C1q~ 8 lymphocyte Antibody-secreting Antibody C1 complex (plasma) cell C1qr2s2 CD4+ helper CDS+ cytolytic T Antigen-presenting Target cell T lymphocyte lymphocyte (CTL) cell (macrophage) forCTL Dendritic cell Natural killer Neutrophil Apoptotic cell (NK) cell * TCR TCR LFA-1 (helper) (cytolytic) CD4 CDS Microbe ~1 .... cell ~ " membrane Dead microbe ~-­ Antigen cytokine (protein) receptor LFA-3 MHC II MHC I ICAM-1 87-1/87-2 BASIC IMMUNOLOGY BASIC IMMUNOLOGY Functions and Disorders of the Immune System Second Edition Abul K. Abbas, MBBS Professor and Chair Department of Pathology University of California, San Francisco, School of Medicine San Francisco, California Andrew H. Lichtman, MD, PhD Associate Professor of Pathology Harvard Medical School Brigham and Women's Hospital Boston, Massachusetts Illustrated by David L. Baker, MA, and Alexandra Baker, MS, CMI [[AUNDERSI An Imprint of Elsevier un.u1 ~ua.;1\.u An Imprint of Elsevier The Curtis Center Independence Square West Philadelphia, PA 19106-3399 ISBN: 0-7216-0241-X BASIC IMMUNOLOGY: FUNCTIONS AND DISORDERS OF THE IMMUNE SYSTEM Copyright © 2004, 2001 Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publisher. Permissions may be sought directly from Elsevier lnc. Rights Department in Philadelphia, USA: phone: (+1)215 238 7869, fax: (+1)215 238 2239, email: [email protected]. You may also complete your request on-line via the Elsevier Science homepage (http://www.elsevier.com), by selecting "Customer Support" and then "Obtaining Permissions." NOTICE Immunology is an ever-changing field. Standard safety precautions must he followed, but as new research and clinical experience broaden our knowledge, changes in treatment and drug therapy may become necessary or appropriate. Readers are advised to check the most current product information provided by the manufacturer of each drug to be administered to verify the recommended dose, the method and duration of administration, and contraindications. It is the responsibility of the treating physician, relying on experience and knowledge of the patient, to determine dosages and the best treatment for each indjvidual patient. Neither the publisher nor the editor assume any liability for any injury and/or damage to persons or property arising from this publication. The Publisher First Edition 2001. Second Edition 2004. Ubrary of Congress Cataloging•in-Publication Data Abbas, Abut K. Basic immunology: functions and disorders of the immune system I Abu! K. Abhas, Andrew H. Lichtman; illustrated by David L. Baker and Alexandra Baker. - 2nd i::d. p.; cm. Includes index. ISBN 0-7216-0241-X 1. Immunology. 2. Immunity. 3. Immunologic diseases. l. Lichtman, Andrew H. II. Ttde. [DNLM: I. Immunity. 2. Hypersensitivity. 3. Immune System-physiology. 4. Immunologic Deficiency Syndromes. QW 504 AlZZb 2004) QR181.AZ8 2004 616.07'9 - dc21 2003050607 Acquisitions Editor. Jason Malley Project Manager: Linda Lewis Grigg Designer: Gene Harris BS/CTP Prinred in China. Last digit is the print number: 9 8 7 6 5 4 3 2 To Ann, Jonathan, Rehana Sheila, Eben, Ariella, Amos, Ezra Preface The second edition of Basic Immunology has been Nevertheless, we can now teach our students, with revised to reflect new advances in our understanding reasonable confidence, how the immune system of the immune system and to improve on the presen works. The second important development has been tation of information in ways most useful to students an increasing emphasis on the roots of immunology, and teachers. We have been extremely gratified by which lie in its role in defense against infections. As how well the first edition of Basic lmmw10logy has a result, we are better able to relate experimental been received by students in. the courses that we results, using simple models, to the more complex, but teach, and the guiding principles on which the book physiologically relevant, issue of host defense against is based have not changed from the first edition. fu infectious pathogens. teachers of immunology, we are becoming increas This book has been written to address the per ingly aware that assimilating detailed information and ceived needs of both medical school and under experimental approaches is difficult in many medical graduate curricula and to take advantage of the new school and undergraduate courses. The problem of understanding of immunology. We have tried to how much detail is appropriate has become a pressing achieve several goals. First, we have presented the one because of the continuous and rapid increase in most important principles governing the function of the amount of information in all the biomedical the immune system. Our fundamental objective has sciences. This problem is compounded by the de