《微生物与免疫学》课程教学资源（书籍教材）Janeway's Immunobiology，8th edition，Kenneth Murphy

GS MMUNO JANEWAY BIOLOGY KENNETH MURPHY

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Preface Janeway's Immunobiology is intended for under- immunodeficiencies or by failures of immunological graduate and graduate courses in as mechanisms.Chapter 16 describes how the immune lasonmediadentsinOhegbootc9ase eonescanemanpntedtnteontstacomb This chapter includes a complete update of the sistent viewnoin evious oditions ar ed th oughout the book as the relevant topics are encountered. illustrates th loss of any component o from the infection.The companion book.Case ons of Allan Mowat.who ext an dditional,integrated and updated Chapter 12.I welcome Casey Weaver's opics(d nbol nco apters 13 appendices on cytokines and chemokines.I thank Barry Kay for hi suggestions in revising Chapter 14. has made important and rapid developments have work on the previous editions. been extensively revised. The skills give the bool its consistent style and ensure defenses the orderly ctically sound p entation are treated in Chapter 2.The complement system is authors clumsy sketches into the informative yet to the editin pter 3 presented as they are encountered,and not confin in communicating information about this book to a single chapter Signaling pathwaysof he Toll aro und the world Patienc e and support. dlike to thankall those people on the revision plan for this edition.I would also like 12)has be antigen.Mucosal immunology (Chapter to tha the many instructors and students who have microhiota and the the of specialized dendritic cells and regulatory Tcells in suggestionsjustice in this edition.Everyeffort has been a greatly appreciate 13-16 the you let me know. discussed earlier with our latest understanding of the causes of disease,whether by inherited or acquired Kenneth Murphy

Preface Janeway's Immunobiology is intended for under￾graduate and graduate courses in immunology, as well as for medical students. The book can be used as an introduction to immunology but its scope is sufficiently comprehensive and deep to be useful for more advanced students and working immunologists. Immunobiology presents immunology from the con￾sistent viewpoint of the host's interaction with an environment full of microbes and pathogens, and illustrates that the loss of any component of this system increases host susceptibility to some particular infection. The companion book, Case Studies in Immunology, provides an additional, integrated discussion of clinical topics (diseases covered in Case Studies are indicated by a symbol in the margin of Immunobiology). This eighth edition retains the overall organization of the previous edition, and chapters in which the field has made important and rapid developments have been extensively revised. The discussion of innate immunity has been substantially expanded and its mechanisms are now treated in two separate chapters, presented in the order in which a pathogen would encounter innate defenses as it attempts to establish an infection. The immediate and soluble defenses are treated in Chapter 2. The complement system is introduced in the context of innate immunity, with the lectin pathway presented before the classical pathway of activation. The induced defenses of innate immunity-including a completely updated treatment of innate sensing-follows in Chapter 3, where various innate cell subsets and their receptors are also described. Signaling pathways are now presented as they are encountered, and not confined to a single chapter. Signaling pathways of the Toll-like receptors and other innate sensors are described in Chapter 3, while antigen receptor signaling pathways and cytokine and apoptotic pathways are retained in Chapter 7. Chapter 10 has been revised to place more emphasis on the trafficking of B cells in peripheral lymphoid organs and the locations at which they encounter antigen. Mucosal immunology (Chapter 12) has been expanded to include more discussion of responses to the commensal microbiota and the role of specialized dendritic cells and regulatory T cells in maintaining tolerance to food antigens and commensal bacteria. The last four chapters-the clinical chapters (Chapters 13-16)-reinforce the basic concepts discussed earlier with our latest understanding of the causes of disease, whether by inherited or acquired I immunodeficiencies or by failures of immunological mechanisms. Chapter 16 describes how the immune response can be manipulated in attempts to combat infectious diseases, transplant rejection, and cancer. This chapter includes a complete update of the immunotherapeutics and vaccine sections. Aspects of evolution, which were confined to the last chapter of previous editions, are now discussed throughout the book as the relevant topics are encountered. The eighth edition has benefited again from the contributions of Allan Mowat, who extensively revised and updated Chapter 12. I welcome Casey Weaver's new contributions to Chapters 13 and 15, and Robert Schreiber's and Joost Oppenheim's revisions to the appendices on cytokines and chemokines. I thank Barry Kay for his suggestions in revising Chapter 14. Most importantly, I acknowledge Charles A. Janeway Jr., Paul Travers, and Mark Walport for their pioneering work on the previous editions. The editors, illustrators, and publishers have con￾tributed in many ways. Eleanor Lawrence's editorial skills give the book its consistent style and ensure the orderly and didactically sound presentation of concepts. Matt McClements has transformed the author's clumsy sketches into the informative yet artistic diagrams that define Janeway's text. Janete Scobie, Bruce Goatly, Sally Huish, Georgina Lucas, and Ioana Moldovan have brought skill and dedication to the editing, proofreading, and typesetting of this edition. Monica Toledo and Michael Morales were key in updating and generating new animations. I thank Adam Sendroff and Lucy Brodie, who are instrumental in communicating information about this book to immunologists around the world, and most of all I thank the publisher Denise Schanck for her incredible patience and support. I would like to thank all those people who read parts or all of the chapters of the seventh edition and advised on the revision plan for this edition. I would also like to thank the many instructors and students who have taken the time to write to me with their suggestions on how to improve the book. I hope I have done those suggestions justice in this edition. Every effort has been made to write a book that is error-free. Nonetheless, you may find them, and I would greatly appreciate it if you let me know. Kenneth Murphy E

