REALLY ESSENTIAL MEDICAL IMMUNOLOGY Arthur Rabson, Ivan M.Roitt, Peter J
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REALLY ESSENTIAL MEDICAL IMMUNOLOGY Arthur Rabson, Ivan M.Roitt, Peter J. Delves SECOND EDITION SECOND EDITION Really Essential Medical Immunology Arthur Rabson MB, BCh, FRCPath Department of Pathology Tufts University School of Medicine Boston USA Ivan M. Roitt DSc, HonFRCP, FRCPath, FRS Department of Immunology & Molecular Pathology Royal Free & University College Medical School London UK Peter J. Delves PhD Department of Immunology & Molecular Pathology Royal Free & University College Medical School London UK © 2005 A. Rabson, I.M. Roitt, P.J. Delves Published by Blackwell Publishing Ltd Blackwell Publishing, Inc., 350 Main Street, Malden, Massachusetts 02148-5020, USA Blackwell Publishing Ltd, 9600 Garsington Road, Oxford OX4 2DQ, UK Blackwell Publishing Asia Pty Ltd, 550 Swanston Street, Carlton, Victoria 3053, Australia The right of the Authors to be identified as the Authors of this Work has been asserted in accordance with the Copyright, Designs and Patents Act 1988. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the prior permission of the publisher. First published 2000 Reprinted 2001 Second edition 2005 Library of Congress Cataloging-in-Publication Data Rabson, Arthur. Really essential medical immunology / Arthur Rabson, Ivan M. Roitt, Peter J. Delves.— 2nd ed. p. ; cm. Rev. ed. of: Really essential medical immunology / Ivan Roitt and Arthur Rabson. 2000. Includes bibliographical references and index. ISBN 1-4051-2115-7 1. Clinical immunology. [DNLM: 1. Immunity. QW 540 R116r 2005] I. Roitt, Ivan M. (Ivan Maurice) II. Delves, Peter J. III. Roitt, Ivan M. (Ivan Maurice). Really essential medical immunology. IV. Title. RC582.R65 2005 616.07’9—dc22 200400393 ISBN 1-4051-2115-7 Acatalogue record for this title is available from the British Library Set in 10/12.5 Palatino by SNP Best-set Typesetter Ltd., Hong Kong Printed and bound in India by Replika Press Pvt., Ltd Commissioning Editor: Martin Sugden Managing Editor: Geraldine Jeffers Production Editors: Fiona Pattison & Alice Nelson Production Controller: Kate Charman For further information on Blackwell Publishing, visit our website: http://www.blackwellpublishing.com The publisher’s policy is to use permanent paper from mills that operate a sustainable forestry policy, and which has been manufactured from pulp processed using acid-free and elementary chlorine-free practices. Furthermore, the publisher ensures that the text paper and cover board used have met acceptable environmental accreditation standards. iii Contents Part 1 The Basis of Immunology Part 4 Immunity to Infection 1Innate Immunity, 1 11 Adversarial Strategies During Infection, 114 2 Specific Acquired Immunity, 17 12 Prophylaxis, 127 Part 2 The Recognition of Antigen Part 5 Clinical Immunology 3 Antibodies, 27 13 Immunodeficiency, 135 4Membrane Receptors for Antigen, 41 14 Hypersensitivity, 148 5The Primary Interaction with Antigen, 50 15 Transplantation, 164 Part 3 The Acquired Immune Response 16 Tumor Immunology, 177 6 The Anatomy of the Immune Response, 62 17 Autoimmune diseases, 188 7Lymphocyte Activation, 75 Glossary, 211 8 The Production of Effectors, 82 Index, 213 9Control Mechanisms, 97 10 Ontogeny, 105 CHAPTER 1 1 Innate immunity External barriers against infection, 1 Complement has a range of defensive biological functions, 9 Phagocytic cells kill microorganisms, 2 Complement can mediate an acute inflammatory The polymorphonuclear neutrophil, 2 reaction, 10 The macrophage, 2 Macrophages can also do it, 10 Pattern recognition receptors (PRRs) on phagocytic cells Humoral mechanisms provide a second defensive recognize and are activated by pathogen-associated strategy, 11 molecular patterns (PAMPs), 4 Acute phase proteins increase in response to infection, 12 Toll-like receptors (TLRs) recognize PAMPs and cause cytokine Extracellular killing, 13 release, 5 Natural killer (NK) cells are part of the innate immune Microbes are engulfed by phagocytosis, 5 system, 13 Killing by reactive oxygen intermediates (ROIs), 6 Natural killer cells also produce cytokines which regulate Other killing mechanisms, 7 inflammation and acquired immune function, 14 Complement facilitates phagocytosis, 7 Eosinophils, 14 Complement and its activation, 7 intact, is impermeable to most infectious agents. When We live in a potentially hostile world filled with a there is skin loss, as for example in burns, infection bewildering array of infectious agents against becomes a major problem. Additionally, most bacteria which we have developed a series of defense fail to survive for long on the skin because of the direct mechanisms at least their equal