HARRISON’S
Rheumatology
Second Edition
Editors
ANTHONY S. FAUCI, MD
Chief, Laboratory of Immunoregulation;
Director, National Institute of Allergy and Infectious...
HARRISON’S
Rheumatology
Editor
Anthony S. Fauci, MD
Chief, Laboratory of Immunoregulation;
Director, National Institute of...
Copyright © 2010 by The McGraw-Hill Companies, Inc. All rights reserved. Except as permitted under the United States Copyr...
v
Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii
Preface. . . . . . . . . . . . . . . . . . . . ...
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ROBERT P. BAUGHMAN, MD
Professor of Medicine, Cincinnati [13]
GERALD BLOOMFIELD, MD, MPH
Department of Internal Medici...
KELLY A. SODERBERG, PhD, MPH
Director, Program Management, Duke HumanVaccine Institute,
Duke University School of Medicine...
ix
In 2006, the first Harrison’s Rheumatology sectional was
introduced with the goal of expanding the outreach of
medical k...
x
NOTICE
Medicine is an ever-changing science. As new research and clinical experi-
ence broaden our knowledge, changes in...
THE IMMUNE
SYSTEM IN HEALTH
AND DISEASE
SECTION I
Barton F. Haynes ■ Kelly A. Soderberg ■ Anthony S. Fauci
DEFINITIONS
• Adaptive immune system—recently evolved system of
i...
• Complement—cascading series of plasma enzymes and
effector proteins whose function is to lyse pathogens
and/or target th...
SECTIONITheImmuneSysteminHealthandDisease
4
(OTHER NAMES) FAMILY MASS, kDa DISTRIBUTION LIGAND(S) FUNCTION
CD1a (T6, HTA-1...
CHAPTER1IntroductiontotheImmuneSystem
5
(OTHER NAMES) FAMILY MASS, kDa DISTRIBUTION LIGAND(S) FUNCTION
CD22 (BL-CAM) Ig 13...
SECTIONITheImmuneSysteminHealthandDisease
6
responses
Note: NK cells, natural killer cells.
FAMILY EXPRESSION EXAMPLES (PA...
cells bind bacterial lipopolysaccharide (LPS) and activate
phagocytic cells to ingest pathogens.
A series of recent discov...
in TLR4 proteins in mice protect from LPS shock, and
TLR mutations in humans protect from LPS-induced
inflammatory disease...
CHAPTER1IntroductiontotheImmuneSystem
9TABLE 1-5
CELLS OF THE INNATE IMMUNE SYSTEM AND THEIR MAJOR ROLES IN TRIGGERING ADA...
(Kupffer cells), bone (osteoclasts), central nervous system
(microglia cells), and synovium (type A lining cells).
In gene...
CHAPTER1IntroductiontotheImmuneSystem
11TABLE 1-6
CYTOKINES AND CYTOKINE RECEPTORS
CYTOKINE RECEPTOR CELL SOURCE CELL TARG...
SECTIONITheImmuneSysteminHealthandDisease
12 TABLE 1-6 (CONTINUED)
CYTOKINES AND CYTOKINE RECEPTORS
CYTOKINE RECEPTOR CELL...
CHAPTER1IntroductiontotheImmuneSystem
13TABLE 1-6 (CONTINUED)
CYTOKINES AND CYTOKINE RECEPTORS
CYTOKINE RECEPTOR CELL SOUR...
SECTIONITheImmuneSysteminHealthandDisease
14 TABLE 1-6 (CONTINUED)
CYTOKINES AND CYTOKINE RECEPTORS
CYTOKINE RECEPTOR CELL...
CHAPTER1IntroductiontotheImmuneSystem
15TABLE 1-6 (CONTINUED)
CYTOKINES AND CYTOKINE RECEPTORS
CYTOKINE RECEPTOR CELL SOUR...
SECTIONITheImmuneSysteminHealthandDisease
16 TABLE 1-7
CC, CXC1, CX3, C1, AND XC FAMILIES OF CHEMOKINES AND CHEMOKINE RECE...
CHAPTER1IntroductiontotheImmuneSystem
17TABLE 1-8
MAJOR STRUCTURAL FAMILIES OF CYTOKINES
Four α-helix- Interleukin-2 (IL-2...
SECTIONITheImmuneSysteminHealthandDisease
18
B cell IgG
antibody
Macrophage
activation
Induce CD8+
cytotoxic
T cells
Activ...
CHAPTER1IntroductiontotheImmuneSystem
19
?
HLA
CD48, NTB-A
MICA, MICB, ULBPs
NCRs
KIRs, CD94
2B4, NTB-A
NKG2D
NK cell Targ...
organisms. In Nippostrongylus brasiliensis helminth infec-
tion, eosinophils are key cytotoxic effector cells in removal
o...
CHAPTER1IntroductiontotheImmuneSystem
21by binding of C3 directly to pathogens and “altered self”
such as tumor cells. In ...
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Harrison's rheumatology, 2nd ed

  1. 1. HARRISON’S Rheumatology Second Edition
  2. 2. Editors ANTHONY S. FAUCI, MD Chief, Laboratory of Immunoregulation; Director, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda DENNIS L. KASPER, MD William Ellery Channing Professor of Medicine, Professor of Microbiology and Molecular Genetics, Harvard Medical School; Director, Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital, Boston DAN L. LONGO, MD Scientific Director, National Institute on Aging, National Institutes of Health, Bethesda and Baltimore EUGENE BRAUNWALD, MD Distinguished Hersey Professor of Medicine, Harvard Medical School; Chairman,TIMI Study Group, Brigham and Women’s Hospital, Boston STEPHEN L. HAUSER, MD Robert A. Fishman Distinguished Professor and Chairman, Department of Neurology, University of California, San Francisco J. LARRY JAMESON, MD, PhD Professor of Medicine;Vice President for Medical Affairs and Lewis Landsberg Dean, Northwestern University Feinberg School of Medicine, Chicago Derived from Harrison’s Principles of Internal Medicine, 17th Edition JOSEPH LOSCALZO, MD, PhD Hersey Professor of Theory and Practice of Medicine, Harvard Medical School; Chairman, Department of Medicine; Physician-in-Chief, Brigham and Women’s Hospital, Boston
  3. 3. HARRISON’S Rheumatology Editor Anthony S. Fauci, MD Chief, Laboratory of Immunoregulation; Director, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda Associate Editor Carol A. Langford, MD, MHS Associate Professor of Medicine; Director, Center forVasculitis Care and Research, Department of Rheumatic and Immunologic Diseases, Cleveland Clinic, Cleveland NewYork Chicago San Francisco Lisbon London Madrid Mexico City Milan New Delhi San Juan Seoul Singapore Sydney Toronto Second Edition
  4. 4. Copyright © 2010 by The McGraw-Hill Companies, Inc. All rights reserved. Except as permitted under the United States Copyright Act of 1976, no part of this publication may be reproduced or distributed in any form or by any means, or stored in a database or retrieval system, without the prior written permission of the publisher. ISBN: 978-0-07-174146-0 MHID: 0-07-174146-1 The material in this eBook also appears in the print version of this title: ISBN: 978-0-07-174143-9, MHID: 0-07-174143-7. All trademarks are trademarks of their respective owners. Rather than put a trademark symbol after every occurrence of a trademarked name, we use names in an editorial fashion only, and to the benefit of the trademark owner, with no intention of infringement of the trademark. Where such designations appear in this book, they have been printed with initial caps. McGraw-Hill eBooks are available at special quantity discounts to use as premiums and sales promotions, or for use in corporate training programs. To contact a representative please e-mail us at bulksales@mcgraw-hill.com. TERMS OF USE This is a copyrighted work and The McGraw-Hill Companies, Inc. (“McGrawHill”) and its licensors reserve all rights in and to the work. Use of this work is subject to these terms. Except as permitted under the Copyright Act of 1976 and the right to store and retrieve one copy of the work, you may not decompile, disassemble, reverse engineer, reproduce, modify, create derivative works based upon, transmit, distribute, disseminate, sell, publish or sublicense the work or any part of it without McGraw-Hill’s prior consent. You may use the work for your own noncommercial and personal use; any other use of the work is strictly prohibited. Your right to use the work may be terminated if you fail to comply with these terms. THE WORK IS PROVIDED “AS IS.” McGRAW-HILL AND ITS LICENSORS MAKE NO GUARANTEES OR WARRANTIES AS TO THE ACCURACY, ADEQUACY OR COMPLETENESS OF OR RESULTS TO BE OBTAINED FROM USING THE WORK, INCLUDING ANY INFORMATION THAT CAN BE ACCESSED THROUGH THE WORK VIA HYPERLINK OR OTHERWISE, AND EXPRESSLY DISCLAIM ANY WARRANTY, EXPRESS OR IMPLIED, INCLUDING BUT NOT LIMITED TO IMPLIED WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE. McGraw-Hill and its licensors do not warrant or guarantee that the functions contained in the work will meet your requirements or that its operation will be uninterrupted or error free. Neither McGraw-Hill nor its licensors shall be liable to you or anyone else for any inaccuracy, error or omission, regardless of cause, in the work or for any damages resulting therefrom. McGraw-Hill has no responsibility for the content of any information accessed through the work. Under no circumstances shall McGraw-Hill and/or its licensors be liable for any indirect, incidental, special, punitive, consequential or similar damages that result from the use of or inability to use the work, even if any of them has been advised of the possibility of such damages. This limitation of liability shall apply to any claim or cause whatsoever whether such claim or cause arises in contract, tort or otherwise.