Instructor and Student Resources Websites Accessible from www.garlandscience.com,these Student Resources:The following resources are provide and each for Janeway's com/stu of the On the websites,the resources may be browsed by Animations and Videos The 40 animations and videos dynamically illustrate of the more diffcult to throughout the text indicate the relevant media. av ctor Site ach Flashc oter contains a set of flashcards.built into the The Art of Janeway's Immuno website,that allow students to review key terms from The images the boo are the text have been optimized for display on a computer The complete glossary from the book is available on or bykeywo be searched and browsed as a Animations and Videos are created for instructors who wish to use the t presentatio s on Window 6 uters or Keynote uo ode to your PC e movi prev ew page from the ovt ha presentations.These will be useful for instructors th would d tart in creating lecture cousell of Ca or example the content of these presentaon the classroom. PowerPoint and Word are registered trademarks of Microsof Corporation in the United Statesand/orother Keynote is a registered trademark ofApple Inc

Instructor and Student Resources Websites Accessible from www.garlandscience.com, these websites provide learning and teaching tools created for Janeway's Immunobiology, Eighth Edition. Below is an overview of the resources available for this book. On the websites, the resources may be browsed by individual chapters and there is a search engine. You can also access the resources available for other Garland Science titles. Instructor Resources: The following resources are available on the Instructor Site: The Art of Janeway's Immunobiology, Eighth Edition The images from the book are available in two convenient formats: PowerPoint® and JPEG. They have been optimized for display on a computer. Figures are searchable by figure number, figure name, or by keywords used in the figure legend from the book. Animations and Videos The 40 animations and videos that are available to students are also available on the Instructor's Site in two formats. The WMV-formatted movies are created for instructors who wish to use the movies in PowerPoint presentations on Windows® computers; the QuickTime-formatted movies are for use in PowerPoint for Apple computers or Keynote® presentations. The movies can easily be downloaded to your PC using the 'download' button on the movie preview page. Figure Integrated Lecture Outlines The section headings, concept headings, and figures from the text have been integrated into PowerPoint presentations. These will be useful for instructors who would like a head start in creating lectures for their course. Like all of Garland Science's PowerPoint presentations, the lecture outlines can be customized. For example, the content of these presentations can be combined with videos on the website to create unique lectures that facilitate interactive learning in the classroom. Student Resources: The following resources are available on the Student Site at www.garlandscience. com/ students/immunobiology: Animations and Videos The 40 animations and videos dynamically illustrate important concepts from the book, and make many of the more difficult topics accessible. Icons located throughout the text indicate the relevant media. Flashcards Each chapter contains a set of flashcards, built into the website, that allow students to review key terms from the text. Glossary The complete glossary from the book is available on the website and can be searched and browsed as a whole or sorted by chapter. PowerPoint and Word are registered trademarks of Microsoft Corporation in the United States and/or other countries. Keynote is a registered trademark of Apple Inc

