Harrisons rheumatology 2010

Cells of the innate immune system include natural killer NK cell lymphocytes, monocytes/macrophages, dendritic cells, neutrophils, basophils, eosinophils, tissue mast cells, and epitheli

Rheumatology

Second Edition

Chief, Laboratory of Immunoregulation;

Director, National Institute of Allergy and Infectious Diseases,

National Institutes of Health, Bethesda

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

Scientific Director, National Institute on Aging,

National Institutes of Health, Bethesda and Baltimore

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

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 for Vasculitis Care and Research,

Department of Rheumatic and Immunologic Diseases,

Cleveland Clinic, Cleveland

New York Chicago San Francisco Lisbon London Madrid Mexico City

Milan New Delhi San Juan Seoul Singapore Sydney Toronto

Second Edition

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1 Introduction to the Immune System 2

Barton F Haynes, Kelly A Soderberg,Anthony S Fauci

2 The Major Histocompatibility Complex 44

Gerald T 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

10 The Vasculitis Syndromes 144

Carol A Langford,Anthony S Fauci

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 InclusionBody Myositis 197

Carol A Langford, Bruce C Gilliland

22 Arthritis Associated with Systemic Disease andOther Arthritides 259

Carol A Langford, Bruce C Gilliland

23 Periarticular Disorders of the Extremities 271

Carol A Langford, Bruce C Gilliland

Appendix

Laboratory Values of Clinical Importance 277

Alexander Kratz, Michael A Pesce, Daniel J Fink

Review and Self-Assessment 299

Charles Wiener, Gerald Bloomfield, Cynthia D Brown, Joshua Schiffer, Adam Spivak

Index 327

CONTENTS

This page intentionally left blank

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 Philadelphia Veteran 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, New York [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, New York [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, New York- Presbyterian Hospital; Director, Allen Pavilion Laboratory, New York [Appendix]

CAROL A LANGFORD, MD, MHS

Associate Professor of Medicine; Director, Center for Vasculitis 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]

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

KELLY A SODERBERG, PhD, MPH

Director, Program Management, Duke Human Vaccine 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]

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 bebalanced against risk Understanding these challengesprovides an opportunity to improve the lives of patients, and it is these factors that make the practice ofrheumatology an immensely rewarding area of internalmedicine

Another facet of rheumatology that has captivatedthe 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 thatthe immune system mediated many forms of joint andtissue injury Laboratory-based investigations have notonly provided firm evidence for the immunologic basis

of these diseases, but they have identified specific anisms involved in the pathogenesis of individual clinicalentities Recognition of the pathways involved in diseaseand the potential to target specific immune effectorfunctions have revolutionized the treatment of manyrheumatic diseases Such investigations will continue toshed insights regarding the pathogenesis of a widerange of rheumatic diseases, and will bring forth noveltherapies that offer even greater potential to lessenpain, reduce joint and organ damage, and improveoverall clinical outcome

mech-This sectional was originally developed in tion of the importance of rheumatology to the practice

recogni-of internal medicine as well as the rapid pace recogni-of tific growth in this specialty This assessment has beenborne 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 Theneed for this sectional is a tribute to the hard work ofmany dedicated individuals at both the bench and thebedside whose contributions have greatly benefited ourpatients It is the continued hope of the editors that thissectional will not only increase knowledge of therheumatic diseases, but also serve to heighten apprecia-tion for this fascinating specialty

scien-Anthony S Fauci, MDCarol A Langford, MD, MHS

PREFACE

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 medicinethroughout 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 New York,

McGraw-Hill, 2008, ISBN 978-0-07-149619-3

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

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 International Work-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 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

• 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 βchains that are associated with the CD3 complex com-posed of invariant γ, δ, ε, ζ, and η chains.TCR-α and -βchains recognize peptide fragments of protein antigenphysically bound in antigen-presenting cell MHC class I

or II molecules, leading to signaling via the CD3 plex to mediate effector functions (Fig 1-7)

com-• 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 thymusfor 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 ofyears from both invertebrate and vertebrate organisms todevelop sophisticated defense mechanisms to protect thehost from microbes and their virulence factors.The normalimmune system has three key properties: a highly diverserepertoire of antigen receptors that enables recognition of anearly infinite range of pathogens; immune memory, tomount rapid recall immune responses; and immunologictolerance, to avoid immune damage to normal self-tissues.From invertebrates, humans have inherited the innateimmune system, an ancient defense system that uses germline–encoded proteins to recognize pathogens Cells of theinnate immune system, such as macrophages, dendritic cells,and natural killer (NK) lymphocytes, recognize pathogen-associated molecular patterns (PAMPs) that are highlyconserved among many microbes and use a diverse set ofpattern recognition receptor molecules (PRRs) Importantcomponents of the recognition of microbes by the innateimmune system include (1) recognition by germ line–encoded host molecules, (2) recognition of key microbevirulence factors but not recognition of self-molecules,and (3) nonrecognition of benign foreign molecules ormicrobes Upon contact with pathogens, macrophages and

NK cells may kill pathogens directly or, in concert withdendritic cells, may activate a series of events that both slowthe infection and recruit the more recently evolved arm ofthe human immune system, the adaptive immune system.Adaptive immunity is found only in vertebrates and isbased on the generation of antigen receptors on T and Blymphocytes by gene rearrangements, such that individual

T or B cells express unique antigen receptors on theirsurface 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, keymolecules (Table 1-1), and mechanisms that make up the

(OTHER NAMES) FAMILY MASS, kDa DISTRIBUTION LIGAND(S) FUNCTION

CD1a (T6, HTA-1) Ig 49 CD, cortical thymocytes, TCR γδ T cells CD1 molecules present

Langerhans type of lipid antigens of intracellular dendritic cells bacteria such as M leprae

and M tuberculosis to

TCR γδ T cells.

CD1b Ig 45 CD, cortical thymocytes, TCR γδ T cells

Langerhans type of dendritic cells CD1c Ig 43 DC, cortical thymocytes, TCR γδ T cells

subset of B cells, Langerhans type of dendritic cells CD1d Ig ? Cortical thymocytes, TCR γδ 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

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

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

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

activation and proliferation CD21 (B2, CR2, RCA 145 Mature B, FDC, subset C3d, C3dg, iC3b, Associates with CD19 and

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

(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, fLC γ CD23 (Fc εRII, C-type 45 B, M, FDC IgE, CD21, Regulates IgE synthesis,

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

of GCs, isotype switching, rescue from apoptosis CD45 (LCA, PTP 180, 200, All leukocytes Galectin-1, CD2, T and B activation, thymo-

transduction, apoptosis CD45RA PTP 210, 220 Subset T, medullary Galectin-1, CD2, Isoforms of CD45 containing

thymocytes, “nạve” 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

CD45RC PTP 210, 220 Subset T, medullary Galectin-1, CD2, Isoforms of CD45 containing

thymocytes, “nạve” 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

subset of T cells CD80 (B7-1, BB1) Ig 60 Activated B and T, CD28, CD152 Co-regulator of T cell

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

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; Fc γ RIIIA, low-affinity IgG receptor isoform A; FDC, follicular dendritic cells; G, granulocytes; GC, germinal center; GPI, glycosyl 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-

phos-gens, see Harrison’s Online at http://harrisons.accessmedicine.com; and for a full list of CD human antigens from the most recent Human shop on Leukocyte Differentiation Antigens (VII), see http://www.ncbi.nlm.nih.gov/prow/guide.

