Immunological Aspects Of Liver Disease

Howard C. Thomas In normal subjects the regulatory apparatus of the immune system permits responses to foreign antigens but suppresses those directed to "self' components. Autoimmune disease occurs as a failure ofthis system either as a result of a primary defect in the regulatory apparatus (primary autoimmunization) or because of a change in the antigenicity of the tissues (secondary autoimmunization). Autoaggressive reactions are characterised by the presence of autoantibodies. When these are directed to membrane displayed antigens (Fig. 1) they are probably of importance in the lysis of hepatocytes. Those directed to cytoplasmic antigens may be useful diagnostically but are of unknown pathogenic significance. When no extrinsic aetiological factor can be identified, the process is assumed to be the result of a failure ofthe regulatory system, allowing the spontaneous expansion of a clone of autoreactive lymphocytes. The defect may be generalised or specific to certain groups of self-antigens and thus the autoimmune disease may be either multi- or unisystemic. The recent development of techniques to enumerate and measure the functional activity of the suppressor lymphocytes which control the effector limbs of the immune system has enabled investigators to test whether the various purported autoimmune diseases do have as their basis a generalised defect in immunoregu lation. Assessment of antigen-specific immunoregulatory function is, however, not yet readily available. liver Membrane I Antigen (LIM) I Liver I HLA, A, B, C, Sensitisation to Specific -;::!IIIL. .

We have been privileged to start our academic careers at the begin ning of the decade in which the immunological roles and hypersensitivity diseases of the gastrointestinal tract and liver have been defined. In the early 1960s IgA was reported to be the main secretory immunoglobulin, immunoblasts were shown to home to the intestinal mucosa and certain serum autoantibodies were described in patients with chronic liver disease. Shortly thereafter IgE and Australia antigen were discovered. Parallel advances in clinical investigation, in particular closed biopsy techniques, facilitated correlation of morphological changes with im munological mechanisms in disease of the gastrointestinal tract and liver. Only 10 years later, the concepts of immunity and hypersensitivity are regularly applied to the pathogenesis, diagnosis, treatment and prog nosis of many chronic diseases in these organs. In designing this book we have attempted to integrate theorectical and clinical immunology as they pertain in 1975; our ultimate aim is aptly described by Brachet as quoted by Professor Paronetto (page 319). We would like to think that this review provides a basis for the next major advances in the fields of gastrointestinal and hepatic immunology. As we see it, the outstanding problem in both sites is how to produce protective immunity without hypersensitivity.

The third edition of this acclaimed work provides clinicians and investigators with a wealth of state-of-the-art information that will lead to fresh approaches in thinking about liver physiology and liver diseases. Developed by a panel of renowned international authors, this edition outlines a range of important advances in our understanding of the liver’s role as an immune organ and the functions of innate and adaptive immunity in the pathogenesis of all liver diseases. Indeed, the liver is a vitally important immune organ producing liver-derived products that can trigger the innate and adaptive immune system to initiate, mediate, regulate, and resolve systemic inflammation. The book begins with an analysis of the core concepts of immunology, including the definition of autoimmunity and its unique application to the liver, a tolerogenic organ. Subsequent chapters then explore the biological elements of liver diseases caused by epigenetics, genetics, and innate and adaptive immunity. Specific clinical presentations and aspects of liver diseases are also examined, such as Hepatitis C, non-alcoholic fatty liver disease and parasitic infections. Closing chapters then discuss liver diseases among specific populations, including pediatrics, those with comorbidities and preexisting conditions, pregnant women, and finally patients with transplanted organs. A timely and invaluable update to the clinical literature, Liver Immunology: Principles and Practice, Third Edition, is once again a comprehensive work that will not only enhance the understanding of liver diseases but also provide the kind of novel insights that greatly accelerates the evidence-based care of children and adults afflicted with these diseases. This volume is again a must-read for clinicians at all levels, for investigators and for students.

The role of the immune response in both the pathology of liver disease and in the modulation ofliver injury has been the subject of intense research. This book aims to present the current understanding of the involvement of the immune response in liver disease. The first chapters examine the role of the immune response in viral infections of the liver. These viruses cause hepatitis of varying severity and it is thought that many of the mechanisms responsible for liver cell injury are immunologically mediated. In addition three of these viruses, hepatitic B, C, and D, are associated with persistent infection and chronic liver disease. The role of the immune response in viral persistence is discussed. Further chapters are devoted to the three major autoimmune liver diseases which are thought to be the result of loss of tolerance to autologous liver tissue. There has been much recent research on cellular immune responses in these diseases but knowledge of the immunological processes which lead to the breakdown of tolerance and the mechanisms of tissue damage are limited. Other research has concentrated on the identification of the antigens which are the targets of this immune response. Linkage disequilibrium between MHC alleles and autoimmune diseases has suggested a role for immunogenetic factors.