Acknowledgments Research,ondon;Steve Reiner,University of Pennsylvania with invaluable advice in developing thisnewedtion. for Medical Research.London. kinger, nstitute Chapter 1:Hans Acha-Orbea,Universite de Lausanne;Eliza- Chapter 9:Katherine Calame,Columbia University;Michael Medicine Lewis Lani .of Francisco versity of Medic al Sch Cambridge. ne The Campus de luminv. ripps Research Michae cine.switerland. Robyn Stanfield.The Scripps Res arch Institute:lan Wilson Chapter 11:Chuck Elson.University of Alabama:Michael The Scripps Research Institute. ld.Ba Case Western Reserve:Thomas MacDon sity of Milan;Michael Russell,University at Buffalo. icine:Barry Sleckmar de Rech pitalier Necker Ir Gena,Ha oI Me cine; 密 Chapter 14:Anne Davidson,Albert Einstein College of RIKEN ；Larry Samel National Human Genome Research Institute.NIH:Art Weiss Pennsylvania School of Medicine:Rikard Holmdahl.Lund University of California,San Francisco. Cancr to Univ RichardHardy,Fox Chase Cancer Center Kris Hogquist.Uni sota;John】 National Institute for Medical Research,London. Chapter Litm. University of South Florida;Martin Flajnik University of Oxford:Bill Heath.University of Melbo Victoria;Anne O'Garra,The National Institute for Medical versity of Alabama at Birmingham

Acknowledgments We would like to thank the following experts who read parts or the whole of the seventh edition chapters and provided us with invaluable advice in developing this new edition. Chapter 1: Hans Acha-Orbea, Universite de Lausanne; Eliza￾beth Godrick, Boston University; Michael Gold, University of British Columbia; Derek McKay, University of Calgary. Chapter 2: Shizuo Akira, Osaka University; Lewis Lanier, University of California, San Francisco; Gabriel Nunez, Uni￾versity of Michigan Medical School; Philip Rosenstiel, Uni￾versity of Kiel, Germany; Hung Bing Shu, Wuhan University, China; Caetano Reis e Sousa, Cancer Research UK; Tada Taniguchi, University of Tokyo; Andrea Tenner, University of California, Irvine; Eric Vivier, Universite de Ia Mediterranee Campus de Luminy. Chapter 3: Bernard Malissen, Centre d' Immunologie Mar￾seille-Luminy; Ellis Reinherz, Harvard Medical School; Robyn Stanfield, The Scripps Research Institute; Ian Wilson, The Scripps Research Institute. Chapter 4: Michael Lieber, University of Southern Califor￾nia; Michael Neuberger, University of Cambridge; David Schatz, Yale University School of Medicine; Barry Sleckman, Washington University School of Medicine, St. Louis; Philip Tucker, University of Texas, Austin. Chapter 5: Siamak Bahram, Centre de Recherche d'Immunologie et d'Hematologie; Peter Cresswell, Yale University School of Medicine; Mitchell Kronenberg, La Jolla Institute for Allergy & Immunology; Philippa Marrack, Howard Hughes Medical Institute; Hans-Georg Rammensee, University ofTubingen, Germany. Chapter 6: Oreste Acuto, University of Oxford; Leslie Berg, University of Massachusetts Medical Center; Doreen Can￾trell, University of Dundee, UK; Andy Chan, Genentech, Inc.; Vigo Heissmeyer, Helmholtz Center Munich; Steve Jameson, University of Minnesota; Gabriel Nunez, University of Mich￾igan Medical School; Takashi Saito, RIKEN; Larry Samel￾son, National Cancer Institute, NIH; Pamela Schwartzberg, National Human Genome Research Institute, NIH; Art Weiss, University of California, San Francisco. Chapter 7: Michael Cancro, University of Pennsylvania School of Medicine; Robert Carter, University of Alabama; Richard Hardy, Fox Chase Cancer Center; Kris Hogquist, Uni￾versity of Minnesota; John Monroe, Genentech, Inc.; Nancy Ruddle, Yale University School of Medicine; Marc Veldhoen, National Institute for Medical Research, London. Chapter 8: Michael Bevan, University of Washington; Frank Carbone, University of Melbourne, Victoria; Gillian Griffiths, University of Oxford; Bill Heath, University of Melbourne, Victoria; Anne O'Garra, The National Institute for Medical Research, London; Steve Reiner, University of Pennsylvania School of Medicine; Brigitta Stockinger, National Institute for Medical Research, London. Chapter 9: Katherine Calame, Columbia University; Michael Cancro, University of Pennsylvania School of Medicine; Robert H. Carter, The University of Alabama, Birmingham; Jason Cyster, University of California, San Francisco; John Kearney, The University of Alabama, Birmingham; Garnett Kelsoe, Duke University; Michael Neuberger, University of Cambridge. Chapter 10: Michael Bevan, University ofWashington; Marc K. Jenkins, University of Minnesota; Robert Modlin, Uni￾versity of California, Los Angeles; Michael Oldstone, The Scripps Research Institute; Michael Russell, University at Buffalo; Federica Sallusto, Institute for Research in Biomedi￾cine, Switzerland. Chapter 11: Chuck Elson, University of Alabama; Michael Lamm, Case Western Reserve University; Thomas MacDon￾ald, Barts and T he London School of Medicine and Dentistry; Kevin Maloy, University of Oxford; Maria Rescigno, Univer￾sity of Milan; Michael Russell, University at Buffalo. Chapter 12: Jean-Laurent Cassanova, Groupe Hospitalier Necker-Enfants-Malades, Paris; Mary Collins, University College London; Alain Fischer, Groupe Hospitalier Necker￾Enfants-Malades, Paris; Raif Geha, Harvard Medical School; Paul Klenerman, Oxford University; Luigi Notarangelo, Har￾vard Medical School; Sarah Rowland-Jones, Oxford Univer￾sity; Adrian Thrasher, London Institute of Child Health. Chapter 13: Cezmi A. Akdis, Swiss Institute of Allergy and Asthma Research; Barry Kay, National Heart and Lung Insti￾tute; Raif Geha, Harvard Medical School; Gabriel Nunez, University of Michigan Medical School; Albert Sheffer, Har￾vard Medical School. Chapter 14: Anne Davidson, Albert Einstein College of Medicine; Robert Fairchild, Cleveland Clinic; Fadi Lak￾kis, University of Pittsburgh; Wayne Hancock, University of Pennsylvania School of Medicine; Rikard Holmdahl, Lund University; Laurence A. Turka, University of Pennsylvania School of Medicine. Chapter 15: Benny Chain, University College London; James Crowe, Vanderbilt University; Glen Dranoff, Dana Farber Cancer Institute; Giuseppe Pantaleo, Universite de Lausanne; Richard 0. Williams, Imperial College of London. Chapter 16: Jim Kaufman, University of Cambridge; Gary W. Litman, University of South Florida; Martin Flajnik, Univer￾sity of Maryland, Baltimore; Robert Schreiber, Washington University School of Medicine, St. Louis; Casey Weaver, Uni￾versity of Alabama at Birmingham