Work-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

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

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

Leucine-rich Macrophages, CD14 Lipopolysaccharide Binds LPS and Toll proteins

epithelial cells Scavenger Macrophage Macrophage Bacterial cell walls Phagocytosis of bacteria

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

Integrins Macrophages, CD11b,c; CD18 LPS Signals cells, activates

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

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

cells bind bacterial lipopolysaccharide (LPS) and activatephagocytic cells to ingest pathogens.

A series of recent discoveries has revealed the anisms of connection between the innate and adaptiveimmune systems; these include (1) a plasma protein,LPS-binding protein, which binds and transfers LPS

mech-to the macrophage LPS recepmech-tor, CD14; and (2) a

human family of proteins called Toll-like receptor teins (TLR), some of which are associated with CD14,

pro-bind LPS, and signal epithelial cells, dendritic cells, andmacrophages to produce cytokines and upregulate cell-surface molecules that signal the initiation of adaptiveimmune responses (Fig 1-1, Tables 1-3,1-4) Proteins

in the Toll family (TLR 1–10) can be expressed onmacrophages, dendritic cells, and B cells as well as on avariety of nonhematopoietic cell types, including respi-ratory epithelial cells (Tables 1-4,1-5) Upon ligation,these receptors activate a series of intracellular eventsthat lead to the killing of bacteria- and viral-infectedcells 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 LPSthrough TLR4 leads to the release of large amounts ofcytokines that mediate LPS-induced shock Mutations

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 chemokines Nucleus

TLR9 CpG ssRNA Endosome TLR7

Triacylated lipopeptides

Plasma membrane

TRAF-6 IRAK

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.)

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 inrecruiting T and B lymphocytes of the adaptive immunesystem to engage in specific antipathogen responses

Monocytes-Macrophages

Monocytes arise from precursor cells within bone row (Fig 1-2) and circulate with a half-life rangingfrom 1 to 3 days Monocytes leave the peripheral circu-lation by marginating in capillaries and migrating into avast extravascular pool Tissue macrophages arise frommonocytes that have migrated out of the circulation and

mar-by in situ proliferation of macrophage precursors in sue Common locations where tissue macrophages (andcertain of their specialized forms) are found are lymphnode, spleen, bone marrow, perivascular connective tis-sue, serous cavities such as the peritoneum, pleura, skinconnective tissue, lung (alveolar macrophages), liver

THE ROLE OF PRR S IN MODULATION OF T CELL RESPONSES

PRR DC OR MACROPHAGE ADAPTIVE IMMUNE FAMILY PRR S LIGAND CYTOKINE RESPONSE RESPONSE

(heterodimer Pam-3-cys (TLR 2/6) High IL-10 T H 2

IFN- α IL-6

Intermediate IL-10 IL-6

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

M tuberculosis

Note: dsRNA, double-strand RNA; ssRNA, single-strand RNA; LPS, lipopolysaccharide; TH 2, helper T cell; T H 1, 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.

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 T H 1 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.

(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 originallythought to be the major antigen-presenting cells (APCs)

of the immune system, it is now clear that cell typescalled dendritic cells are the most potent and effectiveAPCs in the body (see below) Monocytes-macrophagesmediate innate immune effector functions such asdestruction of antibody-coated bacteria, tumor cells, oreven normal hematopoietic cells in certain types ofautoimmune cytopenias Monocytes-macrophages ingest

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 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.

pro-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

IL-4,IL-5 extracellular microbes

CYTOKINES AND CYTOKINE RECEPTORS

CYTOKINE RECEPTOR CELL SOURCE CELL TARGET BIOLOGIC ACTIVITY

IL-1 α,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

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

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 IFN γ 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-23 IL-12Rb1/ Macrophages, other T cells Opposite effects of IL-12 T(IL-17, cγ-IFN)

IL23R cell types IFN α Type I All cells All cells Anti-viral activity Stimulates T cell,

Upregulates MHC class I antigen expression Used therapeutically in viral and autoimmune conditions

IFN β Type I All cells All cells Anti-viral activity Stimulates T cell,

Upregulates MHC class I antigen expression Used therapeutically in viral and autoimmune conditions

IFN γ Type II T cells, NK cells All cells Regulates macrophage and NK cell

histocompatibility antigens TH1 T cell differentiation

TNF α 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

TNF β TNFrI, TNFrII T cells, B cells All cells except Cell cytotoxicity, lymph node and spleen

erythrocytes development

LT β LT βR 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 )

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

precursors, mast cells TGF β Type I, II, III Most cell types Most cell types Downregulates T cell, macrophage and

angiogenesis Lympho- Unknown NK cells, mast cells, T cells, NK cells Chemoattractant for lymphocytes Only

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 nạve T cells, eosinophils, ?NK cells

T cells, eosinophils, Activates basophils and eosinophils

basophils, NK cells Regulates monocyte protease

production

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 nạve 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-1 α 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-1 β 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-3 α/ cells, activated T cells

Exodus-1

ELC/ CCR7 Thymus, lymph Activated T cells Chemoattractant for B and T cells

MIP-3 β 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

T cells some T cell lines SLC/ Unknown Thymic epithelial cells, T cells Chemoattractant for T lymphocytes

DC-CK1/ Unknown Dendritic cells in secondary Nạve T cells May have a role in induction of immune

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 )

CYTOKINES AND CYTOKINE RECEPTORS

CYTOKINE RECEPTOR CELL SOURCE CELL TARGET BIOLOGIC ACTIVITY

GRO α/ 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

GRO β/ CXCR2 Activated granulocytes Neutrophils and Neutrophil chemoattractant and activator MIP-2 α 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, IFN γ-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, IFN γ-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

endothelial cells Suppresses proliferation of

hematopoietic precursors Inhibits endothelial cell proliferation and angiogenesis

Note: IL, interleukin; NK, natural killer; TH 1 and T H 2 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-1 β); 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 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)

lineage-spe-Dendritic Cells

Human dendritic cells (DCs) are heterogenous and tain two subsets, myeloid DCs and plasmacytoid DCs

