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Basic IMMUNOLOGY FU NCTIO N S A N D D ISOR D ER S OF THE IM M U NE SYSTE M

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SIXTH EDITION

Basic IMMUNOLOGY FUNCTIONS A ND DISORDERS OF THE IMMUNE SYSTEM Abul K. Abbas, MBBS

Shiv Pillai, MBBS, PhD

Professor Emeritus, Pathology University of California San Francisco San Francisco, California

Professor of Medicine and Health Sciences and Technology Harvard Medical School Massachusetts General Hospital Boston, Massachusetts

Andrew H. Lichtman, MD, PhD Professor of Pathology Harvard Medical School Brigham and Women’s Hospital Boston, Massachusetts

Illustrations by David L. Baker, MA DNA Illustrations, Inc.

BASIC IMMUNOLOGY: FUNCTIONS AND DISORDERS OF THE IMMUNE SYSTEM, SIXTH EDITION Copyright © 2020 by Elsevier Inc. All rights reserved.

ISBN: 978-0-323-54943-1

No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies, and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency can be found at our website: www.elsevier.com/permissions.

This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).

Notice Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds or experiments described herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made.

To the fullest extent of the law, no responsibility is assumed by Elsevier, authors, editors or contributors for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein.

Previous editions copyrighted 2016, 2014, 2011, 2009, 2006, 2004, and 2001.

International Standard Book Number: 978-0-323-54943-1

Executive Content Strategist: James Merritt Senior Content Strategist: Jeremy Bowes Director, Content Development: Rebecca Gruliow Publishing Services Manager: Julie Eddy Book Production Specialist: Clay S. Broeker Design Direction: Brian Salisbury

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To our students

P R E FAC E The sixth edition of Basic Immunology has been revised to include recent important advances in our knowledge of the immune system. The original goals of this book, from the earliest edition, were to present current concepts in immunology cogently and also in sufficient detail that they would be understood by students of the discipline, as well as to emphasize clinical aspects, including disease pathogenesis and the development of novel therapies based on the basic science of immunology. These are the goals that we continue to strive for.

With improving understanding of the normal immune response, we believe it is possible to present the fundamental knowledge in a concise way. In addition, there has been exciting progress in applying basic principles to understanding and treating human diseases, a topic that is of paramount interest for students of medicine and allied health sciences. Foremost among these recent advances is the development of cancer immunotherapy, which dramatically illustrates how foundational science can be translated into clinical practice.

More specifically, we have focused on the following objectives. First, we have presented the most important principles governing the function of the immune system by synthesizing key concepts from the vast amount of experimental data that have emerged in the field of immunology. Our judgment of what is most important is based largely on what is most clearly established by scientific investigation and is essential for understanding the major functions of the immune system. We have also prioritized content that is relevant to human health and disease. We have realized that in any concise discussion of complex phenomena, it is inevitable that exceptions and caveats cannot be considered in detail, so these have largely been omitted. Second, we have focused on immune responses against infectious microbes, and most of our discussions of the immune system are in this context. Third, we have made liberal use of illustrations to highlight important principles, but we have reduced factual details that may be found in more comprehensive textbooks. Fourth, we have

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also discussed immunologic diseases from the perspective of principles, emphasizing their relation to normal immune responses and avoiding details of clinical syndromes and treatments. We have included selected clinical cases in an appendix to illustrate how the principles of immunology may be applied to common human diseases. Finally, in order to make each chapter readable on its own, we have repeated key ideas in different places in the book. We feel such repetition will help students to grasp the most important concepts.

We hope that students will find this new edition of Basic Immunology clear, cogent, manageable, and enjoyable to read. We hope the book will convey our sense of excitement about how the field has evolved and how it continues to grow in relevance to human health and disease. Finally, although we were spurred to tackle this project because of our associations with medical school courses, we hope the book will be valued by students of allied health and biology as well. We will have succeeded if the book can answer many of the questions these students have about the immune system and, at the same time, encourage them to delve even more deeply into immunology.

Several individuals played key roles in the writing of this book. Our editor, James Merritt, has been an enthusiastic source of encouragement and advice. Our talented illustrator, David Baker, continues to effectively convert our ideas into pictures that are informative and aesthetically pleasing. Our development editor, Rebecca Gruliow, has kept the project organized and on track despite pressures of time and logistics. Clay Broeker has moved the book through the production process in an efficient and professional manner. To all of them we owe our many thanks. Finally, we owe an enormous debt of gratitude to our families, whose support and encouragement have been unwavering.