  5. 5. v Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii Preface. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix SECTION I THE IMMUNE SYSTEM IN HEALTH AND DISEASE 1 Introduction to the Immune System . . . . . . . . . . 2 Barton F. Haynes, Kelly A. Soderberg,Anthony S. Fauci 2 The Major Histocompatibility Complex. . . . . . . 44 GeraldT. Nepom 3 Autoimmunity and Autoimmune Diseases . . . . . 57 Peter E. Lipsky, Betty Diamond SECTION II DISORDERS OF IMMUNE-MEDIATED INJURY 4 Systemic Lupus Erythematosus . . . . . . . . . . . . . 66 Bevra Hannahs Hahn 5 Rheumatoid Arthritis . . . . . . . . . . . . . . . . . . . . 82 Peter E. Lipsky 6 Acute Rheumatic Fever. . . . . . . . . . . . . . . . . . 100 Jonathan R. Carapetis 7 Systemic Sclerosis (Scleroderma) and Related Disorders . . . . . . . . . . . . . . . . . . . . . . 107 JohnVarga 8 Sjögren’s Syndrome . . . . . . . . . . . . . . . . . . . . . 124 Haralampos M. Moutsopoulos 9 The Spondyloarthritides . . . . . . . . . . . . . . . . . 129 Joel D.Taurog 10 TheVasculitis Syndromes . . . . . . . . . . . . . . . . . 144 Carol A. Langford,Anthony S. Fauci 11 Behçet’s Syndrome . . . . . . . . . . . . . . . . . . . . . 166 Haralampos M. Moutsopoulos 12 Relapsing Polychondritis . . . . . . . . . . . . . . . . . 168 Carol A. Langford, Bruce C. Gilliland 13 Sarcoidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . 173 Robert P. Baughman, Elyse E. Lower 14 Familial Mediterranean Fever. . . . . . . . . . . . . . 184 Daniel L. Kastner 15 Amyloidosis . . . . . . . . . . . . . . . . . . . . . . . . . . 189 David C. Seldin, Martha Skinner 16 Polymyositis, Dermatomyositis, and Inclusion Body Myositis. . . . . . . . . . . . . . . . . . . . . . . . . 197 Marinos C. Dalakas SECTION III DISORDERS OF THE JOINTS AND ADJACENT TISSUES 17 Approach to Articular and Musculoskeletal Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210 John J. Cush, Peter E. Lipsky 18 Osteoarthritis . . . . . . . . . . . . . . . . . . . . . . . . . 223 DavidT. Felson 19 Gout and Other Crystal-Associated Arthropathies . . . . . . . . . . . . . . . . . . . . . . . . . 235 H. Ralph Schumacher, Lan X. Chen 20 Infectious Arthritis. . . . . . . . . . . . . . . . . . . . . . 243 Lawrence C. Madoff 21 Fibromyalgia . . . . . . . . . . . . . . . . . . . . . . . . . . 254 Carol A. Langford, Bruce C. Gilliland 22 Arthritis Associated with Systemic Disease and Other Arthritides. . . . . . . . . . . . . . . . . . . . . . . 259 Carol A. Langford, Bruce C. Gilliland 23 Periarticular Disorders of the Extremities . . . . . 271 Carol A. Langford, Bruce C. Gilliland Appendix LaboratoryValues of Clinical Importance . . . . . 277 Alexander Kratz, Michael A. Pesce, Daniel J. Fink Review and Self-Assessment . . . . . . . . . . . . . . . 299 CharlesWiener, Gerald Bloomfield, Cynthia D. Brown, Joshua Schiffer,Adam Spivak Index. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327 CONTENTS
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  7. 7. vii ROBERT P. BAUGHMAN, MD Professor of Medicine, Cincinnati [13] GERALD BLOOMFIELD, MD, MPH Department of Internal Medicine,The Johns Hopkins University School of Medicine, Baltimore [Review and Self-Assessment] CYNTHIA D. BROWN, MD Department of Internal Medicine,The Johns Hopkins University School of Medicine, Baltimore [Review and Self-Assessment] JONATHAN R. CARAPETIS, MBBS, PhD Director, Menzies School of Health Research; Professor, Charles Darwin University,Australia [6] LAN X. CHEN, MD Clinical Assistant Professor of Medicine, University of Pennsylvania, Penn Presbyterian Medical Center and PhiladelphiaVeteran Affairs Medical Center, Philadelphia [19] JOHN J. CUSH, MD Director of Clinical Rheumatology, Baylor Research Institute; Professor of Medicine and Rheumatology, Baylor University Medical Center, Dallas [17] MARINOS C. DALAKAS, MD Professor of Neurology; Chief, Neuromuscular Diseases Section, NINDS, National Institute of Health, Bethesda [16] BETTY DIAMOND, MD Chief,Autoimmune Disease Center,The Feinstein Institute for Medical Research, NewYork [3] ANTHONY S. FAUCI, MD, DSC (Hon), DM&S (Hon), DHL (Hon), DPS (Hon), DLM (Hon), DMS (Hon) Chief, Laboratory of Immunoregulation; Director, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda [1, 10] DAVID T. FELSON, MD, MPH Professor of Medicine and Epidemiology; Chief, Clinical Epidemiology Unit, Boston University, Boston [18] DANIEL J. FINK,† MD, MPH Associate Professor of Clinical Pathology, College of Physicians and Surgeons, Columbia University, NewYork [Appendix] BRUCE C. GILLILAND,† MD Professor of Medicine and Laboratory Medicine, University of Washington School of Medicine, Seattle [12, 21, 22, 23] BEVRA HANNAHS HAHN, MD Professor of Medicine; Chief of Rheumatology;Vice Chair, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles [4] BARTON F. HAYNES, MD Frederic M. Hanes Professor of Medicine and Immunology, Departments of Medicine and Immunology; Director, Duke Human Vaccine Institute, Duke University School of Medicine, Durham [1] DANIEL KASTNER, MD, PhD Chief, Genetics and Genomic Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda [14] ALEXANDER KRATZ, MD, PhD, MPH Assistant Professor of Clinical Pathology, Columbia University College of Physicians and Surgeons;Associate Director, Core Laboratory, Columbia University Medical Center, NewYork- Presbyterian Hospital; Director,Allen Pavilion Laboratory, NewYork [Appendix] CAROL A. LANGFORD, MD, MHS Associate Professor of Medicine; Director, Center forVasculitis Care and Research, Department of Rheumatic and Immunologic Diseases, Cleveland Clinic, Cleveland [10, 12, 21, 22, 23] PETER E. LIPSKY, MD Chief,Autoimmunity Branch, National Institute of Arthritis, Musculoskeletal, and Skin Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda [3, 5, 17] ELYSE E. LOWER, MD Professor of Medicine, University of Cincinnati, Cincinnati [13] LAWRENCE C. MADOFF, MD Associate Professor of Medicine, Harvard Medical School, Boston [20] HARALAMPOS M. MOUTSOPOULOS, MD Professor and Chair, Department of Pathophysiology, School of Medicine, National University of Athens, Greece [8, 11] GERALD T. NEPOM, MD, PhD Director, Benaroya Research Institute atVirginia Mason; Professor, University of Washington School of Medicine, Seattle [2] MICHAEL A. PESCE, PhD Clinical Professor of Pathology, Columbia University College of Physicians and Surgeons; Director of Specialty Laboratory, NewYork Presbyterian Hospital, Columbia University Medical Center, NewYork [Appendix] JOSHUA SCHIFFER, MD Department of Internal Medicine,The Johns Hopkins University School of Medicine, Baltimore [Review and Self-Assessment] H. RALPH SCHUMACHER, MD Professor of Medicine, University of Pennsylvania School of Medicine, Philadelphia [19] DAVID C. SELDIN, MD, PhD Professor of Medicine and Microbiology; Director,Amyloid Treatment and Research Program Section of Hematology-Oncology, Department of Medicine, Boston University School of Medicine and Boston Medical Center, Boston [15] MARTHA SKINNER, MD Professor of Medicine, Boston University School of Medicine; Director, Special Projects,Amyloid Treatment and Research Program, Boston [15] CONTRIBUTORS Numbers in brackets refer to the chapter(s) written or co-written by the contributor. † Deceased
  8. 8. KELLY A. SODERBERG, PhD, MPH Director, Program Management, Duke HumanVaccine Institute, Duke University School of Medicine, Durham [1] ADAM SPIVAK, MD Department of Internal Medicine,The Johns Hopkins University School of Medicine, Baltimore [Review and Self-Assessment] JOEL D.TAUROG, MD Professor of Internal Medicine,William M. and Gatha Burnett Professor for Arthritis Research, University of Texas Southwestern Medical Center, Dallas [9] JOHN VARGA, MD Hughes Professor of Medicine, Northwestern University Feinberg School of Medicine, Chicago [7] CHARLES WIENER, MD Professor of Medicine and Physiology; Vice Chair, Department of Medicine; Director, Osler Medical Training Program, The Johns Hopkins University School of Medicine, Baltimore [Review and Self-Assessment] viii Contributors
  9. 9. ix In 2006, the first Harrison’s Rheumatology sectional was introduced with the goal of expanding the outreach of medical knowledge that began with the first edition of Harrison’s Principles of Internal Medicine, which was pub- lished over 60 years ago. The sectional, which is com- prised of the immunology and rheumatology chapters contained in Harrison’s Principles of Internal Medicine, sought to provide readers with a current view of the sci- ence and practice of rheumatology. After its introduc- tion, we were gratified to learn that this sectional was being utilized not only by young physicians gaining their first exposure to rheumatology, but also by a di- versity of health care professionals seeking to remain updated on the latest advancements within this dy- namic subspecialty of internal medicine.With this edi- tion of the Harrison’s Rheumatology, it remains our goal to provide the expertise of leaders in rheumatology and immunology to all students of medicine who wish to learn more about this important and constantly chang- ing field. The aspects of medical care encompassed by rheuma- tology greatly impact human health. Musculoskeletal symptoms are among the leading reasons that patients seek medical attention, and it is now estimated that one out of three people will be affected by arthritis. Joint and muscle pain not only affect quality of life and pro- duce disability, they may also be heralding symptoms of serious inflammatory, infectious, or neoplastic diseases. Because of their frequency and the morbidity associated with the disease itself, as well as the therapeutic modalities employed, rheumatic diseases impact all physicians. Although the connective tissues form the foundation of rheumatology, this specialty encompasses a wide spec- trum of medical disorders which exemplify the diversity and complexity of internal medicine. Rheumatic dis- eases can range from processes characterized by monar- ticular arthropathy to multisystem illnesses that carry a significant risk of morbidity or mortality. The effective practice of rheumatology therefore requires broad-based diagnostic skills, a strong fundamental understanding of internal medicine, the ability to recognize life-threatening disease, and the knowledge of how to utilize and monitor a wide range of treatments in which benefit must be balanced against risk. Understanding these challenges provides an opportunity to improve the lives of patients, and it is these factors that make the practice of rheumatology an immensely rewarding area of internal medicine. Another facet of rheumatology that has captivated the interest of both clinicians and biomedical researchers is its relationship to immunology and autoimmunity. From early studies in rheumatology, clinical and histo- logic evidence of inflammation supported the view that the immune system mediated many forms of joint and tissue injury. Laboratory-based investigations have not only provided firm evidence for the immunologic basis of these diseases, but they have identified specific mech- anisms involved in the pathogenesis of individual clinical entities. Recognition of the pathways involved in disease and the potential to target specific immune effector functions have revolutionized the treatment of many rheumatic diseases. Such investigations will continue to shed insights regarding the pathogenesis of a wide range of rheumatic diseases, and will bring forth novel therapies that offer even greater potential to lessen pain, reduce joint and organ damage, and improve overall clinical outcome. This sectional was originally developed in recogni- tion of the importance of rheumatology to the practice of internal medicine as well as the rapid pace of scien- tific growth in this specialty. This assessment has been borne out by the numerous advancements in rheuma- tology that have been made even within the short pe- riod of time since the last sectional was published. The need for this sectional is a tribute to the hard work of many dedicated individuals at both the bench and the bedside whose contributions have greatly benefited our patients. It is the continued hope of the editors that this sectional will not only increase knowledge of the rheumatic diseases, but also serve to heighten apprecia- tion for this fascinating specialty. Anthony S. Fauci, MD Carol A. Langford, MD, MHS PREFACE
  10. 10. x NOTICE Medicine is an ever-changing science. As new research and clinical experi- ence broaden our knowledge, changes in treatment and drug therapy are required. The authors and the publisher of this work have checked with sources believed to be reliable in their efforts to provide information that is complete and generally in accord with the standards accepted at the time of publication. However, in view of the possibility of human error or changes in medical sciences, neither the authors nor the publisher nor any other party who has been involved in the preparation or publication of this work warrants that the information contained herein is in every respect accurate or complete, and they disclaim all responsibility for any errors or omissions or for the results obtained from use of the information contained in this work. Readers are encouraged to confirm the information contained herein with other sources. For example, and in particular, readers are advised to check the product information sheet included in the package of each drug they plan to administer to be certain that the information contained in this work is accurate and that changes have not been made in the recommended dose or in the contraindications for administration.This recommendation is of particular importance in connection with new or infrequently used drugs. The global icons call greater attention to key epidemiologic and clinical differences in the practice of medicine throughout the world. The genetic icons identify a clinical issue with an explicit genetic relationship. Review and self-assessment questions and answers were taken from Wiener C, Fauci AS, Braunwald E, Kasper DL, Hauser SL, Longo DL, Jameson JL, Loscalzo J (editors) Bloomfield G, Brown CD, Schiffer J, Spivak A (contributing editors). Harri- son’s Principles of Internal Medicine Self-Assessment and Board Review, 17th ed. NewYork, McGraw-Hill,2008,ISBN 978-0-07-149619-3.