RECEPTOR CHEMOKINE LIGANDS CELL TYPES DISEASE CONNECTION

CCR1 CCL3 (MIP-1 α), 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-1 α), 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-3 β, 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 (GRO α), CXCL2 Neutrophils, monocytes, Inflammatory lung disease, COPD,

(GRO β), 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

aMIP denotes macrophage inflammatory protein, MCP monocyte chemoattractant protein, HCC hemofiltrate chemokine, T H 2 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

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-1 α, (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-3 α, MDC, MIP-1 α, MIP-1β, RANTES, MIP-3β, I-309, SLC, PARC, TECK, GRO α, 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-1 α, 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-1 α,

MIP-1 β, 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 various TLRs 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 withpathogens, both plasmacytoid and myeloid DCs producechemokines that attract T helper cells, B cells, polymor-phonuclear cells, and nạve and memory T cells as well

as regulatory T cells to ultimately dampen the immuneresponse 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 cific antigen presentation and induce dendritic cellcytokine production (Table 1-1) Thus, dendritic cellsare important bridges between early (innate) and later(adaptive) immunity DCs modulate and determine thetypes of immune responses induced by pathogens viathe TLRs expressed on DCs (TLR7-9 on plasmacytoidDCs, TLR4 on monocytoid DCs) and via the TLRadapter proteins that are induced to associate with TLRs(Fig 1-1, Table 1-4) In addition, other PRRs, such asC-type lectins, NOTCH protein domain (NOD), andmannose receptors, upon ligation by pathogen products,

Macrophage activation Induce CD8+

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 (T H 1) cells and T H 2 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, like TLR

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 Fcreceptor–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 cellnever having had previous contact with the target),MHC-unrestricted, non–antibody-mediated killing oftarget cells, which are usually malignant cell types, trans-planted foreign cells, or virus-infected cells Thus, NKcell activity may play an important role in immune sur-veillance and destruction of malignant and virallyinfected host cells NK cell hyporesponsiveness is also

observed in patients with Chédiak-Higashi syndrome, an

autosomal recessive disease associated with fusion of plasmic granules and defective degranulation of neutrophillysosomes

cyto-The ability of NK cells to kill target cells is inverselyrelated to target cell expression of MHC class I molecules.Thus, NK cells kill target cells with low or no levels ofMHC class I expression and are prevented from killing

NCRs KIRs, CD94 2B4, NTB-A NKG2D

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 importantdefense mechanism against these organisms

Neutrophils, Eosinophils, and Basophils

Granulocytes are present in nearly all forms of mation and are amplifiers and effectors of innateimmune responses (Fig 1-3) Unchecked accumulationand activation of granulocytes can lead to host tissuedamage, as seen in neutrophil- and eosinophil-mediated

inflam-systemic necrotizing vasculitis Granulocytes are derived

from stem cells in bone marrow Each type of cyte (neutrophil, eosinophil, or basophil) is derivedfrom a different subclass of progenitor cell, which isstimulated to proliferate by colony-stimulating factors(Table 1-6) During terminal maturation of granulo-cytes, class-specific nuclear morphology and cytoplasmicgranules appear that allow for histologic identification

of superoxide leads to inflammation by direct injury totissue and by alteration of macromolecules such as colla-gen and DNA

Eosinophils express Fc receptors for IgG (CD32) andare potent cytotoxic effector cells for various parasitic

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

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:

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

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 plement system Dashed arrows indicate the functions of

com-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 releasecan be directly effected.Thus, basophils, like most cells ofthe immune system, can be activated in the service ofhost defense against pathogens, or they can be activatedfor mediation release and cause pathogenic responses inallergic and inflammatory diseases

The Complement System

The complement system, an important soluble nent of the innate immune system, is a series of plasmaenzymes, regulatory proteins, and proteins that are acti-vated in a cascading fashion, resulting in cell lysis Thereare four pathways of the complement system: the classicactivation pathway activated by antigen/antibody immunecomplexes, the MBL (a serum collectin; Table 1-3) acti-vation pathway activated by microbes with terminal man-nose groups, the alternative activation pathway activated

compo-by microbes or tumor cells, and the terminal pathway that

is common to the first three pathways and leads to themembrane attack complex that lyses cells (Fig 1-5) Theseries of enzymes of the complement system are serineproteases

Activation of the classic complement pathway viaimmune complex binding to C1q links the innate andadaptive immune systems via specific antibody in theimmune complex The alternative complement activa-tion pathway is antibody-independent and is activated

by 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 gets or based on presumed functions Those cytokinesthat are thought to primarily target leukocytes havebeen named interleukins (IL-1, -2, -3, etc.) Manycytokines that were originally described as having a cer-tain function have retained those names (granulocytecolony-stimulating factor or G-CSF, etc.) Cytokinesbelong in general to three major structural families: thehemopoietin family; the TNF, IL-1, platelet-derivedgrowth factor (PDGF), and transforming growth factor(TGF) β families; and the CXC and c-c chemokinefamilies (Table 1-8) Chemokines are cytokines that reg-ulate cell movement and trafficking; they act through Gprotein–coupled receptors and have a distinctive three-dimensional structure IL-8 is the only chemokine thatearly on was named an interleukin (Table 1-6)

tar-In general, cytokines exert their effects by influencinggene 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 ofimmune responses and the pathogenesis of a variety ofdiseases Indeed, T cells have been categorized on thebasis of the pattern of cytokines that they secrete, whichresults in either humoral immune response (TH2) orcell-mediated immune response (TH1) (Fig 1-3)

Cytokine receptors can be grouped into five general

families based on similarities in their extracellular aminoacid 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 withextracellular 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 aminoacid residues, tryptophan-serine-X-tryptophan-serine(WSXWS) This family can be grouped on the basis ofthe number of receptor subunits they have and on theutilization of shared subunits A number of cytokinereceptors, i.e., IL-6, IL-11, IL-12, and leukemiainhibitory factor, are paired with gp130 There is also acommon 150-kDa subunit shared by IL-3, IL-5, andgranulocyte-macrophage colony-stimulating factor (GM-CSF) receptors The gamma chain (γc) of the IL-2receptor is common to the IL-2, IL-4, IL-7, IL-9, andIL-15 receptors Thus, the specific cytokine receptor isresponsible for ligand-specific binding, while the sub-units such as gp130, the 150-kDa subunit, and γc areimportant in signal transduction The γc gene is on the

X chromosome, and mutations in the γcprotein result in

the X-linked form of severe combined immune deficiency drome (X-SCID).

