Kuby immunology- 7th edn.pdf

FMTOC Page i 12/19/12 10:08 PM user-t044 /Volumes/203/MHR00209/siL52070/disk1of1/0071052070 KUBY Immunology FMTOC Page ii 12/19/12 10:08 PM user-t044...

FMTOC Page i 12/19/12 10:08 PM user-t044 /Volumes/203/MHR00209/siL52070/disk1of1/0071052070 KUBY Immunology FMTOC Page ii 12/19/12 10:08 PM user-t044 /Volumes/203/MHR00209/siL52070/disk1of1/0071052070 Icons Used in This Book Antigenic T cell CD4 Class I MHC Cytokine peptide receptor Cytokine Antibody CD3 CD8 Class II MHC receptor Immature TH cell TC cell Cytotoxic T cell Natural killer cell thymocyte B cell Plasma cell Bone marrow Erythrocyte Platelets stromal cell Neutrophil Basophil Eosinophil Mast cell Dendritic cell Monocyte Macrophage Antigen-presenting cell Class I MHC Class II MHC CD8 CD4 TC cell Altered self cell B cell TH cell FMTOC Page iii 12/19/12 10:08 PM user-t044 /Volumes/203/MHR00209/siL52070/disk1of1/0071052070 KUBY Immunology Judith A. Owen Haverford College Jenni Punt Haverford College Sharon A. Stranford Mount Holyoke College with contributions by Patricia P. Jones Stanford University Seventh Edition W. H. Freeman and Company New York FMTOC Page iv 12/19/12 10:08 PM user-t044 /Volumes/203/MHR00209/siL52070/disk1of1/0071052070 Publisher: Susan Winslow Library of Congress Control Number: 2012950797 Senior Acquisitions Editor: Lauren Schultz North American Edition Associate Director of Marketing: Debbie Clare Cover image: ©2009 Pflicke and Sixt. Originally published in Marketing Assistant: Lindsay Neff The Journal of Experimental Medicine. 206:2925-2935. Developmental Editor: Erica Champion doi:10.1084/jem.20091739. Image provided by Holger Pflicke and Michael Sixt. Developmental Editor: Irene Pech Developmental Coordinator: Sara Ruth Blake International Edition Cover design: Dirk Kaufman Associate Media Editor: Allison Michael Cover image: Nastco/iStockphoto.com Supplements Editor: Yassamine Ebadat North American Edition Senior Project Manager at Aptara: Sherrill Redd ISBN-13: 978-14292-1919-8 Photo Editor: Christine Buese ISBN-10: 1-4292-1919-X Photo Researcher: Elyse Reider International Edition Art Director: Diana Blume ISBN-13: 978-14641-3784-6 ISBN-10: 1-4641-3784-6 Text Designer: Marsha Cohen Illustrations: Imagineering © 1992, 1994, 1997, 2000, 2003, 2007, 2013 by W. H. Freeman and Company Illustration Coordinator: Janice Donnola All rights reserved Production Coordinator: Lawrence Guerra Printed in the United States of America Composition: Aptara®, Inc. Printing and Binding: RR Donnelley First printing North American Edition W. H. Freeman and Company 41 Madison Avenue New York, NY 10010 www.whfreeman.com International Edition Macmillan Higher Education Houndmills, Basingstoke RG21 6XS, England www.macmillanhighered.com/international FMTOC Page v 12/19/12 10:08 PM user-t044 /Volumes/203/MHR00209/siL52070/disk1of1/0071052070 To all our students, fellows, and colleagues who have made our careers in immunology a source of joy and excitement, and to our families who made these careers possible. We hope that future generations of immunology students will find this subject as fasci- nating and rewarding as we have. FMTOC Page vi 12/19/12 10:08 PM user-t044 /Volumes/203/MHR00209/siL52070/disk1of1/0071052070 About the Authors All four authors are active scholars and teachers who have been/are recipients of research grants from the NIH and the NSF. We have all served in various capacities as grant proposal reviewers for NSF, NIH, HHMI, and other funding bodies as well as evaluating manuscripts submitted for publication in immunological journals. In addition, we are all active members of the American Association of Immunologists and have served our national organization in a variety of ways. Judy Owen holds B.A. and M.A. (Hons) degrees from Cambridge University. She pursued her Ph.D. at the University of Pennsylvania with the late Dr. Norman Klinman and her post- doctoral fellowship with Dr. Peter Doherty in viral immunology. She was appointed to the faculty of Haverford College, one of the first undergraduate colleges to offer a course in im- munology, in 1981. She teaches numerous laboratory and lecture courses in biochemistry and immunology and has received several teaching and mentorship awards. She is a participant in the First Year Writing Program and has been involved in curriculum development across the College. Jenni Punt received her A.B. from Bryn Mawr College (magna cum laude) majoring in Biology at Haverford College, She received her VMD (summa cum laude) and Ph.D. in im- munology from the University of Pennsylvania and was a Damon Runyon-Walter Winchell Physician-Scientist fellow with Dr. Alfred Singer at the National Institutes of Health. She was appointed to the faculty of Haverford College in 1996 where she teaches cell biology and im- munology and performs research in T cell development and hematopoiesis. She has received several teaching awards and has contributed to the development of college-wide curricular initiatives. Together, Jenni Punt and Judy Owen developed and ran the first AAI Introductory Im- munology course, which is now offered on an annual basis. Sharon Stranford obtained her B.A. with Honors in Biology from Arcadia University and her Ph.D. in Microbiology and Immunology from Hahnemann (now Drexel) University, where she studied autoimmunity with funding from the Multiple Sclerosis Foundation. She pursued postdoctoral studies in transplantation immunology at Oxford University in England, followed by a fellowship at the University of California, San Francisco, working on HIV/AIDS with