  11. 11. THE IMMUNE SYSTEM IN HEALTH AND DISEASE SECTION I
  12. 12. Barton F. Haynes ■ Kelly A. Soderberg ■ Anthony S. Fauci DEFINITIONS • Adaptive immune system—recently evolved system of immune responses mediated by T and B lymphocytes. Immune responses by these cells are based on specific antigen recognition by clonotypic receptors that are products of genes that rearrange during development and throughout the life of the organism. Additional cells of the adaptive immune system include various types of antigen-presenting cells. • Antibody—B cell–produced molecules encoded by genes that rearrange during B cell development consisting of immunoglobulin heavy and light chains that together form the central component of the B cell receptor for antigen. Antibody can exist as B cell surface antigen- recognition molecules or as secreted molecules in plasma and other body fluids (Table 1-11). • Antigens—foreign or self-molecules that are recog- nized by the adaptive and innate immune systems resulting in immune cell triggering, T cell activation, and/or B cell antibody production. • Antimicrobial peptides—small peptides <100 amino acids in length that are produced by cells of the innate immune system and have anti-infectious agent activity (Table 1-2). • Apoptosis—the process of programmed cell death where by signaling through various “death receptors” on the surface of cells [e.g., tumor necrosis factor (TNF) recep- tors, CD95] leads to a signaling cascade that involves INTRODUCTION TO THE IMMUNE SYSTEM activation of the caspase family of molecules and leads to DNA cleavage and cell death. Apoptosis, which does not lead to induction of inordinate inflammation, is to be contrasted with cell necrosis, which does lead to induction of inflammatory responses. • B lymphocytes—bone marrow–derived or bursal-equivalent lymphocytes that express surface immunoglobulin (the B cell receptor for antigen) and secrete specific anti- body after interaction with antigen (Figs. 1-2, 1-6). • B cell receptor for antigen—complex of surface molecules that rearrange during postnatal B cell development, made up of surface immunoglobulin (Ig) and associ- ated Ig αβ chain molecules that recognize nominal antigen via Ig heavy and light chain variable regions, and signal the B cell to terminally differentiate to make antigen-specific antibody (Fig. 1-8). • CD classification of human leukocyte differentiation antigens— the development of monoclonal antibody technology led to the discovery of a large number of new leukocyte surface molecules. In 1982, the First InternationalWork- shop on Leukocyte Differentiation Antigens was held to establish a nomenclature for cell-surface molecules of human leukocytes. From this and subsequent leuko- cyte differentiation workshops has come the cluster of differentiation (CD) classification of leukocyte antigens (Table 1-1). • Chemokines—soluble molecules that direct and deter- mine immune cell movement and circulation pathways. CHAPTER 1CHAPTER 1 Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3 The Innate Immune System . . . . . . . . . . . . . . . . . . . . . . . . . . . .6 Pattern Recognition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Effector Cells of Innate Immunity . . . . . . . . . . . . . . . . . . . . . . . . 8 Cytokines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 The Adaptive Immune System . . . . . . . . . . . . . . . . . . . . . . . . 22 Cellular Interactions in Regulation of Normal Immune Responses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 Immune Tolerance and Autoimmunity . . . . . . . . . . . . . . . . . . . 31 The Cellular and Molecular Control of Programmed Cell Death . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 Mechanisms of Immune-Mediated Damage to Microbes or Host Tissues . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 Clinical Evaluation of Immune Function . . . . . . . . . . . . . . . . . . 40 Immunotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 ■ Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42 2
  13. 13. • Complement—cascading series of plasma enzymes and effector proteins whose function is to lyse pathogens and/or target them to be phagocytized by neutrophils and monocyte/macrophage lineage cells of the reticu- loendothelial system (Fig. 1-5). • Co-stimulatory molecules—molecules of antigen-present- ing cells (such as B7-1 and B7-2 or CD40) that lead to T cell activation when bound by ligands on activated T cells (such as CD28 or CD40 ligand) (Fig. 1-7). • Cytokines—soluble proteins that interact with specific cellular receptors that are involved in the regulation of the growth and activation of immune cells and medi- ate normal and pathologic inflammatory and immune responses (Tables 1-6, 1-8, 1-9). • Dendritic cells—myeloid and/or lymphoid lineage antigen- presenting cells of the adaptive immune system. Imma- ture dendritic cells, or dendritic cell precursors, are key components of the innate immune system by responding to infections with production of high levels of cytokines. Dendritic cells are key initiators both of innate immune responses via cytokine production and of adaptive immune responses via presentation of antigen to T lymphocytes (Figs. 1-2 and 1-3, Table 1-5). • Innate immune system—ancient immune recognition system of host cells bearing germ line–encoded pattern recogni- tion receptors (PRRs) that recognize pathogens and trig- ger a variety of mechanisms of pathogen elimination.Cells of the innate immune system include natural killer (NK) cell lymphocytes,monocytes/macrophages,dendritic cells, neutrophils, basophils, eosinophils, tissue mast cells, and epithelial cells (Tables 1-2,1-3,1-4,1-5,1-10). • Large granular lymphocytes—lymphocytes of the innate immune system with azurophilic cytotoxic granules that have NK cell activity capable of killing foreign and host cells with few or no self–major histocompati- bility complex (MHC) class I molecules (Fig. 1-4). • Natural killer cells—large granular lymphocytes that kill target cells expressing few or no human leukocyte antigen (HLA) class I molecules, such as malignantly transformed cells and virally infected cells. NK cells express receptors that inhibit killer cell function when self–MHC class I is present (Fig. 1-4). • Pathogen-associated molecular patterns (PAMPs)—Invari- ant molecular structures expressed by large groups of microorganisms that are recognized by host cellular pattern recognition receptors in the mediation of innate immunity (Fig. 1-1). • Pattern recognition receptors (PRRs)—germ line–encoded receptors expressed by cells of the innate immune system that recognize pathogen-associated molecular patterns (Table 1-3). • T cells—thymus-derived lymphocytes that mediate adaptive cellular immune responses including T helper, T regulatory, and cytotoxic T lymphocyte effector cell functions (Figs. 1-2, 1-3, 1-6). • T cell receptor for antigen—complex of surface molecules that rearrange during postnatal T cell development made up of clonotypic T cell receptor (TCR) α and β chains that are associated with the CD3 complex com- posed of invariant γ, δ, ε, ζ, and η chains.TCR-α and -β chains recognize peptide fragments of protein antigen physically bound in antigen-presenting cell MHC class I or II molecules, leading to signaling via the CD3 com- plex to mediate effector functions (Fig. 1-7). • Tolerance—B and T cell nonresponsiveness to antigens that results from encounter with foreign or self-antigens by B and T lymphocytes in the absence of expression of antigen-presenting cell co-stimulatory molecules. Tolerance to antigens may be induced and maintained by multiple mechanisms either centrally (in the thymus for T cells or bone marrow for B cells) or peripherally at sites throughout the peripheral immune system. INTRODUCTION The human immune system has evolved over millions of years from both invertebrate and vertebrate organisms to develop sophisticated defense mechanisms to protect the host from microbes and their virulence factors.The normal immune system has three key properties: a highly diverse repertoire of antigen receptors that enables recognition of a nearly infinite range of pathogens; immune memory, to mount rapid recall immune responses; and immunologic tolerance, to avoid immune damage to normal self-tissues. From invertebrates, humans have inherited the innate immune system, an ancient defense system that uses germ line–encoded proteins to recognize pathogens. Cells of the innate immune system,such as macrophages,dendritic cells, and natural killer (NK) lymphocytes, recognize pathogen- associated molecular patterns (PAMPs) that are highly conserved among many microbes and use a diverse set of pattern recognition receptor molecules (PRRs). Important components of the recognition of microbes by the innate immune system include (1) recognition by germ line– encoded host molecules, (2) recognition of key microbe virulence factors but not recognition of self-molecules, and (3) nonrecognition of benign foreign molecules or microbes. Upon contact with pathogens, macrophages and NK cells may kill pathogens directly or, in concert with dendritic cells,may activate a series of events that both slow the infection and recruit the more recently evolved arm of the human immune system, the adaptive immune system. Adaptive immunity is found only in vertebrates and is based on the generation of antigen receptors on T and B lymphocytes by gene rearrangements, such that individual T or B cells express unique antigen receptors on their surface capable of specifically re cognizing diverse anti- gens of the myriad infectious agents in the environment. Coupled with finely tuned specific recognition mecha- nisms that maintain tolerance (nonreactivity) to self- antigens,T and B lymphocytes bring both specificity and immune memory to vertebrate host defenses. This chapter describes the cellular components, key molecules (Table 1-1), and mechanisms that make up the CHAPTER1IntroductiontotheImmuneSystem 3
  14. 14. SECTIONITheImmuneSysteminHealthandDisease 4 (OTHER NAMES) FAMILY MASS, kDa DISTRIBUTION LIGAND(S) FUNCTION CD1a (T6, HTA-1) Ig 49 CD, cortical thymocytes, TCRγδ T cells CD1 molecules present Langerhans type of lipid antigens of intracellular dendritic cells bacteria such as M. leprae and M. tuberculosis to TCRγδ T cells. CD1b Ig 45 CD, cortical thymocytes, TCRγδ T cells Langerhans type of dendritic cells CD1c Ig 43 DC, cortical thymocytes, TCRγδ T cells subset of B cells, Langerhans type of dendritic cells CD1d Ig ? Cortical thymocytes, TCRγδ T cells intestinal epithelium, Langerhans type of dendritic cells CD2 (T12, LFA-2) Ig 50 T, NK CD58, CD48, Alternative T cell activation, CD59, CD15 T cell anergy, T cell cytokine production, T- or NK-mediated cytolysis, T cell apoptosis, cell adhesion CD3 (T3, Leu-4) Ig γ:25–28, T Associates with T cell activation and δ:21–28, the TCR function; ζ is the signal ε:20–25, transduction components η:21–22, of the CD3 complex ζ:16 CD4 (T4, Leu-3) Ig 55 T, myeloid MHC-II, HIV, T cell selection, T cell gp120, IL-16, activation, signal transduction SABP with p56lck, primary receptor for HIV CD7 (3A1, Leu-9) Ig 40 T, NK K-12 (CD7L) T and NK cell signal transduction and regulation of IFN-γ, TNF-α production CD8 (T8, Leu-2) Ig 34 T MHC-I T cell selection, T cell activation, signal transduction with p56lck CD14 (LPS- LRG 53–55 M, G (weak), not by Endotoxin TLR4 mediates with LPS receptor) myeloid progenitors (lipopolysaccha- and other PAMP activation ride), lipoteichoic of innate immunity acid, PI CD19 (B4) Ig 95 B (except plasma Not known Associates with CD21 and cells), FDC CD81 to form a complex involved in signal transduction in B cell development, activation, and differentiation CD20 (B1) Un- 33–37 B (except plasma cells) Not known Cell signaling, may be assigned important for B cell activation and proliferation CD21 (B2, CR2, RCA 145 Mature B, FDC, subset C3d, C3dg, iC3b, Associates with CD19 and EBV-R, C3dR) of thymocytes CD23, EBV CD81 to form a complex involved in signal transduction in B cell development, activation, and differentiation; Epstein-Barr virus receptor (Continued) TABLE 1-1 HUMAN LEUKOCYTE SURFACE ANTIGENS—THE CD CLASSIFICATION OF LEUKOCYTE DIFFERENTIATION ANTIGENS SURFACE ANTIGEN MOLECULAR