Contents PARTI AN INTRODUCTION TO IMMUNOBIOLOGY AND INNATE IMMUNITY Chapter1 Basic Concepts in Immunoogy 1 Chapter2 Innate Immunity:The First Lines of Defense 西 Chapter3 The Induced Responses of Innate Immunity 75 PART I THE RECOGNITION OF ANTIGEN Chapter4 Anign by B-cell and Tell Receptors 121 Chapter 5 The Generation of Lymphocyte Antigen Receptors 157 Chapter6 Antigen Presentation to T Lymphocytes 201 PART I THE DEVELOPMENT OF MATURE LYMPHOCYTE RECEPTOR REPERTOIRES Chapter 7 Signaling Through Immune-System Receptors 239 Chapter8 The Development and Survival of Lymphocytes 215 PART IV THE ADAPTIVE IMMUNE RESPONSE Chapter 9 T Cell-Mediated Immunity Chapter10 The Humoral Immune Response 387 Chapter 11 Dynamics of Adaptive Immunity Chapter 12 The Mucosal Immune System PARTV THE IMMUNE SYSTEM IN HEALTH AND DISEASE Chapter 13 Failures of Host Defense Mechanisms Chapter14 Allergy and Allergic Diseases Chapter15 Autoimmunity and Transplantation 611 Chapter 16 Manipulation of the Immune Response Appendix I Immunologist's Toolbox with Immunological Constants Appendix ll CDAntigens 763 AppendixIll Cytokines and Their Receptors Appendix IV Chemokines and Their Receptors 高 Biographies Glossary 786 Index 823