Abul K. Abbas Andrew H. Lichtman Shiv Pillai

CONTENTS 1 Introduction to the Immune System, 1 Nomenclature, General Properties, and Components

2 Innate Immunity, 23 The Early Defense Against Infections

3 Antigen Capture and Presentation to Lymphocytes, 51 What Lymphocytes See

4 Antigen Recognition in the Adaptive Immune System, 73 Structure of Lymphocyte Antigen Receptors and Development of Immune Repertoires

5 T Cell–Mediated Immunity, 96 Activation of T Lymphocytes

6 Effector Mechanisms of T Cell–Mediated Immunity, 119 Functions of T Cells in Host Defense

7 Humoral Immune Responses, 137 Activation of B Lymphocytes and Production of Antibodies

8 Effector Mechanisms of Humoral Immunity, 158 Elimination of Extracellular Microbes and Toxins

9 Immunologic Tolerance and Autoimmunity, 177 Self–Nonself Discrimination in the Immune System and Its Failure

10 Immunology of Tumors and Transplantation, 196 Immune Responses to Cancer Cells and Normal Foreign Cells

11 Hypersensitivity, 218 Disorders Caused by Immune Responses

12 Congenital and Acquired Immunodeficiencies, 235 Diseases Caused by Defective Immunity

elected Readings, 252 S Glossary, 260 Appendix I: Principal Features of Selected CD Molecules, 288 Appendix II: Cytokines, 296 Appendix III: Clinical Cases, 300 Index, 313

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Basic IMMUNOLOGY FU NCTIO N S A N D D ISOR D ER S OF THE IM M U NE SYSTE M

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1 Introduction to the Immune System Nomenclature, General Properties, and Components CHAPTER OUTLINE Innate and Adaptive Immunity, 3 Types of Adaptive Immunity, 4 Properties of Adaptive Immune Responses, 6 Specificity and Diversity, 6 Memory, 7 Other Features of Adaptive Immunity, 8 Cells of the Adaptive Immune System, 9 Lymphocytes, 9

Antigen-Presenting Cells, 14 Tissues of the Immune System, 15 Peripheral (Secondary) Lymphoid Organs and Tissues, 15 Lymphocyte Recirculation and Migration into Tissues, 20 Summary, 21

The term “immunity” in a biologic context has historically referred to resistance to pathogens; however, reactions to some noninfectious substances including harmless environmental molecules, tumors, and even unaltered host components are also considered forms of immunity (allergy, tumor immunity, and autoimmunity, respectively). The collection of cells, tissues, and molecules that mediate these reactions is called the immune system, and the coordinated response of these cells and molecules to pathogens and other substances comprises an immune response.

The most important physiologic function of the immune system is to prevent or eradicate infections (Fig. 1.1), and this is the principal context in which immune responses are discussed throughout this book. In addition, it prevents the growth of some tumors, and some cancers can be treated by stimulating immune responses against tumor cells. The immune system also plays a major role in the repair of damaged tissues. Because the immune system can respond to microbial and nonmicrobial substances and also can cause disease under some circumstances,

a more inclusive definition of the immune response is a reaction to microbes, as well as to other molecules that are recognized as foreign, regardless of the physiologic or pathologic consequence of such a reaction. Immunology is the study of immune responses in this broader sense and of the cellular and molecular events that occur after an organism encounters microbes and other foreign molecules.

The importance of the immune system for health is dramatically illustrated by the frequent observation that individuals with defective immune responses are susceptible to serious, often life-threatening infections.

Conversely, stimulating immune responses against microbes through vaccination is the most effective method for protecting individuals against infections; this approach has led to the worldwide eradication of smallpox, the only disease that has been eliminated from civilization by human intervention (Fig. 1.2). The appearance of acquired immunodeficiency syndrome (AIDS) in the 1980s tragically emphasized the importance of the immune system for defending individuals against infection.

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CHAPTER 1

Introduction to the Immune System

Role of the immune system Implications Defense against infections

Deficient immunity results in increased susceptibility to infections; exemplified by AIDS Vaccination boosts immune defenses and protects against infections

Defense against tumors

Potential for immunotherapy of cancer

Control of tissue regeneration and scarring The immune system can injure cells and induce pathologic inflammation The immune system recognizes and responds to tissue grafts and newly introduced proteins

Repair of damaged tissues Immune responses are the cause of allergic, autoimmune, and other inflammatory diseases Immune responses are barriers to transplantation and gene therapy

Fig. 1.1 Importance of the immune system in health and disease. This table summarizes some of the physiologic functions of the immune system and its role in disease. AIDS, Acquired immunodeficiency syndrome.