Dr. Jay Levy. From 1999 to 2001, Sharon was a Visiting Assistant Professor of Biology at Amherst College, and in 2001 joined the faculty of Mount Holyoke College as a Clare Boothe Luce Assistant Professor. She teaches courses in introductory biology, cell biology, immunol- ogy, and infectious disease, as well as a new interdisciplinary course called Controversies in Public Health. Pat Jones graduated from Oberlin College in Ohio with Highest Honors in Biology and obtained her Ph.D. in Biology with Distinction from the Johns Hopkins University. She was a postdoctoral fellow of the Arthritis Foundation for two years in the Department of Biochem- istry and Biophysics at the University of California, San Francisco, Medical School, followed by two years as an NSF postdoctoral fellow in the Departments of Genetics and Medicine/ Immunology at Stanford University School of Medicine. In 1978 she was appointed Assistant Professor of Biology at Stanford and is now a full professor. Pat has received several under- graduate teaching awards, was the founding Director of the Ph.D. Program in Immunology, and in July, 2011, she assumed the position of Director of Stanford Immunology, a position that coordinates activities in immunology across the university. FMTOC Page vii 12/19/12 10:08 PM user-t044 /Volumes/203/MHR00209/siL52070/disk1of1/0071052070 Contents Chapter 1 SUMMARY 23 REFERENCES 23 Overview of the Immune System 1 USEFUL WEB SITES 23 A Historical Perspective of Immunology 2 STUDY QUESTIONS 24 Early vaccination studies led the way to immunology 2 Vaccination is an ongoing, worldwide enterprise 3 Chapter 2 Immunology is about more than just vaccines and infectious disease 4 Cells, Organs, and Micro- Immunity involves both humoral and cellular environments of the Immune components 6 System 27 How are foreign substances recognized by the immune system? 9 Cells of the Immune System 27 Hematopoietic stem cells have the ability to Important Concepts for Understanding differentiate into many types of blood cells 28 the Mammalian Immune Response 11 Hematopoeisis is the process by which hematopoietic Pathogens come in many forms and must first stem cells develop into mature blood cells 32 breach natural barriers 12 Cells of the myeloid lineage are the first responders The immune response quickly becomes tailored to infection 32 to suit the assault 12 Cells of the lymphoid lineage regulate the adaptive Pathogen recognition molecules can be encoded immune response 37 in the germline or randomly generated 14 Primary Lymphoid Organs— Tolerance ensures that the immune system avoids Where Immune Cells Develop 41 destroying the host 15 The bone marrow provides niches for hematopoietic The immune response is composed of two stem cells to self-renew and differentiate into myeloid interconnected arms: innate immunity and cells and B lymphocytes 41 adaptive immunity 16 The thymus is a primary lymphoid organ where Adaptive immune responses typically generate T cells mature 41 memory 17 Secondary Lymphoid Organs— The Good, Bad, and Ugly of the Immune Where the Immune Response Is Initiated 48 System 19 Secondary lymphoid organs are distributed through- Inappropriate or dysfunctional immune out the body and share some anatomical features 48 responses can result in a range of disorders 19 Lymphoid organs are connected to each other and The immune response renders tissue transplantation to infected tissue by two different circulatory challenging 22 systems: blood and lymphatics 48 Cancer presents a unique challenge to the immune The lymph node is a highly specialized secondary response 22 lymphoid organ 50 FMTOC Page viii 12/19/12 10:08 PM user-t044 /Volumes/203/MHR00209/siL52070/disk1of1/0071052070 viii Contents The spleen organizes the immune response against Signal-induced PIP2 breakdown by PLC causes an blood-borne pathogens 53 increase in cytoplasmic calcium ion concentration 75 MALT organizes the response to antigen that Ubiquitination may inhibit or enhance signal enters mucosal tissues 53 transduction 76 The skin is an innate immune barrier and also Frequently Encountered Signaling includes lymphoid tissue 56 Pathways 77 Tertiary lymphoid tissues also organize and maintain The PLC pathway induces calcium release and an immune response 57 PKC activation 77 SUMMARY 60 The Ras/Map kinase cascade activates transcription REFERENCES 60 through AP-1 78 USEFUL WEB SITES 61 PKC activates the NF-κB transcription factor 79 STUDY QUESTIONS 61 The Structure of Antibodies 80 Antibodies are made up of multiple immunoglobulin domains 80 Antibodies share a common structure of two light Chapter 3 chains and two heavy chains 81 There are two major classes of antibody light chains 85 Receptors and Signaling: B and There are five major classes of antibody heavy chains 85 T-Cell Receptors 65 Antibodies and antibody fragments can serve as Receptor-Ligand Interactions 66 antigens 86 Receptor-ligand binding occurs via multiple Each of the domains of the antibody heavy and noncovalent bonds 66 light chains mediate specific functions 88 X-ray crystallography has been used to define How do we quantitate the strength of receptor- the structural basis of antigen-antibody ligand interactions? 