22 The members of the interferon (type II) receptor family

include the receptors for IFN-γ and -β, which share a

similar 210-amino-acid binding domain with conserved

cysteine pairs at both the amino and carboxy termini

The members of the TNF (type III) receptor family share a

common binding domain composed of repeated

cys-teine-rich regions Members of this family include the

p55 and p75 receptors for TNF (TNFR1 and TNFR2,

respectively); CD40 antigen, which is an important B

cell–surface marker involved in immunoglobulin isotype

switching; fas/Apo-1, whose triggering induces

apopto-sis; CD27 and CD30, which are found on activated T

cells and B cells; and nerve growth factor receptor

The common motif for the seven transmembrane helix

family was originally found in receptors linked to

GTP-binding proteins This family includes receptors for

chemokines (Table 1-7),β-adrenergic receptors, and

reti-nal rhodopsin It is important to note that two members

of the chemokine receptor family, CXC chemokine

receptor type 4 (CXCR4) and β chemokine receptor

type 5 (CCR5), have been found to serve as the two

major coreceptors for binding and entry of HIV into

CD4-expressing host cells

Significant advances have been made in defining the

signaling pathways through which cytokines exert their

effects intracellularly The Janus family of protein

tyro-sine kinases (JAK) is a critical element involved in

sig-naling via the hematopoietin receptors Four JAK

kinases, JAK1, JAK2, JAK3, and Tyk2, preferentially bind

different cytokine receptor subunits Cytokine binding

to its receptor brings the cytokine receptor subunits into

apposition and allows a pair of JAKs to

transphosphory-late and activate one another The JAKs then

phospho-rylate the receptor on the tyrosine residues and allow

signaling molecules to bind to the receptor, where these

molecules become phosphorylated Signaling molecules

bind the receptor because they have domains (SH2, or

src homology 2 domains) that can bind phosphorylated

tyrosine residues.There are a number of these important

signaling molecules that bind the receptor, such as the

adapter molecule SHC, which can couple the receptor

to the activation of the mitogen-activated protein kinase

pathway In addition, an important class of substrate of

the JAKs is the signal transducers and activators of

tran-scription (STAT) family of trantran-scription factors STATs

have SH2 domains that enable them to bind to

phos-phorylated receptors, where they are then

phosphory-lated by the JAKs It appears that different STATs have

specificity for different receptor subunits The STATs

then dissociate from the receptor and translocate to the

nucleus, bind to DNA motifs that they recognize, and

regulate gene expression The STATs preferentially bind

DNA motifs that are slightly different from one another

and thereby control transcription of specific genes The

importance of this pathway is particularly relevant to

lymphoid development Mutations of JAK3 itself also

result in a disorder identical to X-SCID; however, sinceJAK3 is found on chromosome 19 and not on the Xchromosome, JAK3 deficiency occurs in boys and girls

THE ADAPTIVE IMMUNE SYSTEM

Adaptive immunity is characterized by antigen-specificresponses to a foreign antigen or pathogen A key feature

of adaptive immunity is that following the initial contact

with antigen (immunologic priming), subsequent antigen

exposure leads to more rapid and vigorous immune

responses (immunologic memory).The adaptive immune

sys-tem consists of dual limbs of cellular and humoral nity The principal effectors of cellular immunity are Tlymphocytes, while the principal effectors of humoralimmunity are B lymphocytes Both B and T lymphocytesderive from a common stem cell (Fig 1-6)

immu-The proportion and distribution of immunocompetentcells in various tissues reflect cell traffic, homing patterns,and functional capabilities Bone marrow is the major site

of maturation of B cells, monocytes-macrophages, dritic cells, and granulocytes and contains pluripotentstem cells that, under the influence of various colony-stimulating factors, are capable of giving rise to allhematopoietic cell types T cell precursors also arise fromhematopoietic stem cells and home to the thymus formaturation Mature T lymphocytes, B lymphocytes,monocytes, and dendritic cells enter the circulation andhome to peripheral lymphoid organs (lymph nodes,spleen) and mucosal surface-associated lymphoid tissue(gut, genitourinary, and respiratory tracts) as well as theskin and mucous membranes and await activation by for-eign antigen

den-T Cells

The pool of effector T cells is established in the thymusearly in life and is maintained throughout life both bynew T cell production in the thymus and by antigen-driven expansion of virgin peripheral T cells into

“memory” T cells that reside in peripheral lymphoidorgans The thymus exports ~2% of the total number ofthymocytes per day throughout life, with the total num-ber of daily thymic emigrants decreasing by ~3% peryear during the first four decades of life

Mature T lymphocytes constitute 70–80% of normalperipheral blood lymphocytes (only 2% of the total-body lymphocytes are contained in peripheral blood),90% of thoracic duct lymphocytes, 30–40% of lymphnode cells, and 20–30% of spleen lymphoid cells Inlymph nodes, T cells occupy deep paracortical areasaround B cell germinal centers, and in the spleen, theyare located in periarteriolar areas of white pulp T cellsare the primary effectors of cell-mediated immunity,with subsets of T cells maturing into CD8+ cytotoxic Tcells capable of lysis of virus-infected or foreign cells

(short-lived effector T cells) Two populations of

long-lived memory T cells are triggered by infections: effector

memory and central memory T cells Effector memory

T cells reside in nonlymphoid organs and respond

rapidly to repeated pathogenic infections with cytokine

production and cytotoxic functions to kill virus-infected

cells Central memory T cells home to lymphoid organs

where they replenish long- and short-lived and effector

memory T cells as needed

In general, CD4+ T cells are also the primary

regula-tory cells of T and B lymphocyte and monocyte

func-tion by the producfunc-tion of cytokines and by direct cell

contact (Fig 1-2) In addition, T cells regulate erythroid

cell maturation in bone marrow, and through cell tact (CD40 ligand) have an important role in activation

con-of B cells and induction con-of Ig isotype switching

Human T cells express cell-surface proteins that markstages of intrathymic T cell maturation or identify spe-cific functional subpopulations of mature T cells Many

of these molecules mediate or participate in important Tcell functions (Table 1-1, Fig 1-6)

The earliest identifiable T cell precursors in bonemarrow are CD34+ pro-T cells (i.e., cells in whichTCR genes are neither rearranged nor expressed) Inthe thymus, CD34+ T cell precursors begin cytoplasmic(c) synthesis of components of the CD3 complex of