Contents I PART I AN INTRODUCTION TO IMMUNOBIOLOGY AND INNATE IMMUNITY Chapter 1 Basic Concepts in Immunology Chapter 2 Innate Immunity: The First Lines of Defense 37 Chapter 3 The Induced Responses of Innate Immunity 75 I PART II I THE RECOGNITION OF ANTIGEN Chapter 4 Antigen Recognition by B-cell and T-cell Receptors 127 Chapter 5 The Generation of Lymphocyte Antigen Receptors 157 Chapter 6 Antigen Presentation toT Lymphocytes 201 I PART Ill I THE DEVELOPMENT OF M ATURE LYMPHOCYTE RECEPTOR REPERTOIRES Chapter 7 Signaling Through Immune-System Receptors 239 Chapter 8 The Development and Survival of Lymphocytes 275 I PART IV I THE ADAPTIVE IMMUNE RESPONSE Chapter 9 T Cell-Mediated Immunity 335 Chapter 10 The Humoral Immune Response 387 Chapter 11 Dynamics of Adaptive Immunity 429 Chapter 12 The Mucosal Immune System 465 I PART V I THE IMMUNE SYSTEM IN HEALTH AND DISEASE Chapter 13 Failures of Host Defense Mechanisms 509 Chapter 14 Allergy and Allergic Diseases 571 Chapter 15 Autoimmunity and Transplantation 611 Chapter 16 Manipulation of the Immune Response 669 Appendix I Immunologist's Toolbox with Immunological Constants 717 Appendix II CD Antigens 763 Appendix Ill Cytokines and Their Receptors 779 Appendix IV Chemokines and Their Receptors 782 Biographies 784 Glossary 786 Index 823

Detailed Contents Part I AN INTRODUCTION TO IMMUNO- BIOLOGY AND INNATE IMMUNITY 32 1-23 s the mo ive means of Chapter 1 Basic Concepts in Immunology adaptive immunity. 3 toChapter 1. 345 -1 tion and induces General references 36 The ellsof th immne systemderiveromprecrin Chapter 2:Innate Immunity:The First Lines 13 The myeloid ina ecomprises most of the cells of the of Defense 14 7espsen The first lines of defense. 38 15 22 9 est 1-6 immune systen 23 10 43 17 2-4 11 salodhagotspoduoesereansot 1-8 Summary. 12 19 The complement system and innate immunity. 0 12 2-5 1-10 多 1i1 meoal的caybessabereceporshtrecognt 1i2 55 1-13 the surtace nts bound to proteins 29 16 1-14 and surv cytes is determined prcepto3 17 2-10 1-15 complement nt cir mstances 17 1-16 2-11 omgertdgecedeatyintheevottonot 21 1-17 212 immunological m non Summary 213 Theffector mechanisms of adaptive immunity. 2-14 complement proteins ini 1-18 ngespoecentetraceularpathogens 2-15 1-19 6 Eces,echestencelmeaiaedimmunilyandregulae 28 2-16 otides bound to two 121 nherite Summary. nIncreasedsscepibliytontecaion une system resul 31 112

