy may play critical roles in the maintenance of unresponsiveness to self antigen. Molecular analysis of the requirements for expression of membrane immunoglobulin molecules has revealed the existence of a complex that appears to be of critical importance in mediating signalling through Ig receptors. In addition, major insights have been obtained into the regulation of expression of genes of immunologic interest.

Recent developments in basic science and clinical rheumatology make it appropriate at this time to create a volume devoted to the immunology of rheumatic diseases. The impact of molecular biology, gene cloning, and new technologies for establishing hybridomas and T-cell lines in the laboratory is now beginning to be felt in clinical medicine. There is a general air of excitement and a feeling that we stand on the threshold of a new era in molecular medicine and clinical science. It is this excitement that we have tried to capture in this book. This volume is divided into five sections entitled Basic Mechanisms, Autoimmunity, Classical Concepts of Rheumatic Diseases, Pathogenetic Mechanisms, and Therapy. This is not an arbitrary arrangement but represents our belief that from an understanding of basic mechanisms of disease pathogenesis will come new and more successful forms of treatment for the sufferers of rheumatic disorders. We have tried in the selection of authors to choose internationally recognized experts who have both a scientific and a clinical orientation to their subjects. We believe the marriage of clinical and basic disciplines represents the best hope for rapid knowledge transfer from the laboratory to the clinic, where such knowledge can be used to improve patient health.

Mechanisms of Lymphocyte Activation and Immune Regulation X Innate Immunity is the proceedings of the Xth International Conference on Mechanisms of Lymphocyte Activation and Immune Regulation: Innate Immunity, held February 6-8, 2004 in Newport Beach, California. It is the tenth volume of its kind to appear in the series Advances in Experimental Medicine and Biology. Topics include toll receptors, dendritic cells, NK cells, and complement receptors.

In recent years, major developments have been made in understanding various genetic and epigenetic regulatory processes that are critical for the generation of B cell repertoires. These include the role of chromatin regulation and nuclear organization in understating the IgH gene regulation. A role and mechanism of DNA repair proteins in somatic hypermutation has been elucidated. Genetic mutation studies have been instrumental in providing insight into some of the mechanisms involved in targeting CSR to various switch DNA regions located upstream of C region genes, especially a role of AID motifs, transcription, and R-loops. Recent studies support a dominant role of receptor editing in central B cell tolerance and signaling pathways that regulate receptor editing in self-reactive and non-self-reactive immature B cells. These were some of the topics of discussion at the 11th International Conference on B cell Biology. These proceedings highlight recent developments in lymphocyte development, Ig gene rearrangements and somatic hypermutation, chromatin structure modification, B lymphocyte signaling and fate, receptor editing, and autoimmunity.

Factorial designs were introduced and popularized by Fisher (1935). Among the early authors, Yates (1937) considered both symmetric and asymmetric factorial designs. Bose and Kishen (1940) and Bose (1947) developed a mathematical theory for symmetric priIi't&-powered factorials while Nair and Roo (1941, 1942, 1948) introduced and explored balanced confounded designs for the asymmetric case. Since then, over the last four decades, there has been a rapid growth of research in factorial designs and a considerable interest is still continuing. Kurkjian and Zelen (1962, 1963) introduced a tensor calculus for factorial arrangements which, as pointed out by Federer (1980), represents a powerful statistical analytic tool in the context of factorial designs. Kurkjian and Zelen (1963) gave the analysis of block designs using the calculus and Zelen and Federer (1964) applied it to the analysis of designs with two-way elimination of heterogeneity. Zelen and Federer (1965) used the calculus for the analysis of designs having several classifications with unequal replications, no empty cells and with all the interactions present. Federer and Zelen (1966) considered applications of the calculus for factorial experiments when the treatments are not all equally replicated, and Paik and Federer (1974) provided extensions to when some of the treatment combinations are not included in the experiment. The calculus, which involves the use of Kronecker products of matrices, is extremely helpful in deriving characterizations, in a compact form, for various important features like balance and orthogonality in a general multifactor setting.