CD34+

Hematopoietic stem cell

CD34+

α,β Germ line

α- Germ line β- V-DJ Rearranged

α-V-J Rearranged β- V-DJ Rearranged

CD7 CD2 cCD3

Mature T

Thymus medulla and peripheral

T cell pools

CD7 CD2 cCD3, TCRαβ CD4

Mature T

CD7 CD2

CD8

Mature T

CD7 CD2

CD8

Immature T

CD7 CD2 cCD3, TCRαβ CD1 CD4, CD8

Early pro-B cell

DJ rearranged

High-chain genes

Germ line

Low-chain genes

Absent

Surface Ig

CD34 CD10 CD19 CD38

Late pro-B cell

VDJ rearranged Germ line

Absent

CD10 CD19 CD20 CD38 CD40

Large pro-B cell

VDJ rearranged Germ line

µ H-chain at surface as part of pre-β receptor

CD19 CD20 CD38 CD40

Small pro-B cell

VDJ rearranged VDJ rearranged

µ H-chain in cytoplasm and at surface

CD19 CD20 CD38 CD40

Immature pro-B cell

VDJ rearranged

IgM expressed

on cell surface

CD19 CD20 CD40

VDJ rearranged

Mature pro-B cell

VDJ rearranged

IgD and IgM made from alternatively spliced H-chain transcripts CD19 CD20 CD21 CD40

VDJ rearranged

Surface marker proteins

Pro-T

CD34+

CD7lo+ or α,β Germ line

IgM IgM

FIGURE 1-6

Development stages of T and B cells Elements of the

devel-oping T and B cell receptor for antigen are shown

schemati-cally The classification into the various stages of B cell

development is primarily defined by rearrangement of the

immunoglobulin (Ig), heavy (H), and light (L) chain genes and

by the absence or presence of specific surface markers

[Adapted from CA Janeway et al, (eds): Immunobiology The Immune Systemic Health and Disease, 4th ed, New York, Garland, 1999, with permission.] The classification of stages

of T cell development is primarily defined by cell surface marker protein expression (sCD3, surface CD3 expression, cCD3, cytoplasmic CD3 expression; TCR, T cell receptor).

24 TCR-associated molecules (Fig 1-6).Within T cell

pre-cursors,TCR for antigen gene rearrangement yields two

T cell lineages, expressing either TCRαβ chains or

TCRγδ chains T cells expressing the TCRαβ chains

constitute the majority of peripheral T cells in blood,

lymph node, and spleen and terminally differentiate into

either CD4+ or CD8+ cells Cells expressing TCRγδ

chains circulate as a minor population in blood; their

functions, although not fully understood, have been

pos-tulated to be those of immune surveillance at epithelial

surfaces and cellular defenses against mycobacterial

organ-isms and other intracellular bacteria through recognition

of bacterial lipids

In the thymus, the recognition of self-peptides on

thymic epithelial cells, thymic macrophages, and

den-dritic cells plays an important role in shaping the T cell

repertoire to recognize foreign antigen (positive selection)

and in eliminating highly autoreactive T cells (negative

selection) As immature cortical thymocytes begin to

express surface TCR for antigen, autoreactive

thymo-cytes are destroyed (negative selection), thymothymo-cytes with

TCRs capable of interacting with foreign antigen

pep-tides in the context of self-MHC antigens are activated

and develop to maturity (positive selection), and

thymo-cytes with TCR that are incapable of binding to

self-MHC antigens die of attrition (no selection) Mature

thy-mocytes that are positively selected are either CD4+

helper T cells or MHC class II–restricted cytotoxic

(killer) T cells, or they are CD8+ T cells destined to

become MHC class I–restricted cytotoxic T cells MHC

class I– or class II–restricted means that T cells recognize

antigen peptide fragments only when they are presented

in the antigen-recognition site of a class I or class II

MHC molecule, respectively (Chap 2)

After thymocyte maturation and selection, CD4 and

CD8 thymocytes leave the thymus and migrate to the

peripheral immune system The thymus continues to be

a contributor to the peripheral immune system, well

into adult life, both normally and when the peripheral T

cell pool is damaged, such as occurs in AIDS and cancer

chemotherapy

Molecular Basis of T Cell Recognition of Antigen

The TCR for antigen is a complex of molecules

consist-ing of an antigen-bindconsist-ing heterodimer of either αβ or γδ

chains noncovalently linked with five CD3 subunits (γ, δ,

ε, ζ, and η) (Fig 1-7) The CD3 ζ chains are either

disulfide-linked homodimers (CD3-ζ2) or

disulfide-linked heterodimers composed of one ζ chain and one η

chain TCRαβ or TCRγδ molecules must be associated

with CD3 molecules to be inserted into the T cell

sur-face membrane, TCRα being paired with TCRβ and

TCRγ being paired with TCRδ Molecules of the CD3

complex mediate transduction of T cell activation signals

via TCRs, while TCRα and -β or -γ and -δ molecules

combine to form the TCR antigen-binding site

The α, β, γ, and δ TCR for antigen molecules haveamino acid sequence homology and structural similari-ties to immunoglobulin heavy and light chains and are

members of the immunoglobulin gene superfamily of

mole-cules The genes encoding TCR molecules are encoded

as clusters of gene segments that rearrange during thecourse of T cell maturation This creates an efficient andcompact mechanism for housing the diversity require-ments of antigen receptor molecules The TCRα chain

is on chromosome 14 and consists of a series of V able), J (joining), and C (constant) regions The TCRβchain is on chromosome 7 and consists of multiple V, D(diversity), J, and C TCRβ loci The TCRγ chain is onchromosome 7, and the TCRδ chain is in the middle ofthe TCRα locus on chromosome 14.Thus, molecules ofthe TCR for antigen have constant (framework) andvariable regions, and the gene segments encoding the α,

(vari-β, γ, and δ chains of these molecules are recombinedand selected in the thymus, culminating in synthesis ofthe completed molecule In both T and B cell precursors(see below), DNA rearrangements of antigen receptorgenes involve the same enzymes, recombinase activatinggene (RAG)1 and RAG2, both DNA-dependent pro-tein kinases