66 binding 90 Interactions between receptors and ligands can be multivalent 67 Signal Transduction in B Cells 91 Receptor and ligand expression can vary during the Antigen binding results in docking of adapter course of an immune response 68 molecules and enzymes into the BCR-Igα/Igβ membrane complex 91 Local concentrations of cytokines and other ligands may be extremely high 68 B cells use many of the downstream signaling pathways described above 92 Common Strategies Used in Many Signaling B cells also receive signals through co-receptors 94 Pathways 69 Ligand binding can induce conformational changes T-Cell Receptors and Signaling 95 in, and/or clustering of, the receptor 71 The T-cell receptor is a heterodimer with variable and constant regions 95 Some receptors require receptor-associated molecules to signal cell activation 71 The T-cell signal transduction complex includes CD3 98 Ligand-induced receptor clustering can alter The T cell co-receptors CD4 and CD8 also bind receptor location 71 the MHC 99 Tyrosine phosphorylation is an early step in many Lck is the first tyrosine kinase activated in T cell signaling pathways 73 signaling 100 Adapter proteins gather members of signaling T cells use downstream signaling strategies similar pathways 74 to those of B cells 100 Phosphorylation on serine and threonine residues SUMMARY 101 is also a common step in signaling pathways 74 REFERENCES 102 Phosphorylation of membrane phospholipids USEFUL WEB SITES 102 recruits PH domain-containing proteins to the cell membrane 75 STUDY QUESTIONS 103 FMTOC Page ix 12/19/12 10:08 PM user-t044 /Volumes/203/MHR00209/siL52070/disk1of1/0071052070 Contents ix Chapter 4 Cytokine storms may have caused many deaths in the 1918 Spanish influenza 137 Receptors and Signaling: Cytokine-Based Therapies 137 Cytokines and Chemokines 105 SUMMARY 138 REFERENCES 138 General Properties of Cytokines and Chemokines 106 USEFUL WEB SITES 139 Cytokines mediate the activation, proliferation, STUDY QUESTIONS 140 and differentiation of target cells 107 Cytokines have numerous biological functions 107 Chapter 5 Cytokines can elicit and support the activation of specific T-cell subpopulations 107 Innate Immunity 141 Cell activation may alter the expression of receptors Anatomical Barriers to Infection 143 and adhesion molecules 109 Epithelial barriers prevent pathogen entry into the Cytokines are concentrated between secreting and body’s interior 143 target cells 110 Antimicrobial proteins and peptides kill would-be Signaling through multiple receptors can fine tune invaders 145 a cellular response 110 Phagocytosis 147 Six Families of Cytokines and Associated Receptor Molecules 111 Microbes are recognized by receptors on phagocytic cells 147 Cytokines of the IL-1 family promote proinflammatory signals 113 Phagocytosed microbes are killed by multiple mechanisms 151 Hematopoietin (Class I) family cytokines share three-dimensional structural motifs, but induce a Phagocytosis contributes to cell turnover and the diversity of functions in target cells 116 clearance of dead cells 152 The Interferon (Class II) cytokine family was the Induced Cellular Innate Responses 152 first to be discovered 119 Cellular pattern recognition receptors activate Members of the TNF cytokine family can signal responses to microbes and cell damage 153 development, activation, or death 123 Toll-like receptors recognize many types of The IL-17 family is a recently discovered, pathogen molecules 153 proinflammatory cytokine cluster 127 C-type lectin receptors bind carbohydrates on the Chemokines direct the migration of leukocytes surfaces of extracellular pathogens 158 through the body 129 Retinoic acid-inducible gene-I-like receptors bind Cytokine Antagonists 133 viral RNA in the cytosol of infected cells 160 The IL-1 receptor antagonist blocks the IL-1 Nod-like receptors are activated by a variety of cytokine receptor 133 PAMPs, DAMPs, and other harmful substances 160 Cytokine antagonists can be derived from cleavage Expression of innate immunity proteins is induced of the cytokine receptor 134 by PRR signaling 160 Some viruses have developed strategies to exploit Inflammatory Responses 166 cytokine activity 134 Inflammation results from innate responses triggered by infection, tissue damage, or harmful Cytokine-Related Diseases 134 substances 167 Septic shock is relatively common and potentially Proteins of the acute phase response contribute lethal 135 to innate immunity and inflammation 168 Bacterial toxic shock is caused by superantigen induction of T-cell cytokine secretion 135 Natural Killer Cells 168 Cytokine activity is implicated in lymphoid and Regulation and Evasion of Innate and myeloid cancers 137 Inflammatory Responses 169 FMTOC Page x 12/19/12 10:08 PM user-t044 /Volumes/203/MHR00209/siL52070/disk1of1/0071052070 x Contents Innate and inflammatory responses can be harmful 169 The Regulation of Complement Activity 210 Innate and inflammatory responses are regulated Complement activity is passively regulated by protein both positively and negatively 172 stability and cell surface composition 210 Pathogens have evolved mechanisms to evade The C1 inhibitor, C1INH, promotes dissociation innate and inflammatory responses 173 of C1 components 211 Interactions Between the Innate and Decay Accelerating Factors promote decay of C3 Adaptive Immune Systems 173 convertases 211 The innate immune system activates and regulates Factor I degrades C3b and C4b 212 adaptive immune responses 174 Protectin inhibits the MAC attack 213 Adjuvants activate innate immune responses to Carboxypeptidases can inactivate the anaphylatoxins, increase the effectiveness of immunizations 175 C3a and C5a 213 Some pathogen clearance mechanisms are common to both innate and adaptive immune responses 176 Complement Deficiencies 213 Ubiquity of Innate Immunity 176 Microbial Complement Evasion Strategies 214 Plants rely on innate immune responses to combat Some pathogens interfere with the