  15. 15. CHAPTER1IntroductiontotheImmuneSystem 5 (OTHER NAMES) FAMILY MASS, kDa DISTRIBUTION LIGAND(S) FUNCTION CD22 (BL-CAM) Ig 130–140 Mature B CDw75 Cell adhesion, signaling through association with p72sky, p53/56lyn, PI3 kinase, SHP1, fLCγ CD23 (FcεRII, C-type 45 B, M, FDC IgE, CD21, Regulates IgE synthesis, B6, Leu-20, lectin CD11b, cytokine release by BLAST-2) CD11c monocytes CD28 Ig 44 T, plasma cells CD80, CD86 Co-stimulatory for T cell activation; involved in the decision between T cell activation and anergy CD40 TNFR 48–50 B, DC, EC, thymic CD154 B cell activation, epithelium, MP, proliferation, and cancers differentiation, formation of GCs, isotype switching, rescue from apoptosis CD45 (LCA, PTP 180, 200, All leukocytes Galectin-1, CD2, T and B activation, thymo- T200, B220) 210, 220 CD3, CD4 cyte development, signal transduction, apoptosis CD45RA PTP 210, 220 Subset T, medullary Galectin-1, CD2, Isoforms of CD45 containing thymocytes, “naïve” T CD3, CD4 exon 4 (A), restricted to a subset of T cells CD45RB PTP 200, 210, All leukocytes Galectin-1, CD2, Isoforms of CD45 containing 220 CD3, CD4 exon 5 (B) CD45RC PTP 210, 220 Subset T, medullary Galectin-1, CD2, Isoforms of CD45 containing thymocytes, “naïve” T CD3, CD4 exon 6 (C), restricted to a subset of T cells CD45RO PTP 180 Subset T, cortical Galectin-1, CD2, Isoforms of CD45 containing thymocytes, CD3, CD4 no differentially spliced “memory” T exons, restricted to a subset of T cells CD80 (B7-1, BB1) Ig 60 Activated B and T, CD28, CD152 Co-regulator of T cell MP, DC activation; signaling through CD28 stimulates and through CD152 inhibits T cell activation CD86 (B7-2, B70) Ig 80 Subset B, DC, EC, CD28, CD152 Co-regulator of T cell activation; activated T, thymic signaling through CD28 epithelium stimulates and through CD152 inhibits T cell activation CD95 (APO-1, Fas) TNFR 135 Activated T and B Fas ligand Mediates apoptosis CD152 (CTLA-4) Ig 30–33 Activated T CD80, CD86 Inhibits T cell proliferation CD154 (CD40L) TNF 33 Activated CD4+ T, CD40 Co-stimulatory for T cell subset CD8+ T, NK, activation, B cell M, basophil proliferation and differentiation Note: CTLA, cytotoxic T lymphocyte–associated protein; DC, dendritic cells; EBV, Epstein-Barr virus; EC, endothelial cells; ECM, extracellular matrix; Fcγ RIIIA, low-affinity IgG receptor isoform A; FDC, follicular dendritic cells; G, granulocytes; GC, germinal center; GPI, glycosyl phos- photidylinositol; HTA, human thymocyte antigen; IgG, immunoglobulin G; LCA, leukocyte common antigen; LPS, lipopolysaccharide; MHC-I, major histocompatibility complex class I; MP, macrophages; Mr, relative molecular mass; NK, natural killer cells; P, platelets; PBT, peripheral blood T cells; PI, phosphotidylinositol; PI3K, phosphotidylinositol 3-kinase; PLC, phospholipase C; PTP, protein tyrosine phosphatase; TCR, T cell receptor; TNF, tumor necrosis factor; TNFR, tumor necrosis factor receptor. For an expanded list of cluster of differentiation (CD) human anti- gens, see Harrison’s Online at http://harrisons.accessmedicine.com; and for a full list of CD human antigens from the most recent Human Work- shop on Leukocyte Differentiation Antigens (VII), see http://www.ncbi.nlm.nih.gov/prow/guide. Sources: Compiled from T Kishimoto et al (eds): Leukocyte Typing VI, New York, Garland Publishing 1997; R Brines et al: Immunology Today 18S:1, 1997; and S Shaw (ed): Protein Reviews on the Web http://www.ncbi/nlm.nih.gov.prow.guide. TABLE 1-1 (CONTINUED) HUMAN LEUKOCYTE SURFACE ANTIGENS—THE CD CLASSIFICATION OF LEUKOCYTE DIFFERENTIATION ANTIGENS SURFACE ANTIGEN MOLECULAR
  16. 16. SECTIONITheImmuneSysteminHealthandDisease 6 responses Note: NK cells, natural killer cells. FAMILY EXPRESSION EXAMPLES (PAMPS) OF PRR Toll-like Multiple cell TLR2-10 (see Fig. 1-1 and Activate innate immune cells to receptors types Table 1-4) respond to multiple Bacterial and viral pathogens and initiate carbohydrates adaptive immune responses. C-type lectins Plasma proteins Collectins Terminal mannose Opsonization of bacteria and virus, activation of complement Humoral Macrophages, Macrophage Carbohydrate on Phagocytosis of pathogens dendritic cell mannose receptor HLA molecules Cellular Natural killer NKG2-A Inhibits killing of host cells (NK) cells expressing HLA+ self peptides Leucine-rich Macrophages, CD14 Lipopolysaccharide Binds LPS and Toll proteins proteins dendritic cells, (LPS) epithelial cells Scavenger Macrophage Macrophage Bacterial cell walls Phagocytosis of bacteria receptors scavenger receptors Pentraxins Plasma protein C-creative proteins Phosphatidyl choline Opsonization of bacteria, activation of complement Plasma protein Serum amyloid P Bacterial cell walls Opsonization of bacteria, activation of complement Lipid Plasma protein LPS binding protein LPS Binds LPS, transfers LPS transferases to CD14 Integrins Macrophages, CD11b,c; CD18 LPS Signals cells, activates dendritic cells, phagocytosis NK cells Note: PAMPs, pathogen-associated molecular patterns. Source: Adapted with permission from R Medzhitov, CA Janeway, Innate immunity: Impact on the adaptive immune response. Curr Opin Immunol 9:4, 1997. innate and adaptive immune systems, and describes how adaptive immunity is recruited to the defense of the host by innate immune responses. An appreciation of the cel- lular and molecular bases of innate and adaptive immune responses is critical to understanding the pathogenesis of inflammatory, autoimmune, infectious, and immunodefi- ciency diseases. THE INNATE IMMUNE SYSTEM All multicellular organisms, including humans, have devel- oped the use of a limited number of germ line–encoded molecules that recognize large groups of pathogens. Because of the myriad human pathogens, host molecules of the human innate immune system sense “danger sig- nals” and either recognize PAMPs, the common molecular structures shared by many pathogens,or recognize host cell molecules produced in response to infection such as heat shock proteins and fragments of the extracellular matrix. PAMPs must be conserved structures vital to pathogen virulence and survival, such as bacterial endotoxin, so that pathogens cannot mutate molecules of PAMPs to evade human innate immune responses. PRRs are host proteins of the innate immune system that recognize PAMPs or host danger signal molecules (Tables 1-2, 1-3). Thus, TABLE 1-3 MAJOR PATTERN RECOGNITION RECEPTORS (PRR) OF THE INNATE IMMUNE SYSTEM PRR PROTEIN SITES OF LIGANDS FUNCTIONS TABLE 1-2 MAJOR COMPONENTS OF THE INNATE IMMUNE SYSTEM Pattern recognition C type lectins, leucine-rich proteins, receptors (PRR) scavenger receptors, pentraxins, lipid transferases, integrins Antimicrobial α-Defensins, β-defensins, peptides cathelin, protegrin, granulsyin, histatin, secretory leukoprotease inhibitor, and probiotics Cells Macrophages, dendritic cells, NK cells, NK-T cells, neutrophils, eosinophils, mast cells, basophils, and epithelial cells Complement Classic and alternative components complement pathway, and proteins that bind complement components Cytokines Autocrine, paracrine, endocrine cytokines that mediate host defense and inflammation, as well as recruit, direct, and regulate adaptive immune
  17. 17. cells bind bacterial lipopolysaccharide (LPS) and activate phagocytic cells to ingest pathogens. A series of recent discoveries has revealed the mech- anisms of connection between the innate and adaptive immune systems; these include (1) a plasma protein, LPS-binding protein, which binds and transfers LPS to the macrophage LPS receptor, CD14; and (2) a human family of proteins called Toll-like receptor pro- teins (TLR), some of which are associated with CD14, bind LPS, and signal epithelial cells, dendritic cells, and macrophages to produce cytokines and upregulate cell- surface molecules that signal the initiation of adaptive immune responses (Fig. 1-1,Tables 1-3, 1-4). Proteins in the Toll family (TLR 1–10) can be expressed on macrophages, dendritic cells, and B cells as well as on a variety of nonhematopoietic cell types, including respi- ratory epithelial cells (Tables 1-4, 1-5). Upon ligation, these receptors activate a series of intracellular events that lead to the killing of bacteria- and viral-infected cells as well as to the recruitment and ultimate activa- tion of antigen-specific T and B lymphocytes (Fig. 1-1). Importantly, signaling by massive amounts of LPS through TLR4 leads to the release of large amounts of cytokines that mediate LPS-induced shock. Mutations CHAPTER1IntroductiontotheImmuneSystem 7recognition of pathogen molecules by hematopoietic and non-hematopoietic cell types leads to activation/produc- tion of the complement cascade, cytokines, and antimicro- bial peptides as effector molecules. In addition, pathogen PAMPs and host danger signal molecules activate dendritic cells to mature and to express molecules on the dendritic cell surface that optimize antigen presentation to respond to foreign antigens. PATTERN RECOGNITION Major PRR families of proteins include C-type lectins, leucine-rich proteins, macrophage scavenger receptor proteins, plasma pentraxins, lipid transferases, and inte- grins (Table 1-3). A major group of PRR collagenous glycoproteins with C-type lectin domains are termed collectins and include the serum protein mannose-binding lectin (MBL). MBL and other collectins, as well as two other protein families—the pentraxins (such as C-reactive protein and serum amyloid P) and macrophage scavenger receptors—all have the property of opsonizing (coating) bacteria for phagocytosis by macrophages and can also activate the complement cascade to lyse bacteria. Integrins are cell-surface adhesion molecules that signal cells after CD14 LPS Inflammatory cytokines and/ or chemokinesNucleus TLR9 CpG ssRNA EndosomeTLR7 or TLR8 MyD88 MyD88MyD88 TIRAPTRIF TRIF TRAM Triacylated lipopeptides Diacylated lipopeptides Flagellin Unknown TLR4 TLR2 TLR1 TLR2 TLR6 TLR5 TLR10 Plasma membrane TRAF-6 IRAK NF-κBMAPK NF-κB IFN-β IRF3 IRF3 TLR3 dsRNA Endosome FIGURE 1-1 Overview of major TLR signaling pathways. All TLRs signal through MyD88, with the exception of TLR3. TLR4 and the TLR2 subfamily (TLR1, TLR2, TLR6) also engage TIRAP. TLR3 signals through TRIF. TRIF is also used in conjunction with TRAM in the TLR4–MyD88-independent pathway. Dashed arrrows indicate translocation into the nucleus. LPS, lipopolysaccharide; dsRNA, double-strand RNA; ssRNA, single-strand RNA; MAPK, mitogen-activated protein kinases; NF-κB, nuclear factor-κB; IRF3, interferon regulatory factor 3. (Adapted from D van Duin, R Medzhitov, AC Shaw, 2005; with permission.)
  18. 18. in TLR4 proteins in mice protect from LPS shock, and TLR mutations in humans protect from LPS-induced inflammatory diseases such as LPS-induced asthma (Fig. 1-1). Cells of invertebrates and vertebrates produce antimi- crobial small peptides (<100 amino acids) that can act as endogenous antibodies (Table 1-2). Some of these pep- tides are produced by epithelia that line various organs, while others are found in macrophages or neutrophils that ingest pathogens. Antimicrobial peptides have been identified that kill bacteria such as Pseudomonas spp., Escherichia coli, and Mycobacterium tuberculosis. EFFECTOR CELLS OF INNATE IMMUNITY Cells of the innate immune system and their roles in the first line of host defense are listed in Table 1-5. Equally important as their roles in the mediation of innate immune responses are the roles that each cell type plays in recruiting T and B lymphocytes of the adaptive immune system to engage in specific antipathogen responses. Monocytes-Macrophages Monocytes arise from precursor cells within bone mar- row (Fig. 1-2) and circulate with a half-life ranging from 1 to 3 days. Monocytes leave the peripheral circu- lation by marginating in capillaries and migrating into a vast extravascular pool. Tissue macrophages arise from monocytes that have migrated out of the circulation and by in situ proliferation of macrophage precursors in tis- sue. Common locations where tissue macrophages (and certain of their specialized forms) are found are lymph node, spleen, bone marrow, perivascular connective tis- sue, serous cavities such as the peritoneum, pleura, skin connective tissue, lung (alveolar macrophages), liver SECTIONITheImmuneSysteminHealthandDisease 8 TABLE 1-4 THE ROLE OF PRRS IN MODULATION OF T CELL RESPONSES PRR DC OR MACROPHAGE ADAPTIVE IMMUNE FAMILY PRRS LIGAND CYTOKINE RESPONSE RESPONSE TLRs TLR2 Lipopeptides Low IL-12p70 TH1 (heterodimer Pam-3-cys (TLR 2/6) High IL-10 TH2 with TLR1 or 6) MALP (TLR 2/1) IL-6 T regulatory TLR3 dsRNA IL-12p70 TH1 IFN-α IL-6 TLR4 E. coli LPS High IL-12p70 TH1 Intermediate IL-10 IL-6 TLR5 Flagellin High IL-12p70 TH1 Low IL-12p70 TH2 TLR7/8 ssRNA High IL-12p70 TH1 Imidazoquinolines IFN-α IL-6 TLR9 CpG DNA High IL-12p70 TH1 Low IL-10 IL-6 IFN-α TLR10 ? ? ? C-type DC-SIGN Env of HIV; core protein H. pylori, Lewis Ag TH2 lectins of HCV; components Suppresses IL-12p70 of M. tuberculosis; Suppression of TLR signaling T regulatory H. pylori, Lewis Ag in DCs NOD NOD2 Muramyl dipeptide Induces IL-10 in DCs Weak T cell response of peptidoglycan (tolerogenic?) Mannose Mannose Mannosylated Suppression of IL-12 and Weak T cell response? receptor receptor lipoarabinomannans TLR signaling in DCs (tolerogenic?) from bacillus Calmette-Guerin and M. tuberculosis Note: dsRNA, double-strand RNA; ssRNA, single-strand RNA; LPS, lipopolysaccharide; TH2, helper T cell; TH1, helper T cell; CpG, sequences in DNA recognized by TLR-9; MALP, macrophage-activating lipopeptide; DC-SIGN, DC-specific C-type lectin; NOD, NOTCH protein domain; TLR, Toll-like receptor; HIV, human immunodeficiency virus; HCV, hepatitis C. Source: B Pulendran, J Immunol 174:2457, 2005. Copyright 2005 The American Association of Immunologists, Inc.; with permission.