Immunology of the Liver contains the proceedings of an International Meeting held at King's College Hospital Medical School in London on July 6-7, 1970. The meeting provided a forum for discussing progress made in understanding the immunology of the liver and tackled topics ranging from the pathology of chronic hepatitis to the occurrence and distribution of tissue antibodies in liver diseases. Cell-mediated responses and manifestations of immunological damage are also explored. Comprised of 33 chapters, this book begins with an introduction to the clinical, morphological, and virological aspects of liver disease. In particular, the clinical spectrum of autoimmune liver disease is considered, along with the pathology of chronic hepatitis. Morphological and immunological studies on chronic aggressive hepatitis and primary biliary cirrhosis are presented. Subsequent chapters focus on antibodies related to mitochondria; leukocyte migration in active chronic hepatitis and primary biliary cirrhosis; immunologic observations and electron microscopy of halothane-induced hepatic injury; and humoral and delayed hypersensitivity in chronic hepatitis. The final sections deal with results of immunosuppressive therapy and the immunology of liver transplantation. This monograph will be of interest to immunologists, pathologists, physiologists, clinicians, and research workers in the field of medicine.

This volume is the definitive book on liver immunology by the major authorities from the U.S. and around the world. Because of the emergence of Hepatitis C as a major health problem, this topic has become increasingly important, and the authors have designed a book that is both authoritative and highly practical, with bulleted points highlighting the key point of each chapter. The major sections are Basic Immunology; Bacterial and Vital Infections; Models of Autoimmune Liver Disease; Autoimmune Liver Disease; and Transplantation.

In 1992, the Falk Symposium No. 70 dealt with the topic `Immunology and Liver'. At that time basic mechanisms of immunology as well as immunopathogenetic mechanisms in viral and autoimmune liver diseases were discussed. Now, 7 years later, the Falk Symposium No. 114, held in Basel, Switzerland, October 20-21 1999 (Part I of the Basel Liver Week 1999), focused on immunology in autoimmune liver diseases. In the first section basic mechanisms of autoimmunity are presented, including the relevance of superantigens and the role of apoptosis. A further topic is the latest developments concerning animal models for autoimmune diseases. Recently the International Autoimmune Hepatitis Group newly defined and reclassified the syndrome of autoimmune hepatitis. Autoimmune hepatitis is now identified and studied in all parts of the world, including Asia and South America. A special variant of autoimmune hepatitis was identified as one organ manifestation of the autoimmune polyendocrine syndrome type 1, a genetic disease caused by mutations in a single transcription factor. Drug- and hepatitis-virus induced immune mediated liver diseases may serve as models for nonhepatic immune mediated disorders. DNA technology has increased our knowledge of the immunogenetic background of autoimmune liver diseases. Among the cholestatic immune mediated liver diseases, significant progress has been made concerning primary biliary cirrhosis, in particular regarding the identification of mitochondrial antigens and the characterisation of the immune reactions directed at them. The involvement of infectious agents in PBC as well as the definition of overlap syndromes is a particular focus for basic and clinical research in this area. Concerning the therapy of autoimmune liver diseases, corticosteroids and azathioprin remain the state of the art for autoimmune hepatitis, while bile acids have become well established in treatment of primary biliary cirrhosis as well as primary sclerosing cholangitis. New drugs in the future will include topical steroids such as budesonide and new immunosuppressive agents like mofetil/mycophenolate. Liver transplantation is the treatment of choice for end stage liver diseases; all autoimmune liver diseases are among the best candidates for liver transplantation. Hopefully, new therapeutic strategies based on the results obtained from experimental models will become everyday clinical practice in the next decade. Therefore this symposium concludes with a discussion.

This book is the proceedings of the Falk Symposium No. 135 held in Prague, Czech Republic, on September 12-13, 2003, and is dedicated to the important issue of immunological aspects of diseases of the liver and gut. Without any doubt, immunological pathways are among the most important and universal factors in the pathogenesis of all diseases. Their importance is also constantly increasing, because these principles have been adopted in clinical practice for both diagnostic and therapeutic procedures. Chapters by prominent experts will stimulate new ideas and set the scene for productive discussion on this topic.