Page i Introduction to Medical Immunology Fourth Edition Edited by Gabriel Virella Medical University of South Carolina Charleston, South Carolina MARCEL DEKKER, INC. N EW Y ORK • B ASEL • H ONG K ONG Page ii Library of Congress Cataloging-in-Publication Data Introduction to medical immunology / edited by Gabriel Virella. — 4th ed. p. cm. Includes bibliographical references and index. ISBN 0-8247-9897-X (hardcover : alk. paper) 1. Clinical immunology. 2. Immunology. I. Virella, Gabriel. [DNLM: 1. Immunity. 2. Immunologic Diseases. QW 504 I6286 1997] RC582.I59 1997 616.07'9—dc21 DNLM/DLC for Library of Congress 97-22373 CIP The publisher offers discounts on this book when ordered in bulk quantities. For more information, write to Special Sales/Professional Marketing at the address below. This book is printed on acid-free paper. Copyright © 1998 by MARCEL DEKKER, INC. All Rights Reserved. Neither this book nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microfilming, and recording, or by any information storage and retrieval system, without permission in writing from the publisher. MARCEL DEKKER, INC. 270 Madison Avenue, New York, New York 10016 http://www.dekker.com Current printing (last digit): 10 9 8 7 6 5 4 3 2 1 PRINTED IN THE UNITED STATES OF AMERICA Page iii PREFACE Ten years after the publication of the first edition of Introduction to Medical Immunology , the ideal immunology textbook continues to be a very elusive target. The discipline continues to grow at a brisk pace, and the concepts tend to become obsolete as quickly as we put them in writing. It is very true of immunology that the more we know, the greater our ignorance. This represents the challenge that makes teaching immunology so exceptional and writing immunology textbooks such a daunting task. The fourth edition of Introduction to Medical Immunology retains the features that make this textbook unique— particularly, its emphasis on the clinical application of immunology —but represents a significant departure from the earlier editions. Most changes have resulted from our strong conviction that this textbook is not written to impress our peers with extraordinary insights or revolutionary knowledge, but rather to be helpful to medical students and young professionals who need an introduction to the field. The requirements that we tried to fulfill were sometimes difficult to conciliate. The text needs to be updated and relatively complete, but not overwhelming. The scientific basis of immunology needs to be clearly conveyed without allowing the detail to obscure the concept. The application to medicine needs to be transparently obvious, but without unnecessary exaggeration. The text must present a reasonably general and succinct overview, while covering areas that appear likely to have a strong impact in the foreseeable future. The book needs to stimulate students to seek more information and to develop their own “thinking” without being merely a model of theoretical dreams (and nightmares). In what is probably not an entirely successful attempt to fulfill some of these goals, we have extensively revised the book, added significant new concepts, and deleted areas that were clearly obsolete. The clinical sections are peppered with cases in order to provide a solid link between the discussion of concrete problems presented by patients with diseases of immunological basis and the relevant immunological principles. More significantly, the book has been rewritten in an outline format. This format allows us to keep the conceptual approach while facilitating the understanding of a reader facing the complexities of immunology with very little background. Of necessity, the book emphasizes that which is well understood, as clearly as we can present it, and we try to promote a general understanding of the discipline at the end of the twentieth century. It is not, and never will be, a finished work. We are certain that we will always wish we could add here and revise there. But we hope that this new edition will be even more successful in focusing the Page iv attention of our readers toward an intrinsically fascinating discipline that seeks understanding of fundamental biological knowledge that has direct impact on the diagnosis and treatment of a variety of conditions in which the immune system plays a key role. GABRIEL VIRELLA, M.D., PH.D. Page v CONTENTS Preface iii Contributors ix Part I. Basic Immunology Gabriel Virella 1. Introduction 1 Gabriel