TCR diversity is created by the different V, D, and Jsegments that are possible for each receptor chain bythe many permutations of V, D, and J segment combina-tions, by “N-region diversification” due to the addition

of nucleotides at the junction of rearranged gene ments, and by the pairing of individual chains to form aTCR dimer As T cells mature in the thymus, the reper-toire of antigen-reactive T cells is modified by selectionprocesses that eliminate many autoreactive T cells,enhance the proliferation of cells that function appro-priately with self-MHC molecules and antigen, andallow T cells with nonproductive TCR rearrangements

seg-to die

TCRαβ cells do not recognize native protein or bohydrate antigens Instead,T cells recognize only short(~9–13 amino acids) peptide fragments derived fromprotein antigens taken up or produced in APCs For-eign antigens may be taken up by endocytosis intoacidified intracellular vesicles or by phagocytosis anddegraded into small peptides that associate with MHCclass II molecules (exogenous antigen-presentationpathway) Other foreign antigens arise endogenously inthe cytosol (such as from replicating viruses) and arebroken down into small peptides that associate withMHC class I molecules (endogenous antigen-presentingpathway) Thus, APCs proteolytically degrade foreignproteins and display peptide fragments embedded in theMHC class I or II antigen-recognition site on theMHC molecule surface, where foreign peptide frag-ments are available to bind to TCRαβ or TCRγδchains of reactive T cells CD4 molecules act as adhe-sives and, by direct binding to MHC class II (DR, DQ,

or DP) molecules, stabilize the interaction of TCR with

peptide antigen (Fig 1-7) Similarly, CD8 molecules

also act as adhesives to stabilize the TCR-antigen

inter-action by direct CD8 molecule binding to MHC class I

(A, B, or C) molecules

Antigens that arise in the cytosol and are processed

via the endogenous antigen-presentation pathway are

cleaved into small peptides by a complex of proteases

called the proteasome From the proteasome, antigen

pep-tide fragments are transported from the cytosol into the

lumen of the endoplasmic reticulum by a heterodimeric

complex termed transporters associated with antigen

process-ing, or TAP proteins There, MHC class I molecules in

the endoplasmic reticulum membrane physically

associ-ate with processed cytosolic peptides Following peptide

association with class I molecules, peptide–class I

com-plexes are exported to the Golgi apparatus, and then to

the cell surface, for recognition by CD8+ T cells

Antigens taken up from the extracellular space via

endocytosis into intracellular acidified vesicles are

degraded by vesicle proteases into peptide fragments

Intracellular vesicles containing MHC class II moleculesfuse with peptide-containing vesicles, thus allowingpeptide fragments to physically bind to MHC class IImolecules Peptide–MHC class II complexes are thentransported to the cell surface for recognition by CD4+

T cells (Chap 2)

Whereas it is generally agreed that the TCRαβreceptor recognizes peptide antigens in the context ofMHC class I or class II molecules, lipids in the cell wall

of intracellular bacteria such as M tuberculosis can also be

presented to a wide variety of T cells, including subsets

of CD4, CD8 TCRαβ T cells, TCRγδ T cells, and asubset of CD8+ TCRαβ T cells Importantly, bacteriallipid antigens are not presented in the context of MHCclass I or II molecules, but rather are presented in thecontext of MHC-related CD1 molecules Some γδ Tcells that recognize lipid antigens via CD1 moleculeshave very restricted TCR usage, do not need antigenpriming to respond to bacterial lipids, and may actually

be a form of innate rather than acquired immunity tointracellular bacteria

PtdIns (4,5)P3 Lipid raft

of NFAT to the nucleus

Integrin activation MAPK activation

Cytoskeletal reorganization RAS

Signaling through the T cell receptor Activation signals are

mediated via immunoreceptor tyrosine-based activation

(ITAM) sequences in LAT and CD3 chains (blue bars) that

bind to enzymes and transduce activation signals to the

nucleus via the indicated intracellular activation pathways.

Ligation of the T-cell receptor (TCR) by MHC complexed with

antigen results in sequential activation of LCK and

g-chain-associated protein kinase of 70 kDa (ZAP70) ZAP70

phos-phorylates several downstream targets, including LAT (linker

for activation of T cells) and SLP76 [SCR homology 2 (SH2)

domain-containing leukocyte protein of 76 kDa] SLP76 is recruited to membrane-bound LAT through its constitutive interaction with GADS (GRB2-related adaptor protein) Together, SLP76 and LAT nucleate a multimolecular signaling complex, which induces a host of downstream responses, including calcium flux, mitogen-activated protein kinase (MAPK) activation, integrin activation, and cytoskeletal reor-

ganization [Adapted from GA Koretzky et al: Nature

6(1):67–78, 2006; with permission.]

26 Just as foreign antigens are degraded and their peptide

fragments presented in the context of MHC class I or

class II molecules on APCs, endogenous self-proteins

also are degraded and self-peptide fragments are

pre-sented to T cells in the context of MHC class I or class II

molecules on APCs In peripheral lymphoid organs, there

are T cells that are capable of recognizing self-protein

fragments but normally are anergic or tolerant, i.e.,

nonre-sponsive to antigenic stimulation, due to lack of

self-antigen upregulating APC co-stimulatory molecules such as

B7-1 (CD80) and B7-2 (CD86) (see below)

Once engagement of mature T cell TCR by foreign

peptide occurs in the context of self–MHC class I or

class II molecules, binding of non–antigen-specific

adhesion ligand pairs such as CD54-CD11/CD18 and

CD58-CD2 stabilizes MHC peptide–TCR binding, and

the expression of these adhesion molecules is

upregu-lated (Fig 1-7) Once antigen ligation of the TCR

occurs, the T cell membrane is partitioned into lipid

membrane microdomains, or lipid rafts, that coalesce the key

signaling molecules TCR/CD3 complex, CD28, CD2,

LAT (linker for activation of T cells), intracellular

acti-vated (dephosphorylated) src family protein tyrosine

kinases (PTKs), and the key CD3ζ-associated protein-70

(ZAP-70) PTK (Fig 1-7) Importantly, during T cell

activation, the CD45 molecule, with protein tyrosine

phosphatase activity, is partitioned away from the TCR

complex to allow activating phosphorylation events to

occur The coalescence of signaling molecules of

acti-vated T lymphocytes in microdomains has suggested that

T cell–APC interactions can be considered immunologic

synapses, analogous in function to neuronal synapses.

After TCR-MHC binding is stabilized, activation

sig-nals are transmitted through the cell to the nucleus and

lead to the expression of gene products important in

mediating the wide diversity of T cell functions such as

the secretion of IL-2 The TCR does not have intrinsic

signaling activity but is linked to a variety of signaling

pathways via immunoreceptor tyrosine-based activation

motifs (ITAMs) expressed on the various CD3 chains

that bind to proteins that mediate signal transduction

Each of the pathways results in the activation of

particu-lar transcription factors that control the expression of

cytokine and cytokine receptor genes Thus,

antigen-MHC binding to the TCR induces the activation of the

src family of PTKs, fyn and lck (lck is associated with

CD4 or CD8 co-stimulatory molecules);

phosphoryla-tion of CD3ζ chain; activaphosphoryla-tion of the related tyrosine

kinases ZAP-70 and syk; and downstream activation of

the calcium-dependent calcineurin pathway, the ras

path-way, and the protein kinase C pathway Each of these

pathways leads to activation of specific families of

tran-scription factors (including NF-AT, fos and jun, and

rel/NF-κB) that form heteromultimers capable of

inducing expression of IL-2, IL-2 receptor, IL-4,TNF-α,

and other T cell mediators

In addition to the signals delivered to the T cell fromthe TCR complex and CD4 and CD8, molecules on the