  19. 19. CHAPTER1IntroductiontotheImmuneSystem 9TABLE 1-5 CELLS OF THE INNATE IMMUNE SYSTEM AND THEIR MAJOR ROLES IN TRIGGERING ADAPTIVE IMMUNITY CELL TYPE MAJOR ROLE IN INNATE IMMUNITY MAJOR ROLE IN ADAPTIVE IMMUNITY Macrophages Phagocytose and kill bacteria; produce Produce IL-1 and TNF-α to upregulate lymphocyte antimicrobial peptides; bind (LPS); adhesion molecules and chemokines to attract produce inflammatory cytokines antigen-specific lymphocyte. Produce IL-12 to recruit TH1 helper T cell responses; upregulate co-stimulatory and MHC molecules to facilitate T and B lymphocyte recognition and activation. Macrophages and dendritic cells, after LPS signaling, upregulate co-stimulatory molecules B7-1 (CD80) and B7-2 (CD86) that are required for activation of antigen-specific anti-pathogen T cells. There are also Toll-like proteins on B cells and dendritic cells that, after LPS ligation, induce CD80 and CD86 on these cells for T cell antigen presentation Plasmacytoid f Produce large amounts of interferon-α IFN-α is a potent activator of macrophage and dendritic cells (DCs) (IFN-α), which has antitumor and antiviral mature DCs to phagocytose invading pathogens of lymphoid lineage activity, and are found in T cell zones of and present pathogen antigens to T and B cells lymphoid organs; they circulate in blood Myeloid dendritic cells Interstitial DCs are strong producers of Interstitial DCs are potent activator of macrophage are of two types; IL-12 and IL-10 and are located in and mature DCs to phagocytose invading interstitial and T cell zones of lymphoid organs, circulate pathogens and present pathogen antigens to Langerhans-derived in blood, and are present in the interstices T and B cells of the lung, heart, and kidney; Langerhans DCs are strong producers of IL-12; are located in T cell zones of lymph nodes, skin epithelia, and the thymic medulla; and circulate in blood Natural killer (NK) cells Kill foreign and host cells that have Produce TNF-α and IFN-γ that recruit TH1 helper low levels of MHC+ self-peptides. T cell responses Express NK receptors that inhibit NK function in the presence of high expression of self-MHC NK-T cells Lymphocytes with both T cell and NK Produce IL-4 to recruit TH2 helper T cell surface markers that recognize lipid responses, IgG1 and IgE production antigens of intracellular bacteria such as M. tuberculosis by CD1 molecules and kill host cells infected with intracellular bacteria Neutrophils Phagocytose and kill bacteria, Produce nitric oxide synthase and nitric oxide that produce antimicrobial peptides inhibit apoptosis in lymphocytes and can prolong adaptive immune responses Eosinophils Kill invading parasites Produce IL-5 that recruits Ig-specific antibody responses Mast cells and basophils Release TNF-α, IL-6, IFN-γ in response Produce IL-4 that recruits TH2 helper T cell to a variety of bacterial PAMPs responses and recruit IgG1- and IgE-specific antibody responses Epithelial cells Produce anti-microbial peptides; tissue Produces TGF-β that triggers IgA-specific specific epithelia produce mediator of antibody responses. local innate immunity, e.g., lung epithelial cells produce surfactant proteins (proteins within the collectin family) that bind and promote clearance of lung invading microbes Note: LPS, lipopolysaccharide; PAMP, pathogen-associated molecular patterns; TNF-α, tumor necrosis factor-alpha; IL-4, IL-5, IL-6, IL-10, and IL-12, interleukin 4, 5, 6, 10, and 12, respectively. Source: Adapted with permission from R Medzhitov, CA Janeway: Innate immunity: Impact on the adaptive immune response. Curr Opinion Immunol 9:4-9, 1997.
  20. 20. (Kupffer cells), bone (osteoclasts), central nervous system (microglia cells), and synovium (type A lining cells). In general, monocytes-macrophages are on the first line of defense associated with innate immunity and ingest and destroy microorganisms through the release of toxic products such as hydrogen peroxide (H2O2) and nitric oxide (NO). Inflammatory mediators produced by macrophages attract additional effector cells such as neu- trophils to the site of infection. Macrophage mediators include prostaglandins; leukotrienes; platelet activating factor; cytokines such as interleukin (IL) 1, tumor necrosis factor (TNF) α, IL-6, and IL-12; and chemokines (Tables 1-6 to 1-9). Although monocytes-macrophages were originally thought to be the major antigen-presenting cells (APCs) of the immune system, it is now clear that cell types called dendritic cells are the most potent and effective APCs in the body (see below). Monocytes-macrophages mediate innate immune effector functions such as destruction of antibody-coated bacteria, tumor cells, or even normal hematopoietic cells in certain types of autoimmune cytopenias. Monocytes-macrophages ingest SECTIONITheImmuneSysteminHealthandDisease 10 FIGURE 1-2 Schematic model of intercellular interactions of adaptive immune system cells. In this figure the arrows denote that cells develop from precursor cells or produce cytokines or antibodies; lines ending with bars indicate suppressive inter- cellular interactions. Stem cells differentiate into either T cells, antigen-presenting dendritic cells, natural killer cells, macrophages, granulocytes, or B cells. Foreign antigen is processed by dendritic cells, and peptide fragments of foreign antigen are presented to CD4+ and/or CD8+ T cells. CD8+ T cell activation leads to induction of cytotoxic T lymphocyte (CTL) or killer T cell generation, as well as induction of cytokine-producing CD8+ cytotoxic T cells. For antibody pro- duction against the same antigen, active antigen is bound to sIg within the B cell receptor complex and drives B cell matu- ration into plasma cells that secrete Ig. TH1 or TH2 CD4+ T cells producing interleukin (IL) 4, IL-5, or interferon (IFN)γ regu- late the Ig class switching and determine the type of antibody produced. CD4+, CD25+ T regulatory cells produce IL-10 and downregulate T and B cell responses once the microbe has been eliminated. GM-CSF, granulocyte-macrophage colony stimulating factor; TNF, tumor necrosis factor. Lymphoid precursor Stem cell B cell Ig IgG IgA IgD IgE IL-12 antigen presentation IL-1,IL-6 phagocytosis of microbes Phagocytosis of microbes; secretion of inflammatory products IFN-α antigen presentation T cell Natural killer cell Immune surveillance of HLA Class I negative cells (malignant and virus-infected cells) Plasmacytoid dendritic cell Myeloid dendritic cell Monocyte/macrophage Neutrophilic granulocyte Bone marrow Thymus CD8+ cytotoxic T cell CD4+ T cell CD4+, CD8+ regulatory cells TH1 TH2 TH0 TR IL-12 IL-4 IFN-γ intracellular microbes IL-4,IL-5 extracellular microbes
  21. 21. CHAPTER1IntroductiontotheImmuneSystem 11TABLE 1-6 CYTOKINES AND CYTOKINE RECEPTORS CYTOKINE RECEPTOR CELL SOURCE CELL TARGET BIOLOGIC ACTIVITY IL-1α,β Type I IL-1r, Monocytes/macrophages, All cells Upregulated adhesion molecule Type II IL-1r B cells, fibroblasts, most expression, neutrophil and macrophage epithelial cells including emigration, mimics shock, fever, thymic epithelium, upregulated hepatic acute phase protein endothelial cells production, facilitates hematopoiesis IL-2 IL-2r α,β, T cells T cells, B cells NK T cell activation and proliferation, B cell common γ cells, monocytes/ growth, NK cell proliferation and macrophages activation, enhanced monocyte/ macrophage cytolytic activity IL-3 IL-3r, T cells, NK cells, mast Monocytes/ Stimulation of hematopoietic progenitors common β cells macrophages, mast cells, eosinophils, bone marrow progenitors IL-4 IL-4r α, T cells, mast cells, T cells, B cells, NK Stimulates TH2 helper T cell differentiation common γ basophils cells, monocytes/ and proliferation. Stimulates B cell Ig macrophages, class switch to IgG1 and IgE neutrophils, anti-inflammatory action on T cells, eosinophils, monocytes endothelial cells, fibroblasts IL-5 IL-5r α, T cells, mast cells Eosinophils, Regulates eosinophil migration and common γ and eosinophils basophils, murine activation B cells IL-6 IL-6r, gp130 Monocytes/macrophages, T cells, B cells, Induction of acute phase protein B cells, fibroblasts, epithelial cells, production, T and B cell differentiation most epithelium including hepatocytes, and growth, myeloma cell growth, thymic epithelium, monocytes/ osteoclast growth and activation endothelial cells macrophages IL-7 IL-7r α, Bone marrow, thymic T cells, B cells, bone Differentiation of B, T and NK cell common γ epithelial cells marrow cells precursors, activation of T and NK cells IL-8 CXCR1, Monocytes/macrophages, Neutrophils, T cells, Induces neutrophil, monocyte and T cell CXCR2 T cells, neutrophils, monocytes/ migration, induces neutrophil adherence fibroblasts, endothelial macrophages, to endothelial cells, histamine release cells, epithelial cells endothelial cells, from basophils, stimulates angiogenesis. basophils Suppresses proliferations of hepatic precursors IL-9 IL-9r α, T cells Bone marrow Induces mast cell proliferation and common γ progenitors, B cells, function, synergizes with IL-4 in IgG T cells, mast cells and IgE production, T cell growth, activation and differentiation IL-10 IL-10r Monocytes/macrophages, Monocytes/ Inhibits macrophage proinflammatory T cells, B cells, macrophages, cytokine production, downregulates keratinocytes, mast cells T cells, B cells, cytokine class II antigen and B7-1 and NK cells, B7-2 expression, inhibits differentiation mast cells of TH1, helper T cells, inhibits NK cell function, stimulates mast cell proliferation and function, B cell activation and differentiation IL-11 IL-11, gp130 Bone marrow stromal cells Megakaryocytes, Induces megakaryocyte colony formation B cells, hepatocytes and maturation, enhances antibody responses, stimulates acute-phase protein production IL-12 IL-12r Activated macrophages, T cells, NK cells Induces TH1 helper T cell formation and (35 kD dendritic cells, neutrophils lymphokine-activated killer cell and 40 kD formation. Increases CD8+ CTL subunits) cytolytic activity; TIL-17, cγ-IFN
  22. 22. SECTIONITheImmuneSysteminHealthandDisease 12 TABLE 1-6 (CONTINUED) CYTOKINES AND CYTOKINE RECEPTORS CYTOKINE RECEPTOR CELL SOURCE CELL TARGET BIOLOGIC ACTIVITY IL-13 IL-13/IL-4 T cells (TH2) Monocytes/ Upregulation of VCAM-1 and C-C macrophages, chemokine expression on endothelial B cells, endothelial cells, B cell activation and cells, keratinocytes differentiation, inhibits macrophage proinflammatory cytokine production IL-14 Unknown T cells Normal and Induces B cell proliferation malignant B cells IL-15 IL-15r α, Monocytes/macrophages, T cells, NK cells T cell activation and proliferation. common γ, epithelial cells, Promotes angiogenesis, and NK cells IL2r β fibroblasts IL-16 CD4 Mast cells, eosinophils, CD4+ T cells, Chemoattraction of CD4+ T cells, CD8+ T cells, monocytes/ monocytes, and eosinophils. Inhibits respiratory epithelium macrophages, HIV replication. Inhibits T cell activation eosinophils through CD3/T cell receptor IL-17 IL17r CD4+ T cells Fibroblasts, Enhanced cytokine secretion endothelium, epithelium IL-18 IL-18r (IL-1R Keratinocytes, T cells, B cells, Upregulated IFNγ production, enhanced related macrophages NK cells NK cell cytotoxicity protein) IL-21 IL-δγ chain/ CD4 T cells NK cells Downregulates NK cell activating IL-21R molecules, NKG2D/DAP10 IL-23 IL-12Rb1/ Macrophages, other T cells Opposite effects of IL-12 T(IL-17, cγ-IFN) IL23R cell types IFNα Type I All cells All cells Anti-viral activity. Stimulates T cell, interferon macrophage, and NK cell activity. Direct receptor anti-tumor effects Upregulates MHC class I antigen expression. Used therapeutically in viral and autoimmune conditions IFNβ Type I All cells All cells Anti-viral activity. Stimulates T cell, interferon macrophage, and NK cell activity. Direct receptor anti-tumor effects Upregulates MHC class I antigen expression. Used therapeutically in viral and autoimmune conditions IFNγ Type II T cells, NK cells All cells Regulates macrophage and NK cell interferon activations. Stimulates immunoglobulin receptor secretion by B cells. Induction of class II histocompatibility antigens. TH1 T cell differentiation TNFα TNFrI, TNFrII Monocytes/macrophages, All cells except Fever, anorexia, shock, capillary leak mast cells, basophils, erythrocytes syndrome, enhanced leukocyte eosinophils, NK cells, cytotoxicity, enhanced NK cell function, B cells, T cells, acute phase protein synthesis, keratinocytes, fibroblasts, pro-inflammatory cytokine induction thymic epithelial cells TNFβ TNFrI, TNFrII T cells, B cells All cells except Cell cytotoxicity, lymph node and spleen erythrocytes development LTβ LTβR T cells All cells except Cell cytotoxicity, normal lymph node erythrocytes development G-CSF G-CSFr; Monocytes/macrophages, Myeloid cells, Regulates myelopoiesis. Enhances gp130 fibroblasts, endothelial endothelial cells survival and function of neutrophils. cells, thymic epithelial Clinical use in reversing neutropenia after cells, stromal cells cytotoxic chemotherapy (Continued)