Virella and Jean-Michel Goust 2. Cells and Tissues Involved in the Immune Response 11 Jean-Michel Goust 3. Major Histocompatibility Complex 31 Gabriel Virella and Barbara E. Bierer 4. The Induction of an Immune Response: Antigens, Lymphocytes, and Accessory Cells 49 Gabriel Virella and An-Chuan Wang 5. Immunoglobulin Structure 75 Gabriel Virella and An-Chuan Wang 6. Biosynthesis, Metabolism, and Biological Properties of Immunoglobulins 91 Janardan P. Pandey 7. Genetics of Immunoglobulins 105 Gabriel Virella 8. Antigen-Antibody Reactions 121 Robert J. Boackle 9. The Complement System 137 Jean-Michel Goust and Anne L. Jackson 10. Lymphocyte Ontogeny and Membrane Markers 163 Jean-Michel Goust and Barbara E. Bierer 11. Cell-Mediated Immunity 187 Page vi Gabriel Virella 12. The Humoral Immune Response and Its Induction by Active Immunization 217 Gabriel Virella 13. Infections and Immunity 239 Part II. Diagnostic Immunology Gabriel Virella 14. Immunoserology 259 Gabriel Virella 15. Diagnostic Evaluation of Humoral Immunity 283 Gabriel Virella and Jean-Michel Goust 16. Diagnostic Evaluation of Lymphocyte Functions and Cell-Mediated Immunity 297 Gabriel Virella 17. Diagnostic Evaluation of Phagocytic Function 317 Part III. Clinical Immunology Jean-Michel Goust, George C. Tsokos, and Gabriel Virella 18. Tolerance and Autoimmunity 335 Christian C. Patrick, Jean-Michel Goust, and Gabriel Virella 19. Organ-Specific Autoimmune Diseases 363 Jean-Michel Goust and George C. Tsokos 20. Systemic Lupus Erythematosus 383 Jean-Michel Goust 21. Rheumatoid Arthritis 399 Gabriel Virella 22. Hypersensitivity Reactions 417 Jean-Michel Goust and Albert F. Finn, Jr. 23. IgE-Mediated (Immediate) Hypersensitivity 433 Gabriel Virella and Mary Ann Spivey 24. Immunohematology 453 Gabriel Virella and George C. Tsokos 25. Immune Complex Diseases 475 Jean-Michel Goust, Henry C. Stevenson-Perez, and Gabriel Virella 26. Immune System Modulators 495 Gabriel Virella and Jonathan S. Bromberg 27. Transplantation Immunology 517 Page vii Henry C. Stevenson-Perez and Kwong-Y. Tsang 28. Tumor Immunology 535 Gabriel Virella and Jean-Michel Goust 29. Malignancies of the Immune System 553 Gabriel Virella 30. Immunodeficiency Diseases 579 Index 621 Page ix CONTRIBUTORS Barbara E. Bierer, M.D. Associate Professor of Medicine, Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston, Massachusetts Robert J. Boackle, Ph.D. Professor and Director of Oral Biology and Professor of Immunology, Division of Stomatology, Medical University of South Carolina, Charleston, South Carolina Jonathan S. Bromberg, M.D., Ph.D. Associate Professor of Surgery, Microbiology, and Immunology, Department of General Surgery, Transplant Division, University of Michigan Hospitals, Ann Arbor, Michigan Albert F. Finn, Jr., M.D. Clinical Assistant Professor, Departments of Medicine, Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina Jean-Michel Goust, M.D. Professor of Immunology, Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina Anne L. Jackson, Ph.D. Consultant, Ridgefield, Washington Janardan P. Pandey, Ph.D. Professor, Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina Christian C. Patrick, M.D., Ph.D. Director of Academic Programs and Associate Member, Department of Infectious Diseases and Pathology and Laboratory Medicine, St. Jude Children's Research Hospital, Memphis, Tennessee Mary Ann Spivey, M.H.S., M.T. (A.S.C.P.), S.B.B. Department of Pathology-Laboratory Medicine, Transfusion Medicine Section, Medical University of South Carolina, Charleston, South Carolina Henry C. Stevenson-Perez, M.D. Senior Investigator, Biologics Evaluation Section, Investigational Drug Branch, National Cancer Institute, National Institutes of Health, Rockville, Maryland Page x Kwong-Y. Tsang, Ph.D. Senior Scientist, Laboratory of Tumor Immunology and Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland George C. Tsokos, M.D. Professor, Department of Medicine, Uniformed Services University of Health Sciences, Bethesda, Maryland, and Department of Clinical Investigations, Walter Reed Army Medical Center, Washington, D.C. Gabriel Virella, M.D., Ph.D. Professor and Vice Chairman of Education, Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina. An-Chuan Wang, Ph.D. Professor, Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina [...]