in effectiveness inhibitory effects of lactic acid and fatty acids in sweat and ingenuity. It is these defense mechanisms that and sebaceous secretions and the low pH which they can establish a state of immunity against infection generate. An exception is Staphylococcus aureus, which (Latin immunitas, freedom from) and whose often infects the relatively vulnerable hair follicles and operation provides the basis for the delightful glands. subject called “Immunology.” Mucus secreted by the membranes lining the inner A number of nonspecific antimicrobial systems surfaces of the body acts as a protective barrier to block (e.g. phagocytosis) have been recognized which the adherence of bacteria to epithelial cells. Microbial are innatein the sense that they are not intrinsically and other foreign particles trapped within the ad- affected by prior contact with the infectious agent hesive mucus are removed by mechanical stratagems and are usually present before the onset of the such as ciliary movement, coughing and sneezing. infectious agent. The innate response is not Among other mechanical factors that help protect the enhanced by previous exposure to the foreign epithelial surfaces, one should also include the wash- organism and the response time is very rapid ing action of tears, saliva and urine. Many of the secret- usually occurring in minutes or hours. We shall ed body fluids contain bactericidal components, such discuss these systems and examine how, in the as acid in gastric juice, spermine and zinc in semen, state of specific acquired immunity, their lactoperoxidase in milk, and lysozyme in tears, nasal effectiveness can be greatly increased. secretions and saliva. Atotally different mechanism is that of microbial an- tagonism where the normal bacterial flora of the body suppresses the growth of many potentially pathogenic EXTERNAL BARRIERS AGAINST INFECTION bacteria and fungi. This is due to competition for essential nutrients or by the production of microbici- The simplest way to avoid infection is to prevent the dal substances. For example, pathogen invasion of the microorganisms from gaining access to the body. The vagina is limited by lactic acid produced by commen- major line of defense is of course the skin which, when sal organisms which metabolize glycogen secreted by 2 PART 1—The basis of immunology Figure 1.1 Ultrastructure of neutrophil. The multilobed nucleus and two main types of cytoplasmic granules are well dis- played. (Courtesy of Dr D. McLaren.) the vaginal epithelium. When protective commensals much of the lysozyme, alkaline phosphatase (figure are disturbed by antibiotics, susceptibility to oppor- 1.2c) and membrane-bound cytochrome b558. tunistic infections such as Candida albicansand Clostrid- ium difficile is increased. The macrophage If microorganisms do penetrate the body, two fur- ther innate defensive operations come into play, the These cells derive from bone marrow promonocytes destructive effect of soluble chemical factors such as which, after differentiation to blood monocytes bactericidal enzymes and the mechanism of phagocy- (figure 1.2a), finally settle in the tissues as mature tosis — literally “eating” by the cell (Milestone 1.1). macrophages where they constitute the mononuclear phagocyte system (figure 1.2d). They are present PHAGOCYTIC CELLS throughout the connective tissue and around the KILL MICROORGANISMS basement membrane of small blood vessels and are particularly concentrated in the lung (figure 1.2f, The polymorphonuclear neutrophil alveolar macrophages), liver (Kupffer cells), and lining of spleen sinusoids and lymph node medullary si- This cell shares a common hematopoietic stem cell pre- nuses, where they are strategically placed to filter off cursor with the other formed elements of the blood and foreign material. Other examples are mesangial cells is the dominant white cell in the bloodstream. It is in the kidney glomerulus, brain microglia and osteo- a nondividing, short-lived cell with a multilobed nu- clasts in bone. Unlike the polymorphonuclear neu- cleus (figures 1.1 & 1.2a,b) and an array of granules trophils, they are long-lived cells with significant which are of two main types (figure 1.1): (i) the primary rough-surface endoplasmic reticulum and mitochon- azurophil granule, which develops early and contains dria. Whereas the neutrophils provide the major de- myeloperoxidase together with most of the nonoxida- fense against pyogenic (pus-forming) bacteria, as a tive antimicrobial effectors, including defensins, rough generalization it may be said that macrophages bactericidal/permeability-increasing (BPI) protein are at their best in combating those bacteria (figure and cathepsin G, and (ii) the peroxidase-negative