first step of infections 177 immunoglobulin-mediated complement activation 215 Invertebrate and vertebrate innate immune Microbial proteins bind and inactivate complement responses show both similarities and differences 177 proteins 215 SUMMARY 180 Microbial proteases destroy complement proteins 215 REFERENCES 181 Some microbes mimic or bind complement USEFUL WEB SITES 182 regulatory proteins 215 STUDY QUESTIONS 182 The Evolutionary Origins of the Complement System 215 SUMMARY 219 Chapter 6 REFERENCES 220 USEFUL WEB SITES 220 The Complement System 187 STUDY QUESTIONS 221 The Major Pathways of Complement Activation 189 The classical pathway is initiated by antibody binding 190 The lectin pathway is initiated when soluble proteins Chapter 7 recognize microbial antigens 195 The alternative pathway is initiated in three The Organization and Expression distinct ways 196 of Lymphocyte Receptor Genes 225 The three complement pathways converge at the formation of the C5 convertase 200 The Puzzle of Immunoglobulin Gene Structure 226 C5 initiates the generation of the MAC 200 Investigators proposed two early theoretical models of antibody genetics 226 The Diverse Functions of Complement 201 Breakthrough experiments revealed that multiple Complement receptors connect complement- gene segments encode the light chain 227 tagged pathogens to effector cells 201 Complement enhances host defense against infection 204 Multigene Organization of Ig Genes 231 Complement mediates the interface between innate Kappa light-chain genes include V, J, and C segments 231 and adaptive immunities 207 Lambda light-chain genes pair each J segment Complement aids in the contraction phase of the with a particular C segment 231 immune response 207 Heavy-chain gene organization includes VH, D, JJ, Complement mediates CNS synapse elimination 210 and CH segments 232 FMTOC Page xi 12/19/12 10:08 PM user-t044 /Volumes/203/MHR00209/siL52070/disk1of1/0071052070 Contents xi The Mechanism of V(D)J Recombination 232 Class II molecules have two non-identical glycoprotein chains 262 Recombination is directed by signal sequences 233 Class I and II molecules exhibit polymorphism in Gene segments are joined by the RAG1/2 the region that binds to peptides 263 recombinase combination 234 V(D)J recombination results in a functional Ig variable General Organization and Inheritance of region gene 235 the MHC 267 V(D)J recombination can occur between The MHC locus encodes three major classes of segments transcribed in either the same or opposite molecules 268 directions 239 The exon/intron arrangement of class I and II genes Five mechanisms generate antibody diversity in reflects their domain structure 270 naïve B cells 239 Allelic forms of MHC genes are inherited in linked groups called haplotypes 270 B-Cell Receptor Expression 242 MHC molecules are codominantly expressed 271 Allelic exclusion ensures that each B cell synthesizes only one heavy chain and one light chain 242 Class I and class II molecules exhibit diversity at both the individual and species levels 273 Receptor editing of potentially autoreactive receptors occurs in light chains 243 MHC polymorphism has functional relevance 276 Ig gene transcription is tightly regulated 244 The Role of the MHC and Expression Mature B cells express both IgM and IgD antibodies Patterns 277 by a process that involves mRNA splicing 246 MHC molecules present both intracellular and extracellular antigens 278 T-Cell Receptor Genes and Expression 247 MHC class I expression is found throughout the Understanding the protein structure of the TCR body 278 was critical to the process of discovering the genes 247 Expression of MHC class II molecules is primarily The β-chain gene was discovered simultaneously restricted to antigen-presenting cells 279 in two different laboratories 249 MHC expression can change with changing A search for the α-chain gene led to the γ-chain conditions 279 gene instead 250 T cells are restricted to recognizing peptides TCR genes undergo a process of rearrangement presented in the context of self-MHC alleles 281 very similar to that of Ig genes 251 Evidence suggests different antigen processing TCR expression is controlled by allelic exclusion 253 and presentation pathways 284 TCR gene expression is tightly regulated 253 The Endogenous Pathway of Antigen Processing and Presentation 285 SUMMARY 255 Peptides are generated by protease complexes REFERENCES 256 called proteasomes 285 USEFUL WEB SITES 257 Peptides are transported from the cytosol to the RER 285 STUDY QUESTIONS 258 Chaperones aid peptide assembly with MHC class I molecules 286 The Exogenous Pathway of Antigen Chapter 8 Processing and Presentation 288 Peptides are generated from internalized molecules The Major Histocompatibility in endocytic vesicles 288 Complex and Antigen The invariant chain guides transport of class II Presentation 261 MHC molecules to endocytic vesicles 289 The Structure and Function of MHC Molecules 262 Peptides assemble with class II MHC molecules by displacing CLIP 289 Class I molecules have a glycoprotein heavy chain and a small protein light chain 262 Cross-Presentation of Exogenous Antigens 291 FMTOC Page xii 12/19/12 10:08 PM user-t044 /Volumes/203/MHR00209/siL52070/disk1of1/0071052070 xii Contents Dendritic cells appear to be the primary cross- Apoptosis allows cells to die without triggering presenting cell type 292 an inflammatory response 318 Mechanisms and Functions of Cross-Presentation 292 Different stimuli initiate apoptosis, but all activate caspases 318 Presentation of Nonpeptide Antigens 293 Apoptosis of