... helper T lymphocytes Antibodies (+ complement or cytotoxic cells); cytotoxic T lymphocytes; macrophages Mechanisms Processing and/or presentation of antigen; recognition by specific receptors on lymphocytes Release of cytokines; signals mediated by interaction between cell membrane molecules Complement-mediated lysis; opsonization and phagocytosis; cytotoxicity Consequences Activation of T and B lymphocytes... lymphocytes with receptors able to interact with epitopes expressed by self-antigens During embryonic differentiation the immune system eliminates or turns off auto-reactive lymphocytes The state of tolerance is maintained during the lifetime of healthy individuals by mechanisms not fully understood VII General Overview One of the most difficult intellectual exercises in immunology is to try to understand... (phagocytosis), while others are inserted into cytoplasmic membranes and cause their disruption, leading to cell death 5 Antibodies can cause the destruction of microorganisms by promoting their ingestion by phagocytic cells or their destruction by cytotoxic cells Phagocytosis is particularly important for the elimination of bacteria and involves the binding of antibodies and complement components to the... response T lymphocytes can have suppressor functions d To date, there are no known markers that perfectly differentiate T lymphocytes with different functions, although it is possible to differentiate cells with predominant helper function from those with predominant cytotoxic function e T-cell mediated cytotoxicity is an apoptotic process that appears to be mediated by two separate pathways One involves... esterases) into the cytoplasm The exact way in which granzymes induce apoptosis has not been established, but granzyme-induced apoptosis is Ca2+-dependent The other pathway, which can be easily demonstrated in knock-out laboratory animals in whom the perforin gene is inactivated or by carrying out killing experiments in buffers without Ca2+, depends on signals delivered by the cytotoxic cell to the target... triggered the immune response, it is able to induce their ingestion by phagocytic cells If bound to live cells, antibody may induce the attachment of cytotoxic cells that cause the death of the antibody-coated cell (antibody-dependent cellular cytotoxicity; ADCC) The ingestion of microorganisms or particles coated with antibody is enhanced when an amplification effector system known as complement is activated... large granular lymphocytes These cells do not carry antigen receptors of any kind, but can recognize antibody molecules bound to target cells and destroy those cells using Page 14 the same general mechanisms involved on T-lymphocyte cytotoxicity (antibody-dependent cellular cytotoxicity) They also have a recognition mechanism that allows them to destroy tumor cells and virus-infected cells D Monocytes and... of lymphocytes throughout the body, moving from one system to another Page 23 Figure 2.7 Diagrammatic representation of the histological structure of the tonsils (Reproduced with permission from Junqueira, L.C., Carneiro, J., and Contopoulas, J., Basic Histology, 2nd ed Lang, Los Altos, CA, 1971.) Figure 2.8 Diagrammatic representation of the topography of the lymphoid follicles of a Peyer's patch (Reproduced...Page 1 1 Introduction Gabriel Virella I Introduction A The fundamental observation that led to the development of immunology as a scientific discipline was that an individual can become resistant for life to a certain disease after having contracted it only once The term immunity, derived from the Latin “immunis” (exempt), was adopted to designate this naturally acquired... or histocompatibility antigens, which are generically grouped as the MHC, is responsible for graft rejection VI Self Versus Non-Self Discrimination The immune response is triggered by the interaction of an antigenic determinant with specific receptors on lymphocytes It is calculated that there are several million different receptors in lymphocytes necessary to respond to the wide diversity of epitopes . edition of Introduction to Medical Immunology , the ideal immunology textbook continues to be a very elusive target. The discipline continues to grow at a brisk pace, and the concepts tend to become. Page i Introduction to Medical Immunology Fourth Edition Edited by Gabriel Virella Medical University of South Carolina Charleston, South Carolina MARCEL DEKKER,. not written to impress our peers with extraordinary insights or revolutionary knowledge, but rather to be helpful to medical students and young professionals who need an introduction to the field.