T cell such as CD28 and inducible co-stimulator (ICOS)and molecules on dendritic cells such as B7-1 (CD80)and B7-2 (CD86) also deliver important co-stimulatorysignals that upregulate T cell cytokine production and areessential for T cell activation If signaling through CD28

or ICOS does not occur, or if CD28 is blocked, the Tcell becomes anergic rather than activated (see “ImmuneTolerance and Autoimmunity” later in the chapter)

sent Superantigens are protein molecules capable of

acti-vating up to 20% of the peripheral T cell pool, whereasconventional antigens activate <1 in 10,000 T cells.T cellsuperantigens include staphylococcal enterotoxins andother bacterial products Superantigen stimulation ofhuman peripheral T cells occurs in the clinical setting of

staphylococcal toxic shock syndrome, leading to massive

over-production of T cell cytokines that leads to hypotensionand shock

lym-to those described in T cells (Fig 1-8) Unlike T cells,which recognize only processed peptide fragments ofconventional antigens embedded in the notches ofMHC class I and class II antigens of APCs, B cells arecapable of recognizing and proliferating to wholeunprocessed native antigens via antigen binding to Bcell surface Ig (sIg) receptors B cells also express surfacereceptors for the Fc region of IgG molecules (CD32) aswell as receptors for activated complement components(C3d or CD21, C3b or CD35).The primary function of

B cells is to produce antibodies B cells also serve asAPCs and are highly efficient at antigen processing.Their antigen-presenting function is enhanced by avariety of cytokines Mature B cells are derived frombone marrow precursor cells that arise continuouslythroughout life (Fig 1-6)

B lymphocyte development can be separated intoantigen-independent and antigen-dependent phases

Antigen-independent B cell development occurs in

pri-mary lymphoid organs and includes all stages of B cell

maturation up to the sIg+ mature B cell

Antigen-dependent B cell maturation is driven by the interaction

of antigen with the mature B cell sIg, leading to

mem-ory B cell induction, Ig class switching, and plasma cell

formation Antigen-dependent stages of B cell

matura-tion occur in secondary lymphoid organs, including

lymph node, spleen, and gut Peyer’s patches In contrast

to the T cell repertoire that is generated intrathymically

before contact with foreign antigen, the repertoire of B

cells expressing diverse antigen-reactive sites is modified

by further alteration of Ig genes after stimulation by

antigen—a process called somatic mutation—which occurs

in lymph node germinal centers

During B cell development, diversity of the

antigen-binding variable region of Ig is generated by an ordered

set of Ig gene rearrangements that are similar to therearrangements undergone by TCR α, β, γ, and δ genes.For the heavy chain, there is first a rearrangement of Dsegments to J segments, followed by a second rearrange-ment between a V gene segment and the newly formedD-J sequence; the C segment is aligned to the V-D-Jcomplex to yield a functional Ig heavy chain gene (V-D-J-C) During later stages, a functional κ or λ lightchain gene is generated by rearrangement of a V seg-ment to a J segment, ultimately yielding an intact Igmolecule composed of heavy and light chains

The process of Ig gene rearrangement is regulatedand results in a single antibody specificity produced byeach B cell, with each Ig molecule comprising one type

of heavy chain and one type of light chain Althougheach B cell contains two copies of Ig light and heavychain genes, only one gene of each type is productively

activation

Cytoskeletal reorganization

B

RAS

NCK VAV1 LYN

SYK

FIGURE 1-8

B cell receptor (BCR) activation results in the sequential

activation of protein tyrosine kinases, which results in the

for-mation of a signaling complex and activation of downstream

pathways as shown Whereas SLP76 is recruited to the

membrane through GADS and LAT, the mechanism of SLP65

recruitment is unclear Studies have indicated two

mecha-nisms: (a) direct binding by the SH2 domain of SLP65 to

immunoglobulin (Ig) of the BCR complex or (b) membrane

recruitment through a leucine zipper in the amino terminus of

SLP65 and an unknown binding partner ADAP,

adhesion-and degranulation-promoting adaptor protein; AP1, activator

protein 1; BTK, Bruton’s tyrosine kinase; DAG, erol; GRB2, growth-factor-receptor-bound protein 2; HPK1, haematopoietic progenitor kinase 1; InsP3, inositol-1,4,5- trisphosphate; ITK, interleukin-2-inducible T-cell kinase; NCK, noncatalytic region of tyrosine kinase; NF-B, nuclear factor B; PKC, protein kinase C; PLC, phospholipase C; PtdIns(4,5)P2, phosphatidylinositol-4,5-bisphosphate; RAS- GRP, RAS guanyl-releasing protein; SOS, son of sevenless

diacylglyc-homologue; SYK, spleen tyrosine kinase [Adapted from

GA Koretzky et al: Nat Rev Immunol 6(1):67, 2006; with permission.]

There are ~300 Vκ genes and 5 Jκ genes, resulting in

the pairing of Vκ and Jκ genes to create >1500 different

light chain combinations.The number of distinct κ light

chains that can be generated is increased by somatic

mutations within the Vκ and Jκ genes, thus creating

large numbers of possible specificities from a limited

amount of germ-line genetic information As noted

above, in heavy chain Ig gene rearrangement, the VH

domain is created by the joining of three types of

germ-line genes called VH, DH, and JH, thus allowing for even

greater diversity in the variable region of heavy chains

than of light chains

The most immature B cell precursors (early pro-B

cells) lack cytoplasmic Ig (cIg) and sIg (Fig 1-6) The

large pre-B cell is marked by the acquisition of the

sur-face pre-BCR composed of µ heavy (H) chains and a

pre-B light chain, termed ψLC ψLC is a surrogate light

chain receptor encoded by the nonrearranged V pre-B

and the λ5 light chain locus (the pre-BCR) Pro- and

pre-B cells are driven to proliferate and mature by

sig-nals from bone marrow stroma—in particular, IL-7

Light chain rearrangement occurs in the small pre-B cell

stage such that the full BCR is expressed at the

imma-ture B cell stage Immaimma-ture B cells have rearranged Ig

light chain genes and express sIgM As immature B cells

develop into mature B cells, sIgD is expressed as well as

sIgM At this point, B lineage development in bone

marrow is complete, and B cells exit into the peripheral

circulation and migrate to secondary lymphoid organs

to encounter specific antigens

Random rearrangements of Ig genes occasionally

generate self-reactive antibodies, and mechanisms must

be in place to correct these mistakes One such

mecha-nism is BCR editing, whereby autoreactive BCRs are

mutated to not react with self-antigens If receptor

edit-ing is unsuccessful in eliminatedit-ing autoreactive B cells,

then autoreactive B cells undergo negative selection in

the bone marrow through induction of apoptosis after

BCR engagement of self-antigen

After leaving the bone marrow, B cells populate

peripheral B cell sites, such as lymph node and spleen, and

await contact with foreign antigens that react with each B

cell’s clonotypic receptor Antigen-driven B cell activation

occurs through the BCR, and a process known as somatic

hypermutation takes place whereby point mutations in

rearranged H- and L-genes give rise to mutant sIg

mole-cules, some of which bind antigen better than the original

sIg molecules Somatic hypermutation, therefore, is a

process whereby memory B cells in peripheral lymph

organs have the best binding, or the highest-affinity

bodies This overall process of generating the best

anti-bodies is called affinity maturation of antibody.