peripheral T cells is mediated by the SUMMARY 295 extrinsic (Fas) pathway 320 REFERENCES 295 TCR-mediated negative selection in the thymus USEFUL WEB SITES 296 induces the intrinsic (mitochondria-mediated) apoptotic pathway 321 STUDY QUESTIONS 296 Bcl-2 family members can inhibit or induce apoptosis 321 SUMMARY 324 Chapter 9 REFERENCES 325 USEFUL WEB SITES 326 T-Cell Development 299 STUDY QUESTIONS 327 Early Thymocyte Development 301 Thymocytes progress through four double-negative stages 301 Chapter 10 Thymocytes can express either TCRαβ or TCRγδ receptors 302 B-Cell Development 329 DN thymocytes undergo β-selection, which results The Site of Hematopoiesis 330 in proliferation and differentiation 303 The site of B-cell generation changes during gestation 330 Positive and Negative Selection 304 Hematopoiesis in the fetal liver differs from that in the adult bone marrow 332 Thymocytes “learn” MHC restriction in the thymus 305 T cells undergo positive and negative selection 305 B-Cell Development in the Bone Marrow 332 Positive selection ensures MHC restriction 307 The stages of hematopoiesis are defined by cell- surface markers, transcription-factor expression, Negative selection (central tolerance) ensures and immunoglobulin gene rearrangements 334 self-tolerance 310 The earliest steps in lymphocyte differentiation culminate The selection paradox: Why don’t we delete all cells in the generation of a common lymphoid progenitor 337 we positively select? 312 The later steps of B-cell development result in An alternative model can explain the thymic commitment to the B-cell phenotype 339 selection paradox 313 Immature B cells in the bone marrow are Do positive and negative selection occur at the exquisitely sensitive to tolerance induction 344 same stage of development, or in sequence? 314 Many, but not all, self-reactive B cells are deleted Lineage Commitment 314 within the bone marrow 345 Several models have been proposed to explain B cells exported from the bone marrow are still lineage commitment 314 functionally immature 345 Double-positive thymocytes may commit to other Mature, primary B-2 B cells migrate to the lymphoid types of lymphocytes 316 follicles 349 Exit from the Thymus and Final Maturation 316 The Development of B-1 and Marginal-Zone B Cells 351 Other Mechanisms That Maintain Self-Tolerance 316 B-1 B cells are derived from a separate developmental TREG cells negatively regulate immune responses 317 lineage 351 Peripheral mechanisms of tolerance also protect Marginal-zone cells share phenotypic and functional against autoreactive thymocytes 318 characteristics with B-1 B cells and arise at the T2 stage 352 Apoptosis 318 Comparison of B- and T-Cell Development 352 FMTOC Page xiii 12/19/12 10:08 PM user-t044 /Volumes/203/MHR00209/siL52070/disk1of1/0071052070 Contents xiii SUMMARY 354 Chapter 12 REFERENCES 355 USEFUL WEB SITES 355 B-Cell Activation, Differentiation, STUDY QUESTIONS 356 and Memory Generation 385 T-Dependent B-Cell Responses 388 T-dependent antigens require T-cell help to Chapter 11 generate an antibody response 388 Antigen recognition by mature B cells provides a T-Cell Activation, Differentiation, survival signal 389 and Memory 357 B cells encounter antigen in the lymph nodes and spleen 390 T-Cell Activation and the Two-Signal Hypothesis 358 B-cell recognition of cell-bound antigen results in Costimulatory signals are required for optimal T-cell membrane spreading 391 activation and proliferation 359 What causes the clustering of the B-cell receptors Clonal anergy results if a costimulatory signal is absent 363 upon antigen binding? 392 Cytokines provide Signal 3 364 Antigen receptor clustering induces internalization Antigen-presenting cells have characteristic and antigen presentation by the B cell 393 costimulatory properties 365 Activated B cells migrate to find antigen-specific Superantigens are a special class of T-cell activators 366 T cells 393 T-Cell Differentiation 368 Activated B cells move either into the extra- follicular space or into the follicles to form germinal Helper T cells can be divided into distinct subsets 370 centers 395 The differentiation of T helper cell subsets is regulated Plasma cells form within the primary focus 395 by polarizing cytokines 371 Other activated B cells move into the follicles and Effector T helper cell subsets are distinguished by initiate a germinal center response 396 three properties 372 Somatic hypermutation and affinity selection occur Helper T cells may not be irrevocably committed within the germinal center 398 to a lineage 378 Class switch recombination occurs within the Helper T-cell subsets play critical roles in immune germinal center after antigen contact 401 health and disease 378 Most newly generated B cells are lost at the end of T-Cell Memory 379 the primary immune response 403 Naïve, effector, and memory T cells display broad Some germinal center cells complete their differences in surface protein expression 379 maturation as plasma cells 403 TCM and TEM are distinguished by their locale and B-cell memory provides a rapid and strong commitment to effector function 380 response to secondary infection 404 How and when do memory cells arise? 380 T-Independent B-Cell Responses 406 What signals induce memory cell commitment? 381 T-independent antigens stimulate antibody production without the need for T-cell help 406 Do memory cells reflect the heterogeneity of effector cells generated during a primary response? 381 Two novel subclasses of B cells mediate the response to T-independent antigens 407 Are there differences between CD4+ and CD8+ memory T cells? 