  23. 23. CHAPTER1IntroductiontotheImmuneSystem 13TABLE 1-6 (CONTINUED) CYTOKINES AND CYTOKINE RECEPTORS CYTOKINE RECEPTOR CELL SOURCE CELL TARGET BIOLOGIC ACTIVITY GM-CSF GM-CSFr, T cells, monocytes/ Monocytes/ Regulates myelopoiesis. Enhances common β macrophages, macrophages, macrophage bactericidal and tumoricidal fibroblasts, endothelial neutrophils, activity. Mediator of dendritic cell cells, thymic epithelial eosinophils, maturation and function. Upregulates cells fibroblasts, NK cell function. Clinical use in reversing endothelial cells neutropenia after cytotoxic chemotherapy M-CSF M-CSFr Fibroblasts, endothelial Monocytes/ Regulates monocyte/macrophage (c-fms pro- cells, monocytes/ macrophages production and function tooncogene) macrophages, T cells, B cells, epithelial cells including thymic epithelium LIF LIFr; gp130 Activated T cells, bone Megakaryocytes, Induces hepatic acute phase protein marrow stromal cells, monocytes, production. Stimulates macrophage thymic epithelium hepatocytes, differentiation. Promotes growth of possibly myeloma cells and hematopoietic lymphocyte progenitors. Stimulates thromboiesis subpopulations OSM OSMr; LIFr; Activated monocytes/ Neurons, hepato- Induces hepatic acute phase protein gp130 macrophages and T cells, cytes, monocytes/ production. Stimulates macrophage bone marrow stromal macrophages, differentiation. Promotes growth of cells, some breast adipocytes, alveolar myeloma cells and hematopoietic carcinoma cell lines, epithelial cells, progenitors. Stimulates thromboiesis. myeloma cells embryonic stem Stimulates growth of Kaposi’s cells, melanocytes, sarcoma cells endothelial cells, fibroblasts, myeloma cells SCF SCFr (c-kit Bone marrow stromal Embryonic stem Stimulates hematopoietic progenitor cell protoonco- cells and fibroblasts cells, myeloid and growth, mast cell growth, promotes gene) lymphoid embryonic stem cell migration precursors, mast cells TGFβ Type I, II, III Most cell types Most cell types Downregulates T cell, macrophage and (3 iso- TGFβ granulocyte responses. Stimulates forms) receptor synthesis of matrix proteins. Stimulates angiogenesis Lympho- Unknown NK cells, mast cells, T cells, NK cells Chemoattractant for lymphocytes. Only tactin/ double negative known chemokine of C class SCM-1 thymocytes, activated CD8+ T cells MCP-1 CCR2 Fibroblasts, smooth Monocytes/ Chemoattractant for monocytes, muscle cells, macrophages, activated memory T cells, and NK activated PBMCs NK cells, memory cells. Induces granule release from T cells, basophils CD8+ T cells and NK cells. Potent histamine releasing factor for basophiles. Suppresses proliferation of hematopoietic precursors. Regulates monocyte protease production MCP-2 CCR1, CCR2 Fibroblasts, Monocytes/ Chemoattractant for monocytes, memory activated PBMCs macrophages, and naïve T cells, eosinophils, ?NK cells. T cells, eosinophils, Activates basophils and eosinophils. basophils, NK cells Regulates monocyte protease production
  24. 24. SECTIONITheImmuneSysteminHealthandDisease 14 TABLE 1-6 (CONTINUED) CYTOKINES AND CYTOKINE RECEPTORS CYTOKINE RECEPTOR CELL SOURCE CELL TARGET BIOLOGIC ACTIVITY MCP-3 CCR1, CCR2 Fibroblasts, Monocytes/ Chemoattractant for monocytes, memory activated PBMCs macrophages, T and naïve T cells, dendritic cells, cells, eosinophils, eosinophils, ?NK cells. Activates basophils, NK basophils and eosinophils. Regulates cells, dendritic cells monocyte protease production MCP-4 CCR2, CCR3 Lung, colon, small Monocytes/ Chemoattractant for monocytes, T cells, intestinal epithelial cells, macrophages, eosinophils and basophils activated endothelial cells T cells eosinophils, basophils Eotaxin CCR3 Pulmonary epithelial Eosinophils, Potent chemoattractant for eosinophils cells, heart basophils and basophils. Induces allergic airways disease. Acts in concert with IL-5 to activate eosinophils. Antibodies to eotaxin inhibit airway inflammation TARC CCR4 Thymus, dendritic cells, T cells, NK cells Chemoattractant for T and NK cells activated T cells MDC CCR4 Monocytes/macrophages, Activated T cells Chemoattractant for activated T cells. dendritic cells, thymus Inhibits infection with T cell tropic HIV MIP-1α CCR1, CCR5 Monocytes/macrophages, Monocytes/ Chemoattractant for monocytes, T cells, T cells macrophages, dendritic cells, NK cells, and weak T cells, dendritic chemoattractant for eosinophils and cells, NK cells, basophils. Activates NK cell function. eosinophils, Suppresses proliferation of basophils hematopoietic precursors. Necessary for myocarditis associated with coxsackie virus infection. Inhibits infection with monocytotropic HIV MIP-1β CCR5 Monocytes/ Monocytes/ Chemoattractant for monocytes, T cells, macrophages, T cells macrophages, and NK cells. Activates NK cell function. T cells, NK cells, Inhibits infection with monocytotropic dendritic cells HIV RANTES CCR1, Monocytes/macrophages, Monocytes/ Chemoattractant for monocytes/ CCR2, T cells, fibroblasts, macrophages, macrophages, CD4+ CD45Ro+T cells, CCR5 eosinophils T cells, NK cells, CD8+ T cells, NK cells, eosinophils, and dendritic cells, basophils. Induces histamine release eosinophils, from basophils. Inhibits infections with basophils monocytotropic HIV LARC/ CCR6 Dendritic cells, fetal liver T cells, B cells Chemoattractant for lymphocytes MIP-3α/ cells, activated T cells Exodus-1 ELC/ CCR7 Thymus, lymph Activated T cells Chemoattractant for B and T cells. MIP-3β node, appendix and B cells Receptor upregulated on EBV infected B cells and HSV infected T cells I-309/ CCR8 Activated T cells Monocytes/ Chemoattractant for monocytes. Prevents TCA-3 macrophages, glucocorticoid-induced apoptosis in T cells some T cell lines SLC/ Unknown Thymic epithelial cells, T cells Chemoattractant for T lymphocytes. TCA-4/ lymph node, appendix Inhibits hematopoiesis Exodus-2 and spleen DC-CK1/ Unknown Dendritic cells in secondary Naïve T cells May have a role in induction of immune PARC lymphoid tissues responses TECK Unknown Dendritic cells, thymus, T cells, monocytes/ Thymic dendritic cell-derived cytokine, liver, small intestine macrophages, possibly involved in T cell development dendritic cells (Continued)
  25. 25. CHAPTER1IntroductiontotheImmuneSystem 15TABLE 1-6 (CONTINUED) CYTOKINES AND CYTOKINE RECEPTORS CYTOKINE RECEPTOR CELL SOURCE CELL TARGET BIOLOGIC ACTIVITY GROα/ CXCR2 Activated granulocytes, Neutrophils, Neutrophil chemoattractant and activator. MGSA monocyte/macrophages, epithelial cells, Mitogenic for some melanoma cell and epithelial cells ?endothelial cells lines. Suppresses proliferation of hematopoietic precursors. Angiogenic activity GROβ/ CXCR2 Activated granulocytes Neutrophils and Neutrophil chemoattractant and activator. MIP-2α and monocyte/ ?endothelial cells Angiogenic activity macrophages NAP-2 CXCR2 Platelets Neutrophils, Derived from platelet basic protein. basophils Neutrophil chemoattractant and activator IP-10 CXCR3 Monocytes/macrophages, Activated T cells, IFNγ-inducible protein that is a T cells, fibroblasts, tumor infiltrating chemoattractant for T cells. Suppresses endothelial cells, lymphocytes, proliferation of hematopoietic precursors epithelial cells ?endothelial cells, ?NK cells MIG CXCR3 Monocytes/macrophages, Activated T cells, IFNγ-inducible protein that is a T cells, fibroblasts tumor infiltrating chemoattractant for T cells. Suppresses lymphocytes proliferation of hematopoietic precursors SDF-1 CXCR4 Fibroblasts T cells, dendritic Low potency, high efficacy T cell cells, ?basophils, chemoattractant. Required for ?endothelial cells B-lymphocyte development. Prevents infection of CD4+, CXCR4+ cells by T cell tropic HIV Fractalkine CX3CR1 Activated endothelial cells NK cells, T cells, Cell surface chemokine/mucin hybrid monocytes/ molecule that functions as a macrophages chemoattractant, leukocyte activator and cell adhesion molecule PF-4 Unknown Platelets, megakaryocytes Fibroblasts, Chemoattractant for fibroblasts. endothelial cells Suppresses proliferation of hematopoietic precursors. Inhibits endothelial cell proliferation and angiogenesis Note: IL, interleukin; NK, natural killer; TH1 and TH2 helper T cell subsets; Ig, immunoglobulin; CXCR, CXC-type chemokine receptor; B7-1, CD80, B7-2, CD86; PBMC, peripheral blood mononuclear cells; VCAM, vascular cell adhesion molecule; IFN, interferon; MHC, major histocom- patibility complex; TNF, tumor necrosis factor; G-CSF, granulocyte colony- stimulating factor; GM-CSF, granulocyte-macrophage CSF; M-CSF, macrophage CSF; HIV, human immunodeficiency virus; LIF, leukemia inhibitory factor; OSM, oncostatin M; SCF, stem cell factor; TGF, transform- ing growth factor; MCP, monocyte chemotactic protein; CCR, CC-type chemokine receptor; TARC, thymus and activation-regulated chemokine; MDC, macrophage-derived chemokine; MIP, macrophage inflammatory protein; RANTES, regulated on activation, normally T-cell expressed and secreted; LARC, liver and activation-regulated chemokine; EBV, Epstein-Barr virus; ELC, EB11 ligand chemokine (MIP-1β); HSV, herpes simplex virus; TCA, T-cell activation protein; DC-CK, dendritic cell chemokine; PARC, pulmonary and activation-regulated chemokine; SLC, secondary lymphoid tissue chemokine; TECK, thymus expressed chemokine; GRP, growth-related peptide; MGSA, melanoma growth-stimulating activity; NAP, neu- trophil-activating protein; IP-10, IFN-γ-inducible protein-10; MIG, monoteine induced by IFN-γ; SDF, stromal cell-derived factor; PF, platelet factor. Source: Used with permission from Sundy JS, Patel DD, and Haynes BF: Appendix B, in Inflammation, Basic Principles and Clinical Correlates, 3rd ed, J Gallin and R Snyderman (eds). Philadelphia, Lippincott Williams and Wilkins, 1999. bacteria or are infected by viruses, and in doing so, they frequently undergo apoptosis. Macrophages that are “stressed” by intracellular infectious agents are recognized by dendritic cells as infected and apoptotic cells and are phagocytosed by dendritic cells. In this manner, dendritic cells “cross-present” infectious agent antigens of macrophages to T cells. Activated macrophages can also mediate antigen-nonspecific lytic activity and eliminate cell types such as tumor cells in the absence of antibody. This activity is largely mediated by cytokines (i.e.,TNF-α and IL-1). Monocytes-macrophages express lineage-spe- cific molecules (e.g., the cell-surface LPS receptor, CD14) as well as surface receptors for a number of mol- ecules, including the Fc region of IgG, activated comple- ment components, and various cytokines (Table 1-6). Dendritic Cells Human dendritic cells (DCs) are heterogenous and con- tain two subsets, myeloid DCs and plasmacytoid DCs.