been to synthesize the key concepts from the vast velopment of integrated curricula in many medical amount of experimental data that emerge in the schools, with reduced time for didactic teaching and rapidly advancing field of immunology. The choice of an increasing emphasis on social and behavioral sci what is most important is based largely on what is ences and primary health care. For all these reasons, most clearly established by experimentation, what our we have realized the value for many medical students students find puzzling, and what explains the won of presenting the principles of immunology in a derful efficiency and economy of the immune system. concise and clear manner. [nevitably, however, such a choice will have an It is our view that several developments have come element of bias, and our bias is toward emphasizing together to make the goal of a concise and modem the cellular interactions in immune responses and consideration of immunology a realistic one. Most limiting the description of many of the underlying important, immunology has matured as a discipline, biochemical and molecular mechanisms to the essen so that it has now reached the stage when the essen tial facts. Second, we have focused on immune tial components of the immune system, and how they responses against infectious microbes, and all our interact in immune responses, are understood quite discussions of the immune system are in this con well. There are, of course, many details to be filled in, text. Third, we have emphasized immune responses in and the longstanding challenge of applying basic humans (rather than experimental animals), drawing principles to human diseases remains a difficult task. on parallels with experimental situations whenever vii viii Preface necessary. Fourth, we have made liberal use of illus human health and disease. Finally, although we were trations to highlight imponant principles but have spurred to tackle this project because of our associa reduced factual detaUs that may be found in more tions with medical school courses, we hope the book comprehensive texcbuoks. Fifth, we have discussed will he valued more widely by students of allied health immunologic diseases also from the perspective of and biology as well. We will have succeeded if the principles, emphasizing their relation to normal book can answer many of the questions these students immune responses and avoiding details of clinical have about the immune system and, at the same time, syndromes and treatments. We have added selected encourage them to delve even more deeply into clinical cases in the Appendix, to illustrate how the immunology. concepts of immunology may be applied to common Several individuals played key roles in the writing human diseases. Finally, we have realized that in any of this book. Our eJitor, Jason Malley, has been a concise discussion of complex phenomena, it is skilled and helpful colleague throughout. We have inevitable that exceptions and caveats will fall by the been fortunate to again work with David and wayside. We have avoided exceptions and caveats Alexandra Baker of DNA lllustrations, who have without hesitation, but with a willingness to modify translated ideas into pictures that are informative and our conclusions as new information continues to aesthetically pleasing. Our project manager, Linda emerge. Grigg, kept the project organized and on track despite It is our hope that students will find this book clear, pressures of time and logistics. To all of them we owe cogent, and manageable. Most important, we hope our many thanks. the book will convey our sense of wonder about the immune system and excitement about how the field Abul K. Abbas has evolved and how it continues to be relevant to Andrew H. Lichtman Contents Introduction to the Immune System Immunologic Tolerance and The Nomenclature, General Properties, and Autoimmunity Components of the Immune System ..................... ! Self-Nonself Discrimination in the Immune System and Its Failure ..................................... 161 Innate Immunity The Early Defense Against Infections ................ 21 Immune Responses Against Tumors and Transplants Antigen Capture and Presentation to Immunity to Noninfectious Transformed and Foreign Cells ................................................... 177 Lymphocytes What Lymphocytes See ..................................... .41 Hypersensitivity Diseases Disorders Caused by Immune Responses .......... 193 Antigen Recognition in the Adaptive Immune System Structure of Lymphocyte Antigen Receptors 12 Congenital and Acquired and the Development of Immune Repertoires ......6 3 Immunodeficiencies Diseases Caused by Defective Immune Responses ........................................................ 