381 Negative Regulation of B Cells 411 How are memory cells maintained over many years? 381 Negative signaling through CD22 shuts down unnecessary BCR signaling 411 SUMMARY 381 Negative signaling through the FcγRIIb receptor REFERENCES 382 inhibits B-cell activation 411 USEFUL WEB SITES 383 B-10 B cells act as negative regulators by STUDY QUESTIONS 383 secreting IL-10 411 FMTOC Page xiv 12/19/12 10:08 PM user-t044 /Volumes/203/MHR00209/siL52070/disk1of1/0071052070 xiv Contents SUMMARY 412 Naïve lymphocytes sample stromal cells in the REFERENCES 413 lymph nodes 461 USEFUL WEB SITES 414 Naïve lymphocytes browse for antigen along reticular networks in the lymph node 461 STUDY QUESTIONS 414 Immune Cell Behavior during the Innate Immune Response 464 Antigen-presenting cells travel to lymph nodes Chapter 13 and present processed antigen to T cells 465 Unprocessed antigen also gains access to lymph- Effector Responses: Cell-and node B cells 465 Antibody-Mediated Immunity 415 Immune Cell Behavior during the Adaptive Antibody-Mediated Effector Functions 416 Immune Response 467 + Antibodies mediate the clearance and destruction Naïve CD4 T cells arrest their movements after of pathogen in a variety of ways 416 engaging antigens 468 + Antibody isotypes mediate different effector functions 419 B cells seek help from CD4 T cells at the border between the follicle and paracortex of the Lymph Node 468 Fc receptors mediate many effector functions of antibodies 423 Dynamic imaging approaches have been used to address a controversy about B-cell behavior in Cell-Mediated Effector Responses 427 germinal centers 470 + Cytotoxic T lymphocytes recognize and kill infected CD8 T cells are activated in the lymph node via a or tumor cells via T-cell receptor activation 428 multicellular interaction 471 Natural killer cells recognize and kill infected cells and Activated lymphocytes exit the lymph node and tumor cells by their absence of MHC class I 435 recirculate 472 NKT cells bridge the innate and adaptive immune A summary of our current understanding 472 systems 441 The immune response contracts within 10 to 14 days 474 Experimental Assessment of Cell-Mediated Immune Cell Behavior in Peripheral Cytotoxicity 444 Tissues 474 Co-culturing T cells with foreign cells stimulates Chemokine receptors and integrins regulate homing the mixed-lymphocyte reaction 444 of effector lymphocytes to peripheral tissues 474 CTL activity can be demonstrated by cell-mediated Effector lymphocytes respond to antigen in lympholysis 445 multiple tissues 475 The graft-versus-host reaction is an in vivo indication SUMMARY 480 of cell-mediated cytotoxicity 446 REFERENCES 481 SUMMARY 446 USEFUL WEB SITES 482 REFERENCES 447 STUDY QUESTIONS 482 USEFUL WEB SITES 448 STUDY QUESTIONS 448 Chapter 15 Chapter 14 Allergy, Hypersensitivities, and The Immune Response Chronic Inflammation 485 in Space and Time 451 Allergy: A Type I Hypersensitivity Reaction 486 Immune Cell Behavior before Antigen IgE antibodies are responsible for type I hypersensitivity 487 Is Introduced 455 Many allergens can elicit a type I response 487 Naïve lymphocytes circulate between secondary IgE antibodies act by cross-linking Fcε receptors on and tertiary lymphoid tissues 455 the surfaces of innate immune cells 487 FMTOC Page xv 12/19/12 10:08 PM user-t044 /Volumes/203/MHR00209/siL52070/disk1of1/0071052070 Contents xv IgE receptor signaling is tightly regulated 491 Chapter 16 Innate immune cells produce molecules responsible for type I hypersensitivity symptoms 491 Tolerance, Autoimmunity, and Type I hypersensitivities are characterized by both Transplantation 517 early and late responses 494 Establishment and Maintenance of Tolerance 518 There are several categories of type I hypersensitivity reactions 494 Antigen sequestration is one means to protect self antigens from attack 519 There is a genetic basis for type I hypersensitivity 497 Central tolerance limits development of autoreactive Diagnostic tests and treatments are available for T cells and B cells 520 type I hypersensitivity reactions 498 Peripheral tolerance regulates autoreactive cells The hygiene hypothesis has been advanced to in the circulation 520 explain increases in allergy incidence 501 Autoimmunity 525 Antibody-Mediated (Type II) Hypersensitivity Reactions 501 Some autoimmune diseases target specific organs 526 Transfusion reactions are an example of type II Some autoimmune diseases are systemic 529 hypersensitivity 501 Both intrinsic and extrinsic factors can favor Hemolytic disease of the newborn is caused by susceptibility to autoimmune disease 531 type II reactions 503 Several possible mechanisms have been proposed for the induction of autoimmunity 533 Hemolytic anemia can be drug induced 504 Autoimmune diseases can be treated by general or Immune Complex-Mediated (Type III) pathway-specific immunosuppression 534 Hypersensitivity 505 Transplantation Immunology 536 Immune complexes can damage various tissues 505 Graft rejection occurs based on immunologic Immune complex-mediated hypersensitivity can principles 536 resolve spontaneously 505 Graft rejection follows a predictable clinical course 541 Autoantigens can be involved in immune complex- mediated reactions 506 Immunosuppressive therapy can be either general or target-specific 543 Arthus reactions are localized type III hypersensitivity reactions 506 Immune tolerance to allografts is favored in certain instances 545 Delayed-Type (Type IV) Hypersensitivity (DTH) 506 Some organs are more amenable to clinical The initiation of a type IV DTH response