  26. 26. SECTIONITheImmuneSysteminHealthandDisease 16 TABLE 1-7 CC, CXC1, CX3, C1, AND XC FAMILIES OF CHEMOKINES AND CHEMOKINE RECEPTORSa CHEMOKINE RECEPTOR CHEMOKINE LIGANDS CELL TYPES DISEASE CONNECTION CCR1 CCL3 (MIP-1α), CCL5 (RANTES), T cells, monocytes, Rheumatoid arthritis, multiple CCL7 (MCP-3), CCL14 (HCC1) eosinophils, basophils sclerosis CCR2 CCL2 (MCP-1), CCL8 (MCP-2), CCL7 Monocytes, dendritic cells Atherosclerosis, rheumatoid arthritis, (MCP-3), CCL13 (MCP-4), (immature), memory multiple sclerosis, resistance to CCL16 (HCC4) T cells intracellular pathogens, Type 2 diabetes mellitus CCR3 CCL11 (eotaxin), CCL13 (eotaxin-2), Eosinophils, basophils, Allergic asthma and rhinitis CCL7 (MCP-3), CCL5 (RANTES), mast cells, TH2, platelets CCL8 (MCP-2), CCL13 (MCP-4) CCR4 CCL17 (TARC), CCL22 (MDC) T cells (TH2) dendritic Parasitic infection, graft rejection, cells (mature), basophils, T-cell homing to skin macrophages, platelets CCR5 CCL3 (MIP-1α), CCL4 (MIP-1β), T cells, monocytes HIV-1 coreceptor (T-tropic strains), CCL5 (RANTES), CCL11 (eotaxin), transplant rejection CCL14 (HCC1), CCL16 (HCC4) CCR6 CCL20 (MIP-3β, LARC) T cells (T regulatory and Mucosal humoral immunity, allergic memory), B cells, asthma, intestinal T-cell homing dendritic cells CCR7 CCL19 (ELC), CCL21 (SLC) T cells, dendritic cells Transport of T cells and dendritic (mature) cells to lymph nodes, antigen presentation, and cellular immunity CCR8 CCL1 (1309) T cells (TH2), monocytes, Dendritic-cell migration to lymph dendritic cells node, type 2 cellular immunity, granuloma formation CCR9 CCL25 (TECK) T cells, IgA+ plasma cells Homing of T cells and IgA+ plasma cells to the intestine, inflammatory bowel disease CCR10 CCL27 (CTACK, CCL28 (MEC) T cells T-cell homing to intestine and skin CXCR1 CXCL8 (interleukin-8), CXCL6 (GCP2) Neutrophils, monocytes Inflammatory lung disease, COPD CXCR2 CXCL8, CXCL1 (GROα), CXCL2 Neutrophils, monocytes, Inflammatory lung disease, COPD, (GROβ), CXCL3 (GROγ), CXCL5 microvascular angiogenic for tumor growth (ENA-78), CXCL6 endothelial cells CXCR3-A CXCL9 (MIG), CXCL10 (IP-10), Type 1 helper cells, mast Inflammatory skin disease, multiple CXCL11 (I-TAC) cells, mesangial cells sclerosis, transplant rejection CXCR3-B CXCL4 (PF4), CXCL9 (MIG), Microvascular endothelial Angiostatic for tumor growth CXCL10 (IP-10), CXCL11 (I-TAC) cells, neoplastic cells CXCR4 CXCL12 (SDF-1) Widely expressed HIV-1 coreceptor (T-cell–tropic), tumor metastases, hematopoiesis CXCR5 CXCL13 (BCA-1) B cells, follicular Formation of B cell follicles helper T cells CXCR6 CXCL16 (SR-PSOX) CD8+ T cells, natural Inflammatory liver disease, killer cells, and memory atherosclerosis (CXCL16) CD4+ T cells CX3CR1 CX3CL1 (fractalkine) Macrophages, endothelial Atherosclerosis cells, smooth-muscle cells XCR1 XCL1 (lymphotactin), XCL2 T cells, natural killer cells Rheumatoid arthritis, IgA nephropathy, tumor response a MIP denotes macrophage inflammatory protein, MCP monocyte chemoattractant protein, HCC hemofiltrate chemokine, TH2 type 2 helper T cells, TARC thymus and activation-regulated chemokine, MDC macrophage-derived chemokine, LARC liver and activation-regulated chemokine, ELC Epstein-Barr I1-ligand chemokine, SLC secondary lymphoid-tissue chemokine, TECK thymus-expressed chemokine, CTACK cutaneous T- cell–attracting chemokine, and MEC mammary-enriched chemokine. GCP denotes granulocyte chemotactic protein, COPD chronic obstructive pul- monary disease, GRO growth-regulated oncogene, ENA epithelial-cell–derived neutrophil-activating peptide, MIG monokine induced by interferon-γ, IP-10 interferon inducible 10, I-TAC interferon-inducible T-cell alpha chemoattractant, PF platelet factor, SDF stromal-cell–derived factor, HIV human immunodeficiency virus, BCA-1 B cell chemoattractant 1, and SR-PSOX scavenger receptor for phosphatidylserinecontaining oxidized lipids Source: From Charo and Ransohoff, 2006; with permission.
  27. 27. CHAPTER1IntroductiontotheImmuneSystem 17TABLE 1-8 MAJOR STRUCTURAL FAMILIES OF CYTOKINES Four α-helix- Interleukin-2 (IL-2) subfamily: bundle family Interleukins: IL-2, IL-3, IL-4, IL-5, IL-6, interleukins IL-7, IL-9, IL-11, IL-12, IL-13, IL-15, IL-21, IL-23 Not called interleukins: Colony-stimulat- ing factor-1 (CSF1), granulocyte– macrophage colony-stimulating factor (CSF2), Flt-3 ligand, erythropoietin (EPO), thrombopoietin (THPO), leukocyte inhibitory factor (LIF) Not interleukins: Growth hormone (GH1), prolactin (PRL), leptin (LEP), cardiotrophin (CTF1), ciliary neurotrophic factor (CNTF), cytokine receptor-like factor 1 (CLC or CLF) Interferon (IFN) subfamily: IFN-β, IFN-α IL-10 subfamily: IL-10, IL-19, IL-20, IL-22, IL-24 and IL-26 IL-1 family IL-1α, (IL1A), IL-1β, (IL1B), IL-18 (IL18) and paralogues, IL-17A, IL-17B, IL-17C, IL-17D, IL-17E, IL-17F Chemokines IL-8, MCP-1, MCP-2, MCP-3, MCP-4, eotaxin, TARC, LARC/MIP-3α, MDC, MIP-1α, MIP-1β, RANTES, MIP-3β, I-309, SLC, PARC, TECK, GROα, GROβ, NAP-2, IP-19, MIG, SDF-1, PF4 Note: GRO, growth-related peptide; IL interleukin; IP, INFg-inducible protein; LARC, liver and activation-regulated chemokine; MCP, mono- cyte chemotactic protein; MDC, macrophage-derived chemokine; MIG monoteine-induced by IFNg; MIP, macrophage inflammatory protein; NAP, neutrophil-activating protein; PARC, pulmonary and acti- vation-regulated chemokine; PF4, platelet factor; RANTES, regulated on activation normally T cell expressed and secreted; SDF, stromal- cell derived factor; SLC, secondary lymphoid tissue. Source: Adapted with permission from JW Schrader, Trends Immunology 23:573, 2002. TABLE 1-9 CYTOKINES FAMILIES GROUPED BY STRUCTURAL SIMILARITY Hematopoietins IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-9, IL-11, IL-12, IL-15, IL-16, IL-17, IL-21, IL-23, EPO, LIF, GM-CSF, G-CSF, OSM, CNTF, GH, and TPO TNF-α, LT-α, LT-β, CD40L, CD30L, CD27L, 4-1BBL, OX40, OPG, and FasL IL-1 IL-1α, IL-1β, IL-1ra, IL-18, bFGF, aFGF, and ECGF PDGF PDGF A, PDGF B, and M-CSF TGF-β TGF-β and BMPs (1,2,4 etc.) C-X-C IL-8, Gro-α/β/γ, NAP-2, ENA78, chemokines GCP-2, PF4, CTAP-3, Mig, and IP-10 C-C chemokines MCP-1, MCP-2, MCP-3, MIP-1α, MIP-1β, RANTES Note: aFGF, acidic fibroblast growth factor; 4-1 BBL, 401 BB ligand; bFGF, basic fibroblast growth factor; BMP, bone marrow morphogenetic proteins; C-C, cysteine-cysteine; CD, cluster of differentiation; CNTF, ciliary neurotrophic factor; CTAP, connective tissue activating pep- tide; C-X-C, cysteine-x-cysteine; ECGF, endothelial cell growth fac- tor; EPO, erythropoietin; FasL, Fas ligand; GCP-2, granulocyte chemotactic protein-2; G-CSF, granulocyte colony-stimulating fac- tor; GH, growth hormone; GM-CSF, granulocyte colony-stimulating factor; Gro, growth-related gene products; IFN, interferon; IL, inter- leukin; IP, interferon-γ inducible protein; LIF, leukemia inhibitory fac- tor; LT, lymphotoxin; MCP, monocyte chemoattractant; M-CSF, macrophage colony-stimulating factor; Mig, monokine induced by interferon-γ; MIP, macrophage inflammatory protein; NAP-2, neu- trophil activating protein-2; OPG, osteoprotegerin; OSM, oncostatin M; PDGF, platelet-derived growth factor; PF, platelet factor; R, receptor; RANTES, regulated on activation, normal T cell-expressed and –secreted; TGF, transforming growth factor; TNF, tumor necrosis factor; TPO, thyroperoxidase. Myeloid DCs can differentiate into either macrophages/ monocytes or tissue-specific DCs such as Langerhans cells in skin. Plasmacytoid DCs are inefficient antigen- presenting cells but are potent producers of type I inter- feron (IFN) (e.g., IFN-α) in response to viral infections. The maturation of DCs is regulated through cell-to-cell contact and soluble factors, and DCs attract immune effectors through secretion of chemokines. When dendritic cells come in contact with bacterial products, viral proteins, or host proteins released as dan- ger signals from distressed host cells (Figs. 1-2, 1-3), infectious agent molecules bind to variousTLRs and acti- vate dendritic cells to release cytokines and chemokines that drive cells of the innate immune system to become activated to respond to the invading organism, and recruit T and B cells of the adaptive immune system to respond. Plasmacytoid DCs produce IFN-α that is antiviral and activates NK cell killing of pathogen- infected cells; it also activates T cells to mature into antipathogen killer T cells. Following contact with pathogens, both plasmacytoid and myeloid DCs produce chemokines that attract T helper cells, B cells, polymor- phonuclear cells, and naïve and memory T cells as well as regulatory T cells to ultimately dampen the immune response once the pathogen is controlled.TLR engagement on dendritic cells upregulates dendritic cell MHC class II, B7-1 (CD80), and B7-2 (CD86), which enhance spe- cific antigen presentation and induce dendritic cell cytokine production (Table 1-1). Thus, dendritic cells are important bridges between early (innate) and later (adaptive) immunity. DCs modulate and determine the types of immune responses induced by pathogens via the TLRs expressed on DCs (TLR7-9 on plasmacytoid DCs, TLR4 on monocytoid DCs) and via the TLR adapter proteins that are induced to associate with TLRs (Fig. 1-1, Table 1-4). In addition, other PRRs, such as C-type lectins, NOTCH protein domain (NOD), and mannose receptors, upon ligation by pathogen products,
  28. 28. SECTIONITheImmuneSysteminHealthandDisease 18 B cell IgG antibody Macrophage activation Induce CD8+ cytotoxic T cells Activation of TH1 CD4+ T cells Dendritic Cell Activation of TH2 CD4+ T cells IL-2, IFN-γ, IL-3 TNF-α, TNF-β, GM-CSF Inhibition of TH2 responses Inhibition of TH1 type responses Opsonize microbes for phagocytosis Kill opsonized microbes Kill microbe infected cells Mast cell basophil B cell IgM, G, A, and E antibody Eosinophil Regulation of vascular permeability; allergic responses; protective responses to bacteria, viruses, and parasitic infections Direct antibody killing of microbes and opsonize for microbial phagocytosis Kill parasites IL-3, IL-4, IL-5, IL-6, IL-10, IL-13 Dendritic Cell FIGURE 1-3 CD4+ helper T1 (TH1) cells and TH2 T cells secrete dis- tinct but overlapping sets of cytokines. TH1 CD4+ cells are frequently activated in immune and inflammatory reactions against intracellular bacteria or viruses, while TH2 CD4+ cells are frequently activated for certain types of antibody produc- tion against parasites and extracellular encapsulated bacte- ria; they are also activated in allergic diseases. GM-CSF, granulocyte-macrophage colony stimulating factor; IFN, inter- feron; IL, interleukin; TNF, tumor necrosis factor. (Adapted from S Romagnani: CD4 effector cells, in J Gallin, R Snyderman (eds): Inflammation: Basic Principles and Clinical Correlates, 3d ed. Philadelphia, Lippincott Williams & Wilkins, 1999, with permission.) activate cells of the adaptive immune system and, likeTLR stimulation, by a variety of factors, determine the type and quality of the adaptive immune response that is trig- gered (Table 1-4). Large Granular Lymphocytes/Natural Killer Cells Large granular lymphocytes (LGLs) or NK cells account for ~5–10% of peripheral blood lymphocytes. NKs cells are nonadherent,nonphagocytic cells with large azurophilic cytoplasmic granules. NKs cells express surface receptors for the Fc portion of IgG (CD16) and for NCAM-I (CD56), and many NK cells express some T lineage markers, particularly CD8, and proliferate in response to IL-2. NK cells arise in both bone marrow and thymic microenvironments. Functionally, NK cells share features with both monocytes-macrophages and neutrophils in that they mediate both antibody-dependent cellular cytotoxicity (ADCC) and NK cell activity. ADCC is the binding of an opsonized (antibody-coated) target cell to an Fc receptor–bearing effector cell via the Fc region of anti- body, resulting in lysis of the target by the effector cell. NK cell activity is the nonimmune (i.e., effector cell never having had previous contact with the target), MHC-unrestricted, non–antibody-mediated killing of target cells, which are usually malignant cell types, trans- planted foreign cells, or virus-infected cells. Thus, NK cell activity may play an important role in immune sur- veillance and destruction of malignant and virally infected host cells. NK cell hyporesponsiveness is also observed in patients with Chédiak-Higashi syndrome, an autosomal recessive disease associated with fusion of cyto- plasmic granules and defective degranulation of neutrophil lysosomes. The ability of NK cells to kill target cells is inversely related to target cell expression of MHC class I molecules. Thus, NK cells kill target cells with low or no levels of MHC class I expression and are prevented from killing