Lymphocytes that synthesize IgG, IgA, and IgE are

derived from sIgM+, sIgD+ mature B cells Ig class

switching occurs in lymph node and other peripherallymphoid tissue germinal centers CD40 on B cells andCD40 ligand on T cells constitute a critical co-stimulatoryreceptor-ligand pair of immune-stimulatory molecules.Pairs of CD40+ B cells and CD40 ligand+ T cells bindand drive B cell Ig switching via T cell–produced cytokinessuch as IL-4 and TGF-β IL-1, -2, -4, -5, and -6 synergize

to drive mature B cells to proliferate and differentiateinto Ig-secreting cells

Humoral Mediators of Adaptive Immunity: Immunoglobulins

Immunoglobulins are the products of differentiated B cellsand mediate the humoral arm of the immune response.The primary functions of antibodies are to bind specifi-cally to antigen and bring about the inactivation orremoval of the offending toxin, microbe, parasite, orother foreign substance from the body The structuralbasis of Ig molecule function and Ig gene organizationhas provided insight into the role of antibodies in nor-mal protective immunity, pathologic immune-mediateddamage by immune complexes, and autoantibody for-mation against host determinants

All immunoglobulins have the basic structure of twoheavy and two light chains (Fig 1-8) Immunoglobulinisotype (i.e., G, M, A, D, E) is determined by the type of

Ig heavy chain present IgG and IgA isotypes can bedivided further into subclasses (G1, G2, G3, G4, and A1,A2) based on specific antigenic determinants on Ig heavychains The characteristics of human immunoglobulinsare outlined in (Table 1-11) The four chains are cova-lently linked by disulfide bonds Each chain is made up

of a V region and C regions (also called domains),

them-selves made up of units of ~110 amino acids Light chainshave one variable (VL) and one constant (CL) unit; heavychains have one variable unit (VH) and three or fourconstant (CH) units, depending on isotype As the namesuggests, the constant, or C, regions of Ig molecules aremade up of homologous sequences and share the sameprimary structure as all other Ig chains of the same iso-type and subclass Constant regions are involved in bio-logic functions of Ig molecules The CH2domain of IgGand the CH4units of IgM are involved with the binding

of the C1q portion of C1 during complement tion The CH region at the carboxy-terminal end of theIgG molecule, the Fc region, binds to surface Fc recep-tors (CD16, CD32, CD64) of macrophages, dendriticcells, NK cells, B cells, neutrophils, and eosinophils.Variable regions (VL and VH) constitute the antibody-binding (Fab) region of the molecule.Within the VLand

activa-VH regions are hypervariable regions (extreme sequencevariability) that constitute the antigen-binding siteunique to each Ig molecule The idiotype is defined

as the specific region of the Fab portion of the Igmolecule to which antigen binds Antibodies against the

idiotype portion of an antibody molecule are called

anti-idiotype antibodies The formation of such antibodies in

vivo during a normal B cell antibody response may

gen-erate a negative (or “off ”) signal to B cells to terminate

antibody production

IgG constitutes ~75–85% of total serum

immunoglob-ulin The four IgG subclasses are numbered in order of

their level in serum, IgG1 being found in greatest

amounts and IgG4 the least IgG subclasses have clinical

relevance in their varying ability to bind macrophage

and neutrophil Fc receptors and to activate complement

(Table 1-11) Moreover, selective deficiencies of certain

IgG subclasses give rise to clinical syndromes in which

the patient is inordinately susceptible to bacterial

infec-tions IgG antibodies are frequently the predominant

antibody made after rechallenge of the host with

anti-gen (secondary antibody response)

IgM antibodies normally circulate as a 950-kDa

pen-tamer with 160-kDa bivalent monomers joined by a

mol-ecule called the J chain, a 15-kDa nonimmunoglobulin

molecule that also effects polymerization of IgA

mole-cules IgM is the first immunoglobulin to appear in the

immune response (primary antibody response) and is the

initial type of antibody made by neonates Membrane IgM

in the monomeric form also functions as a major antigenreceptor on the surface of mature B cells (Fig 1-8) IgM is

an important component of immune complexes inautoimmune diseases For example, IgM antibodies againstIgG molecules (rheumatoid factors) are present in high

titers in rheumatoid arthritis, other collagen diseases, and some infectious diseases (subacute bacterial endocarditis).

IgA constitutes only 7–15% of total serum ulin but is the predominant class of immunoglobulin insecretions IgA in secretions (tears, saliva, nasal secretions,gastrointestinal tract fluid, and human milk) is in the form

immunoglob-of secretory IgA (sIgA), a polymer consisting immunoglob-of two IgAmonomers, a joining molecule, again called the J chain, and

a glycoprotein called the secretory protein Of the two IgA

subclasses, IgA1 is primarily found in serum, whereas IgA2

is more prevalent in secretions IgA fixes complement viathe alternative complement pathway and has potent antivi-ral activity in humans by prevention of virus binding to res-piratory and gastrointestinal epithelial cells

IgD is found in minute quantities in serum and,together with IgM, is a major receptor for antigen onthe B cell surface IgE, which is present in serum in very

TABLE 1-11

PHYSICAL, CHEMICAL, AND BIOLOGIC PROPERTIES OF HUMAN IMMUNOGLOBULINS

PROPERTY IgG IgA IgM IgD IgE

Usual molecular form Monomer Monomer, Pentamer, Monomer Monomer

G3, G4

Serum level in average adult, mg/mL 9.5–12.5 1.5–2.6 0.7–1.7 0.04 0.0003

Binding cells via Fc Macrophages, Lymphocytes Lymphocytes None Mast cells,

lymphocytes Biologic properties Placental transfer, Secretory Primary Ab Marker Allergy,

secondary immunoglobulin responses for antiparasite

responses

Source: After L Carayannopoulos and JD Capra, in WE Paul (ed): Fundamental Immunology, 3d ed New York, Raven, 1993; with permission.