involves transplantation than others 546 sensitization by antigen 507 SUMMARY 549 The effector phase of a classical DTH response is REFERENCES 550 induced by second exposure to a sensitizing antigen 507 USEFUL WEB SITES 551 The DTH reaction can be detected by a skin test 508 STUDY QUESTIONS 551 Contact dermatitis is a type IV hypersensitivity response 508 Chronic Inflammation 509 Infections can cause chronic inflammation 509 Chapter 17 There are noninfectious causes of chronic inflammation 510 Infectious Diseases and Vaccines 553 Obesity is associated with chronic inflammation 510 The Importance of Barriers to Infection and Chronic inflammation can cause systemic disease 510 the Innate Response 554 SUMMARY 513 Viral Infections 555 REFERENCES 515 Many viruses are neutralized by antibodies 556 USEFUL WEB SITES 515 Cell-mediated immunity is important for viral STUDY QUESTIONS 516 control and clearance 556 FMTOC Page xvi 12/19/12 10:08 PM user-t044 /Volumes/203/MHR00209/siL52070/disk1of1/0071052070 xvi Contents Viruses employ several different strategies to evade B-cell immunodeficiencies exhibit depressed host defense mechanisms 556 production of one or more antibody isotypes 601 Influenza has been responsible for some of the Disruptions to innate components may also impact worst pandemics in history 557 adaptive responses 601 Bacterial Infections 560 Complement deficiencies are relatively common 603 Immune responses to extracellular and intracellular Immunodeficiency that disrupts immune regulation bacteria can differ 560 can manifest as autoimmunity 603 Bacteria can evade host defense mechanisms at Immunodeficiency disorders are treated by several different stages 563 replacement therapy 604 Tuberculosis is primarily controlled by CD4+ T cells 564 Animal models of immunodeficiency have been used to study basic immune function 604 Diphtheria can be controlled by immunization with inactivated toxoid 565 Secondary Immunodeficiencies 606 Parasitic Infections 565 HIV/AIDS has claimed millions of lives worldwide 607 Protozoan parasites account for huge worldwide The retrovirus HIV-1 is the causative agent of AIDS 608 disease burdens 565 HIV-1 is spread by intimate contact with infected body fluids 610 A variety of diseases are caused by parasitic worms (helminths) 567 In vitro studies have revealed the structure and life cycle of HIV-1 612 Fungal Infections 569 Infection with HIV-1 leads to gradual impairment Innate immunity controls most fungal infections 569 of immune function 615 Immunity against fungal pathogens can be acquired 571 Active research investigates the mechanism of Emerging and Re-emerging Infectious Diseases 571 progression to AIDS 616 Some noteworthy new infectious diseases have Therapeutic agents inhibit retrovirus replication 619 appeared recently 572 A vaccine may be the only way to stop the Diseases may re-emerge for various reasons 573 HIV/AIDS epidemic 621 Vaccines 574 SUMMARY 623 REFERENCES 623 Protective immunity can be achieved by active or passive immunization 574 USEFUL WEB SITES 624 There are several vaccine strategies, each with STUDY QUESTIONS 624 unique advantages and challenges 578 Conjugate or multivalent vaccines can improve immunogenicity and outcome 583 Chapter 19 Adjuvants are included to enhance the immune response to a vaccine 585 Cancer and the Immune System 627 Terminology and Common Types of Cancer 627 SUMMARY 586 REFERENCES 587 Malignant Transformation of Cells 628 USEFUL WEB SITES 588 DNA alterations can induce malignant transformation 629 STUDY QUESTIONS 588 The discovery of oncogenes paved the way for our understanding of cancer induction 629 Genes associated with cancer control cell proliferation and survival 630 Chapter 18 Malignant transformation involves multiple steps 633 Immunodeficiency Disorders 593 Tumor Antigens 634 Primary Immunodeficiencies 593 Tumor-specific antigens are unique to tumor cells 636 Combined immunodeficiencies disrupt adaptive Tumor-associated antigens are normal cellular immunity 597 proteins with unique expression patterns 636 FMTOC Page xvii 12/19/12 10:08 PM user-t044 /Volumes/203/MHR00209/siL52070/disk1of1/0071052070 Contents xvii The Immune Response to Cancer 638 Hemagglutination inhibition reactions are used to detect the presence of viruses and of antiviral antibodies 658 Immunoediting both protects against and promotes tumor growth 639 Bacterial agglutination can be used to detect antibodies to bacteria 659 Key immunologic pathways mediating tumor eradication have been identified 639 Antibody Assays Based on Antigen Binding to Some inflammatory responses can promote cancer 642 Solid-Phase Supports 659 Some tumor cells evade immune recognition Radioimmunoassays are used to measure the and activation 643 concentrations of biologically relevant proteins and hormones in bodily fluids 659 Cancer Immunotherapy 644 ELISA assays use antibodies or antigens covalently Monoclonal antibodies can be targeted to tumor cells 644 bound to enzymes 660 Cytokines can be used to augment the immune The design of an ELISA assay must consider various response to tumors 646 methodological options 662 Tumor-specific T cells can be expanded and ELISPOT assays measure molecules secreted by reintroduced into patients 647 individual cells 663 New therapeutic vaccines may enhance the anti-tumor Western blotting can identify a specific protein immune response 647 in a complex protein mixture 664 Manipulation of costimulatory signals can improve Methods to Determine the Affinity of Antigen- cancer immunity 647 Antibody Interactions 664 Combination cancer therapies are