  29. 29. CHAPTER1IntroductiontotheImmuneSystem 19 ? HLA CD48, NTB-A MICA, MICB, ULBPs NCRs KIRs, CD94 2B4, NTB-A NKG2D NK cell Target cell Receptors Ligands + + + – – FIGURE 1-4 Receptors and ligands involved in human NK cell-mediated cytotoxicity. NK cell activation is the final result of the engagement of a number of receptors that have opposite functions. A simplified model of the surface receptors and their ligands involved in NK cell activation (green) or inactiva- tion (red) is shown. KIRS are killer immunoglobulin-like receptors. In the absence of inhibitory signals, activating NK cell receptor ligation with molecules on the target cell results in NK cell triggering and target cell lysis. This event occurs in MHC class I HLA-defective cells, such as tumors or virus- infected cells. In the case of normal cells that express MHC class I, the interaction between inhibitory receptors and MHC class I delivers signals that overcome NK cell triggering, thus preventing target cell lysis. Although the cellular natural cytotoxic receptor (NCR) ligands have not yet been identified, the ligands for NG2D are represented by stress-inducible MICA, MICB, and ULBPs. The ligand for 2B4 is CD48, which is expressed by hematopoietic cells, whereas the ligand for NTB-A is itself on target cells. The + and – symbols denote activating or inhibitory signals, respectively. (From A Moretta et al: Nat Immunol 3:6, 2002; with permission.) target cells with high levels of class I expression. NK cells have surface-inhibiting killer immunoglobulin-like recep- tors (KIRs) that bind to classic MHC class I molecules in a polymorphic way and inhibit NK cell killing of human leukocyte antigen (HLA) positive cells. NK cell inactiva- tion by KIRs is a central mechanism to prevent damage to normal host cells. However, to eliminate malignant and virally infected cells, NK cells also require activation through recognition of NK activation molecules on the surface of target cells (Fig. 1-4).Three molecules on NK cells—NKp46, NKp30, and NKp44—are collectively referred to as natural cytotoxicity receptors (NCRs) and mediate NK cell activation against target cells; the ligands to which they bind on target cells remain unknown. In addition, two coreceptors on NK cells, 2B4 and NTB-A, can serve as either activators or inhibitors of NK cells, depending on the ligand and signaling pathways that become activated. Thus, NK cell signaling is a highly coordinated series of inhibiting and activating signals that are coordinated to all NK cells such that they do not respond to uninfected, nonmalignant self-cells, but they are activated to attack malignant and virally infected cells. Recent evidence suggests that NK cells, though not pos- sessing rearranging immune recognition genes, may be able to mediate recall responses for certain immune reac- tions such as contact hypersensitivity. Some NK cells express CD3 and are termed NK/T cells. NK/T cells can also express oligoclonal forms of the TCR for antigen that can recognize lipid molecules of intracellular bacteria when presented in the context of CD1 molecules on APCs.This mode of recognition of intracellular bacteria such as Listeria monocytogenes and M. tuberculosis by NK/T cells leads to induction of activation of DCs and is thought to be an important defense mechanism against these organisms. Neutrophils, Eosinophils, and Basophils Granulocytes are present in nearly all forms of inflam- mation and are amplifiers and effectors of innate immune responses (Fig. 1-3). Unchecked accumulation and activation of granulocytes can lead to host tissue damage, as seen in neutrophil- and eosinophil-mediated systemic necrotizing vasculitis. Granulocytes are derived from stem cells in bone marrow. Each type of granulo- cyte (neutrophil, eosinophil, or basophil) is derived from a different subclass of progenitor cell, which is stimulated to proliferate by colony-stimulating factors (Table 1-6). During terminal maturation of granulo- cytes, class-specific nuclear morphology and cytoplasmic granules appear that allow for histologic identification of granulocyte type. Neutrophils express Fc receptors for IgG (CD16) and receptors for activated complement components (C3b or CD35). Upon interaction of neutrophils with opsonized bacteria or immune complexes, azurophilic granules (containing myeloperoxidase, lysozyme, elastase, and other enzymes) and specific granules (containing lactoferrin, lysozyme, collagenase, and other enzymes) are released, and microbicidal superoxide radicals (O2 – ) are generated at the neutrophil surface. The generation of superoxide leads to inflammation by direct injury to tissue and by alteration of macromolecules such as colla- gen and DNA. Eosinophils express Fc receptors for IgG (CD32) and are potent cytotoxic effector cells for various parasitic
  30. 30. organisms. In Nippostrongylus brasiliensis helminth infec- tion, eosinophils are key cytotoxic effector cells in removal of these parasites. Key to regulation of eosinophil cyto- toxicity to N. brasiliensis worms are antigen-specific T helper cells that produce IL-4, thus providing an example of regulation of innate immune responses by adaptive immunity antigen-specific T cells. Intracytoplasmic con- tents of eosinophils, such as major basic protein, eosinophil cationic protein, and eosinophil-derived neurotoxin, are capable of directly damaging tissues and may be responsible in part for the organ system dysfunction in the hypereosinophilic syndromes. Since the eosinophil granule contains anti-inflammatory types of enzymes (histami- nase, arylsulfatase, phospholipase D), eosinophils may homeostatically downregulate or terminate ongoing inflam- matory responses. Basophils and tissue mast cells are potent reservoirs of cytokines such as IL-4 and can respond to bacteria and viruses with antipathogen cytokine production through multiple TLRs expressed on their surface. Mast cells and basophils can also mediate immunity through the bind- ing of antipathogen antibodies. This is a particularly important host defense mechanism against parasitic dis- eases. Basophils express high-affinity surface receptors for IgE (FcRI) and, upon cross-linking of basophil-bound IgE by antigen, can release histamine, eosinophil chemo- tactic factor of anaphylaxis, and neutral protease—all mediators of allergic immediate (anaphylaxis) hypersensi- tivity responses (Table 1-10). In addition, basophils express surface receptors for activated complement SECTIONITheImmuneSysteminHealthandDisease 20 TABLE 1-10 EXAMPLES OF MEDIATORS RELEASED FROM HUMAN CELLS AND BASOPHILS MEDIATOR ACTIONS Histamine Smooth-muscle contraction, increased vascular permeability Slow reacting Smooth-muscle contraction substance of anaphylaxis (SRSA) (leukotriene C4, D4, E4) Eosinophil chemotactic Chemotactic attraction of factor of anaphylaxis eosinophils (ECF-A) Platelet-activating Activates platelets to secrete factor serotonin and other mediators: smooth-muscle contraction; induces vascular permeability Neutrophil chemotactic Chemotactic attraction of factor (NCF) neutrophils Leukotactic activity Chemotactic attraction of (leukotriene B4) neutrophils Heparin Anticoagulant Basophil kallikrein of Cleaves kininogen to form anaphylaxis (BK-A) bradykinin Mannose-binding lectin activation pathway MBL-MASP1-MASP2 Microbes with terminal mannose groups Classic activation pathway Bacteria, fungi, virus, or tumor cells C3 (H2O) Alternative activation pathway C1q-C1r-C1s Antigen/antibody immune complex C4 C4 C2 C3 C3b C5 C6 C7 C8 poly-C9 C2 P D B Terminal pathway Immune complex modification Clearance of apoptotic cells Anaphylatoxin Anaphylatoxin Lysis Opsonin Lymphocyte activation Membrane perturbation FIGURE 1-5 The four pathways and the effector mechanisms of the com- plement system. Dashed arrows indicate the functions of pathway components. (After BJ Morley, MJ Walport: The Complement Facts Books. London, Academic Press, Chap 2, 2000; with permission.) components (C3a, C5a), through which mediator release can be directly effected.Thus, basophils, like most cells of the immune system, can be activated in the service of host defense against pathogens, or they can be activated for mediation release and cause pathogenic responses in allergic and inflammatory diseases. The Complement System The complement system, an important soluble compo- nent of the innate immune system, is a series of plasma enzymes, regulatory proteins, and proteins that are acti- vated in a cascading fashion, resulting in cell lysis.There are four pathways of the complement system: the classic activation pathway activated by antigen/antibody immune complexes, the MBL (a serum collectin;Table 1-3) acti- vation pathway activated by microbes with terminal man- nose groups, the alternative activation pathway activated by microbes or tumor cells, and the terminal pathway that is common to the first three pathways and leads to the membrane attack complex that lyses cells (Fig. 1-5).The series of enzymes of the complement system are serine proteases. Activation of the classic complement pathway via immune complex binding to C1q links the innate and adaptive immune systems via specific antibody in the immune complex. The alternative complement activa- tion pathway is antibody-independent and is activated
  31. 31. CHAPTER1IntroductiontotheImmuneSystem 21by binding of C3 directly to pathogens and “altered self” such as tumor cells. In the renal glomerular inflamma- tory disease IgA nephropathy, IgA activates the alternative complement pathway and causes glomerular damage and decreased renal function. Activation of the classic complement pathway via C1, C4, and C2 and activation of the alternative pathway via factor D, C3, and factor B both lead to cleavage and activation of C3. C3 activation fragments, when bound to target surfaces such as bacteria and other foreign antigens, are critical for opsonization (coating by antibody and complement) in preparation for phagocytosis. The MBL pathway substitutes MBL- associated serine proteases (MASPs) 1 and 2 for C1q, C1r, and C1s to activate C4.The MBL activation path- way is activated by mannose on the surface of bacteria and viruses. The three pathways of complement activation all converge on the final common terminal pathway. C3 cleavage by each pathway results in activation of C5, C6, C7, C8, and C9, resulting in the membrane attack com- plex that physically inserts into the membranes of target cells or bacteria and lyses them. Thus, complement activation is a critical component of innate immunity for responding to microbial infec- tion.The functional consequences of complement acti- vation by the three initiating pathways and the terminal pathway are shown in Fig. 1-5. In general the cleavage products of complement components facilitate microbe or damaged cell clearance (C1q, C4, C3), promote acti- vation and enhancement of inflammation (anaphylatox- ins, C3a, C5a), and promote microbe or opsonized cell lysis (membrane attack complex). CYTOKINES Cytokines are soluble proteins produced by a wide vari- ety of hematopoietic and nonhematopoietic cell types (Tables 1-6 to 1-9). They are critical for both normal innate and adaptive immune responses, and their expres- sion may be perturbed in most immune, inflammatory, and infectious disease states. Cytokines are involved in the regulation of the growth, development, and activation of immune system cells and in the mediation of the inflammatory response. In general, cytokines are characterized by considerable redundancy; different cytokines have similar functions. In addition, many cytokines are pleiotropic in that they are capable of acting on many different cell types. This pleiotropism results from the expression on multiple cell types of receptors for the same cytokine (see below), leading to the formation of “cytokine networks.” The action of cytokines may be (1) autocrine when the tar- get cell is the same cell that secretes the cytokine, (2) paracrine when the target cell is nearby, and (3) endocrine when the cytokine is secreted into the circulation and acts distal to the source. Cytokines have been named based on presumed tar- gets or based on presumed functions. Those cytokines that are thought to primarily target leukocytes have been named interleukins (IL-1, -2, -3, etc.). Many cytokines that were originally described as having a cer- tain function have retained those names (granulocyte colony-stimulating factor or G-CSF, etc.). Cytokines belong in general to three major structural families: the hemopoietin family; the TNF, IL-1, platelet-derived growth factor (PDGF), and transforming growth factor (TGF) β families; and the CXC and c-c chemokine families (Table 1-8). Chemokines are cytokines that reg- ulate cell movement and trafficking; they act through G protein–coupled receptors and have a distinctive three- dimensional structure. IL-8 is the only chemokine that early on was named an interleukin (Table 1-6). In general, cytokines exert their effects by influencing gene activation that results in cellular activation, growth, differentiation, functional cell-surface molecule expres- sion, and cellular effector function. In this regard, cytokines can have dramatic effects on the regulation of immune responses and the pathogenesis of a variety of diseases. Indeed, T cells have been categorized on the basis of the pattern of cytokines that they secrete, which results in either humoral immune response (TH2) or cell-mediated immune response (TH1) (Fig. 1-3). Cytokine receptors can be grouped into five general families based on similarities in their extracellular amino acid sequences and conserved structural domains. The immunoglobulin (Ig) superfamily represents a large number of cell-surface and secreted proteins.The IL-1 receptors (type 1, type 2) are examples of cytokine receptors with extracellular Ig domains. The hallmark of the hematopoietic growth factor (type 1) receptor family is that the extracellular regions of each receptor contain two conserved motifs. One motif, located at the N terminus, is rich in cysteine residues. The other motif is located at the C terminus proximal to the transmembrane region and comprises five amino acid residues, tryptophan-serine-X-tryptophan-serine (WSXWS). This family can be grouped on the basis of the number of receptor subunits they have and on the utilization of shared subunits. A number of cytokine receptors, i.e., IL-6, IL-11, IL-12, and leukemia inhibitory factor, are paired with gp130. There is also a common 150-kDa subunit shared by IL-3, IL-5, and granulocyte-macrophage colony-stimulating factor (GM- CSF) receptors. The gamma chain (γc) of the IL-2 receptor is common to the IL-2, IL-4, IL-7, IL-9, and IL-15 receptors. Thus, the specific cytokine receptor is responsible for ligand-specific binding, while the sub- units such as gp130, the 150-kDa subunit, and γc are important in signal transduction. The γc gene is on the X chromosome, and mutations in the γc protein result in the X-linked form of severe combined immune deficiency syn- drome (X-SCID).

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