209 Cell-Mediated Immune Responses Activation of T Lymphocytes by Cell-Associated Microbes ...................................8 3 Suggested Readings ............................................... 225 6 Effector Mechanisms of Cell-Mediated APPENDIX I Immunity Principal Features of CD Molecules ................... 229 Eradication of Intracellular Microbes ............... 105 APPENDIX II Humoral Immune Responses Glossary ................................................................. 263 Activation of B Lymphocytes and Production of Antibodies ................................................... 123 APPENDIX /II Clinical Cases ........................................................ 291 Effector Mechanisms of Humoral Immunity The Elimination of Extracellular Microbes and Toxins ....................................................... 143 Index ..................................................................... .301 ix The Nomenclature, General Properties, and Components ~ of the Immune System ~ lnate ...S Adllptlve .._.nltJ lJpes of Adaptive Immunity Prupertles of Adaptive ....._ Responses • Specificity I •Memory mmunity is defined as resistance to disease, specifically infectious disease. The collection of cells, tissues, and Phases of Immune Responses molecules that mediate resistance to infections is called the Cells or 111e .._ System immune system, and the coordinated reaction of these cells and • Lymphocytes molecules to infectious microbes is the immune response. • Antigen-Presenting Cells Immunology is the study of the immune system and its • Effector Cells responses to invading pathogens. The physiologic function of Tissues of the lmmuae Systllln the immune system is to prevent infections and to eradicate • Peripheral Lymphoid Organs established infections, and this is the principal context in • Lymphocyte Recirculation which immune responses are discussed throughout this book. Sunnaiy The importance of the immune system for health is dra matically illustrated by the frequent observation that individ- uals with defective immune responses are susceptible to serious, often life-threatening infections (Fig. 1-l). Conversely, stimulating immune responses against microbes by the process of vaccination is the most effective method for protect ing individuals against infections and is, for example, the approach that has led to the worldwide eradication of smallpox (Fig. 1-2). The emergence of the acquired immuno deficiency syndrome (AIDS) since the 1980s has tragically emphasized the importance of the immune system for defending individuals against infections. But the impact of immunology goes beyond infectious disease (see Fig. 1-l). The immune response is the major barrier to successful organ transplantation, an increasingly used therapy for organ 1 2 Basic Immunology: Functions and Disorders of the Immune System l I Role of the immune system implications Deficient immunity results in increased susceptibility to infections; exemplified by AIDS Defense against infections Vaccination boosts immune defenses and protects against infections The immune system recognizes and responds to tissue grafts Immune responses are important barriers to transplantation and gene therapy and newly introduced proteins Defense against tumors Potential for immunotherapy of cancer Antibodies are highly specific Immunologic approaches for laboratory reagents for detecting any class testing are widely used in clinical medicine of molecules and research Figure 1-1 The importance of the immune system. Some of the functions and fea1ures of the immune system, and their importance in health and disease, are summarized. Disease Max. number Number of Percent of cases cases in 2000 change Diphtheria 206,939 (1921) 2 -99.99 Measles 894,134 (1941) 63 -99.99 Mumps 152,209 (1968) 315 -99.80 Pertussis 265,269 (1934) 6,755 -97.73 Polio (paralytic) 21,269 (1952) 0 -100.0 Rubella 57,686 (1969) 152 -99.84 Tetanus 1,560 (1923) 26 -98.44 Haemophilus -20,000 (1984} 1,212 -93.14 influenzae type B Hepatitis B 26,611 (1985) 6,646 -75.03 Figure 1-2 The effectiveness of vaccination for some common Infectious diseases. There is a striking decrease in the incidence of selected infectious diseases for which effective vaccines have been developed. In some cases, such as with hepatitis 8, a vaccine has become available and the incidence of the disease is continuing to decrease. (Adapted from Oren stein WA, AR Hinman, KJ Bart, and SC Hadler. Immunization. In Gl Mandell, JE Bennett. and R Dolin [eds]. Principles and Practices of Infectious Diseases, 4th ed. Churchill Livingstone. New York. 1995. and Morbidity and Mortality Weekly Reports, Centers for Disease Control 49:1159-1201, 2001.)