yielding Equilibrium dialysis can be used to measure surprising results 648 antibody affinity for antigen 665 SUMMARY 649 Surface plasmon resonance is commonly used REFERENCES 650 for measurements of antibody affinity 667 USEFUL WEB SITES 650 Microscopic Visualization of Cells and STUDY QUESTIONS 651 Subcellular Structures 668 Immunocytochemistry and immunohistochemistry use enzyme-conjugated antibodies to create images Chapter 20 of fixed tissues 668 Immunoelectron microscopy uses gold beads Experimental Systems to visualize antibody-bound antigens 669 and Methods 653 Immunofluorescence-Based Imaging Techniques 669 Antibody Generation 654 Fluorescence can be used to visualize cells Polyclonal antibodies are secreted by multiple clones and molecules 669 of antigen-specific B cells 654 Immunofl uorescence microscopy uses antibodies A monoclonal antibody is the product of a single conjugated with fluorescent dyes 669 stimulated B cell 654 Confocal fluorescence microscopy provides three- Monoclonal antibodies can be modified for use in dimensional images of extraordinary clarity 670 the laboratory or the clinic 655 Multiphoton fluorescence microscopy is a variation Immunoprecipitation- Based Techniques 656 of confocal microscopy 670 Immunoprecipitation can be performed in solution 656 Intravital imaging allows observation of immune Immunoprecipitation of soluble antigens can be responses in vivo 671 performed in gel matrices 656 Flow Cytometry 672 Immunoprecipitation allows characterization of cell-bound molecules 657 Magnetic Activated Cell Sorting 677 Agglutination Reactions 658 Cell Cycle Analysis 678 Hemagglutination reactions can be used to detect any Tritiated (3H) thymidine uptake was one of the antigen conjugated to the surface of red blood cells 658 first methods used to assess cell division 678 FMTOC Page xviii 12/19/12 10:08 PM user-t044 /Volumes/203/MHR00209/siL52070/disk1of1/0071052070 xviii Contents Colorimetric assays for cell division are rapid and Transgenic animals carry genes that have been eliminate the use of radioactive isotopes 678 artificially introduced 684 Bromodeoxyuridine-based assays for cell division use Knock-in and knockout technologies replace an antibodies to detect newly synthesized DNA 678 endogenous with a nonfunctional or engineered gene copy 685 Propidium iodide enables analysis of the cell cycle status of cell populations 678 The cre/lox system enables inducible gene deletion in selected tissues 687 Carboxyfluorescein succinimidyl ester can be used to follow cell division 679 SUMMARY 689 REFERENCES 690 Assays of Cell Death 679 USEFUL WEB SITES 690 The 51Cr release assay was the first assay used STUDY QUESTIONS 691 to measure cell death 679 Fluorescently labeled annexin V measures phosphatidyl serine in the outer lipid envelope of apoptotic cells 680 The TUNEL assay measures apoptotically generated Appendix I DNA fragmentation 680 Caspase assays measure the activity of enzymes CD Antigens A-1 involved in apoptosis 681 Biochemical Approaches Used to Elucidate Signal Transduction Pathways 681 Appendix II Biochemical inhibitors are often used to identify intermediates in signaling pathways 681 Cytokines B-1 Many methods are used to identify proteins that interact with molecules of interest 682 Appendix III Whole Animal Experimental Systems 682 Animal research is subject to federal guidelines Chemokines and Chemokine that protect nonhuman research subjects 682 Receptors C-1 Inbred strains can reduce experimental variation 683 Congenic resistant strains are used to study the effects of particular gene loci on immune Glossary G-1 responses 684 Answers to Study Questions AN-1 Adoptive transfer experiments allow in vivo examination of isolated cell populations 684 Index I-1 FMTOC Page xix 12/19/12 10:08 PM user-t044 /Volumes/203/MHR00209/siL52070/disk1of1/0071052070 Feature Boxes in Kuby 7e Clinical Focus Classic Experiment Box 1.1 Vaccine Controversy: What’s Truth and What’s Box 2.1 Isolating Hematopoietic Stem Cells p. 29 Myth? p. 5 Box 2.3 The Discovery of a Thymus—and Two p. 46 Box 1.2 Passive Antibodies and the Iditarod p. 8 Box 3.1 The Elucidation of Antibody Structure p. 82 Box 1.3 The Hygiene Hypothesis p. 20 Box 3.3 The Discovery of the T-Cell Receptor p. 96 Box 2.2 Stem Cells—Clinical Uses and Potential p. 42 Box 6.1 The Discovery of Properdin p. 198 Box 3.2 Defects in the B-Cell Signaling Protein Btk Lead Box 7.1 Hozumi and Tonegawa’s Experiment: DNA to X-Linked Agammaglobulinemia p. 93 Recombination Occurs in immunoglobulin Box 4.2 Therapy with Interferons p. 120 Genes in Somatic Cells p. 227 Box 4.4 Cytokines and Obesity p. 136 Box 8.3 Demonstration of the Self-MHC Restriction of Box 5.2 Genetic Defects in Components of Innate CD8⫹ T Cells p. 282 and Inflammatory Responses Associated with Box 9.1 Insights about Thymic Selection from the First Disease p. 170 TCR Transgenic Mouse Have Stood the Test of Box 6.2 The Complement System as a Therapeutic Time p. 308 Target p. 208 Box 10.3 The Stages of B-Cell Development: Box 7.3 Some Immunodeficiencies Result from Impaired Characterization of the Hardy Fractions p. 342 Receptor Gene Recombination p. 255 Box 11.1 Discovery of the First Costimulatory Receptor: Box 8.2 MHC Alleles and Susceptibility to Certain CD28 p. 362 Diseases p. 277 Box 12.1 Experimental Proof That Somatic Box 8.4 Deficiencies in TAP Can Lead to Bare Hypermutation and Antigen- Induced Selection Lymphocyte Syndrome p. 287 Occurred Within the Germinal Centers p. 399 Box 9.2 How Do T Cells That Cause Type 1 Diabetes Box 13.2 Rethinking Immunological Memory: NK Cells Es