In contrast to these beneficial roles, abnormal immune responses cause many inflammatory diseases with serious morbidity and mortality. The immune response is the major barrier to the success of organ transplantation, which is often used to treat organ failure. The products of immune cells can also be of great practical use. For example, antibodies, which are proteins made by certain cells of the immune system, are used in clinical laboratory testing and in research as highly specific reagents for detecting a wide variety of molecules in the circulation and in cells and tissues. Antibodies designed to block or eliminate potentially harmful molecules and cells are used widely for the treatment of immunologic diseases, cancers, and other types of disorders. For all these reasons, the field of immunology has captured the attention of clinicians, scientists, and the lay public.

This chapter introduces the nomenclature of immunology, important general properties of all immune responses, and the cells and tissues that are the principal components of the immune system. In particular, the following questions are addressed: • What types of immune responses protect individuals from infections?

• What are the important characteristics of immunity, and what mechanisms are responsible for these characteristics?

• H ow are the cells and tissues of the immune system organized to find and respond to microbes in ways that lead to their elimination?

The basic principles introduced here set the stage for more detailed discussions of immune responses in later chapters. A Glossary of the important terms used in this book is provided near the end of the book.

INNATE AND ADAPTIVE IMMUNITY Host defenses are grouped under innate immunity, which provides immediate protection against microbial invasion, and adaptive immunity, which develops more slowly and provides more specialized defense against infections (Fig. 1.3). Innate immunity, also called natural immunity or native immunity, is always present in healthy individuals (hence the term innate), prepared to block the entry of microbes and to rapidly eliminate microbes that do succeed in entering host tissues. Adaptive immunity, also called specific immunity or acquired immunity, requires proliferation and differentiation of lymphocytes in response to microbes before it can provide effective defense (i.e., it adapts to the presence of microbial invaders). Innate immunity is phylogenetically older, and the more specialized and powerful adaptive immune response evolved later.

CHAPTER 1

Introduction to the Immune System

Disease

Maximum number Number of of cases (year) cases in 2014

Diptheria Measles Mumps Pertussis Polio (paralytic)

206,939 (1921)

0

894,134 (1941)

72

152,209 (1968)

40

265,269 (1934)

311

21,269 (1952)

0

57,686 (1969) Rubella Tetanus 1,560 (1923) ~20,000 (1984) Hemophilus influenzae type B infection

0

Hepatitis B

58

26,611 (1985)

3

0 134

Fig. 1.2 Effectiveness of vaccination for some common infectious diseases in the United States. Many infectious diseases for which effective vaccines have been developed have been virtually eradicated in the United States and other developed countries. (Modified from Orenstein WA, Hinman AR, Bart KJ, Hadler SC. Immunization. In: Mandell GL, Bennett JE, Dolin R, editors: Principles and practices of infectious diseases, 4th ed. New York: Churchill Livingstone, 1995; and MMWR 66, No. 1, 2017.)

In innate immunity, the first line of defense is provided by epithelial barriers of the skin and mucosal tissues and by cells and natural antibiotics present in epithelia, all of which function to block the entry of microbes. If microbes do breach epithelia and enter the tissues or circulation, several other components of the innate immune system defend against them, including phagocytes and innate lymphoid cells, and several plasma proteins, such as the complement system. In addition to providing early defense against infections, innate immune responses are required to initiate adaptive immune responses against the infectious agents.

The components and mechanisms of innate immunity are discussed in detail in Chapter 2.

The adaptive immune system consists of lymphocytes with highly diverse and variable receptors for foreign substances, and the products of these cells, such as antibodies. Adaptive immune responses are essential for defense against infectious microbes that are pathogenic for humans (i.e., capable of causing disease) and may have evolved to resist innate immunity. The cells and molecules of innate immunity recognize structures shared by classes of microbes, whereas the lymphocytes of adaptive immunity express receptors that specifically

recognize a much wider variety of molecules produced by microbes, as well as noninfectious molecules. Any molecule that is specifically recognized by lymphocytes or antibodies is called an antigen. Adaptive immune responses often use the cells and molecules of the innate immune system to eliminate microbes. For example, antibodies (a component of adaptive immunity) bind to microbes, and these coated microbes avidly bind to and activate phagocytes (a component of innate immunity), which ingest and destroy the microbes. Examples of the cooperation between innate and adaptive immunity are discussed in later chapters.

By convention, the term immune response generally refers to adaptive immunity, and that is the focus of most of this chapter.

The cells of the immune system are located in different tissues and serve different roles in host defense.

Most of these cells are derived from bone marrow precursors that circulate in the blood and are called leukocytes (white blood cells). Others are present in tissues at all times. Some of these cells function mainly in innate immunity, others in adaptive immunity, and some function in both types of responses. These cells are grouped into two broad categories—lymphoid cells (most of

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