Detailed Contents � AN INTRODUCTION TO IMMUNO￾BIOLOGY AND INNATE IMMUNITY Chapter 1 Basic Concepts in Immunology Principles of innate and adaptive immunity. 1-1 1-2 1-3 1-4 1-5 1-6 1-7 1-8 The immune system recognizes infection and induces protective responses. The cells of the immune system derive from precursors in the bone marrow. The myeloid lineage comprises most of the cells of the innate immune system. The l�mphoid lineage comprises the lymphocytes of the adaptive 1mmune system and the natural killer cells of innate immunity. Lymphocytes mature in the bone marrow or the thymus and then congregate in lymphoid tissues throughout the body. Most infectious agents activate the innate immune system and induce an inflammatory response. Pattern recognition receptors of the innate immune system provide an initial discrimination between self and nonself. Adaptive immune responses are initiated by antigen and antigen-presenting cells in secondary lymphoid tissues. 1 3 3 4 4 8 9 10 11 12 1-9 Lymphocytes activated by antigen give rise to clones of antigen-specific effector cells that mediate adaptive immunity. 12 1-10 Clonal selection of lymphocy1es is the central principle of adaptive immunity. 1-11 The structure of the antibody molecule illustrates the central puzzle of adaptive immunity. 1-12 Each developing lymphocyte generates a unique antigen receptor by rearranging its receptor gene segments. 1-13 Immunoglobulins bind a wide variety of chemical structures, whereas the T-cell receptor is specialized to recognize foreign antigens as peptide fragments bound to proteins of the major histocompatibility complex. 1-14 The development and survival of lymphocy1es is determined by signals received through their antigen receptors. 1-15 Lymphocytes encounter and respond to antigen in the peripheral lymphoid organs. 1-16 Lymphocyte activation requires additional signals beyond 13 14 15 16 17 17 those relayed from the antigen receptor when antigen binds. 21 1-17 Lymphocytes activated by antigen proliferate in the peripheral lymphoid organs, generating effector cells and immunological memory. Summary. 22 25 The effector mechanisms of adaptive immunity. 25 1-18 Antibodies protect against extracellular pathogens and their toxic products. 26 1-19 T cells orchestrate cell-mediated immunity and regulate B-cell responses to most antigens. 28 1-20 CD4 and CDS T cells recognize peptides bound to two different classes of MHC molecules. 29 1-21 Inherited and acquired defects in the immune system result in increased susceptibility to infection. 31 1-22 Understanding adaptive immune responses is important for the control of allergies, autoimmune disease and the rejection of transplanted organs. ' 32 1-23 Vaccination is the most effective means of controlling infectious diseases. 33 Summary. Summary to Chapter 1. General references. Chapter 2: Innate Immunity: The First Lines 34 35 36 of Defense 37 The first lines of defense. 38 2-1 Infectious diseases are caused by diverse living agents that replicate in their hosts. 38 2-2 Infectious agents must overcome innate host defenses to establish a focus of infection. 42 2-3 Epithelial surfaces of the body provide the first line of defense against infection. 43 2-4 Epithelial cells and phagocy1es produce several kinds of antimicrobial proteins. 44 Summary. 47 The complement system and innate immunity. 48 2-5 The complement system recognizes features of microbial surfaces and marks them for destruction by the deposition �C3� � 2-6 2-7 2-8 The lectin pathway uses soluble receptors that recognize microbial surfaces to activate the complement cascade. The classical pathway is initiated by activation of the C1 complex and is homologous to the lectin pathway. Complement activation is largely confined to the surface on which it is initiated. 2-9 The al!ernative pathway is an amplification loop for C3b formation that 1s accelerated by recognition of pathogens 52 55 56 by properdin. 57 2-10 Membrane and plasma proteins that regulate the formation and stability of C3 convertases determine the extent of complement activation under different circumstances. 59 2-11 Complement developed early in the evolution of multicellular organisms. 61 2-12 Surface-bound C3 convertase deposits large numbers of C3b fragments on pathogen surfaces and generates C5 convertase activity. 62 2-13 I ngesti?n of complement -tagged pathogens by phagocytes 1s mediated by receptors for the bound complement proteins. 62 2-14 The small fragments of some complement proteins initiate a local inflammatory response. 64 2-15 The terminal complement proteins polymerize to form pores 1n membranes that can kill certain pathogens. 65 2-16 Complement control proteins regulate all three pathways of complement activation and protect the host from their destructive effects. 66 Summary. Questions. Section references. 71 71 72

xi Chapter3 The Induced Responses of Innate Immunity 15 13 75 PatiecmT inges Part ll THE RECOGNITION OF ANTIGEN 32 Chapter 4 Antigen Recognition by B-cell and T-cell Receptors To-liker an ancient pathogen 127 The structure of a typical antibody molecule 128 are activated by many different 36 CD14 regio 130 37 43 130 4-4 3-8 The NOD eceptors act as intracellular sensors of 31 45 The have 39 olasmic viral RNAs Summary 3-10 action of the antibody molecule with 134 3-11 a shares many components with Toll signaling 4-6 32 TLR and NO 4.7 bind a via con of the antig Summary 4-8 bind to conformational shapes on the surfaces Induced innate responses to infection. % 4-9 Antigen-antibody interactions involve a variety of forces 3-13 Summary. 138 tanteiec Antigen recognition by T cells 19 3-14 4-10 102 315 4-11 103 140 4.12 3-16 cells that the MHC 105 141 317 4-13 107 318 Cytokines rele 4-14 143 ate the ase 10g 3-19 make several 415 111 的 3-20 416 113 147 321 NK cells p 4-17 The CD4 and CD8 cell ins of T ells are 113 Ke a 148 322 中 418 150 117 419 bears an altemative recepto 3-23 pathway made up chains. 117 Summary. 324 mmary to Chapter 4. ym 118 Summar 120 15 Summary to Chapter 3. 120 Section references 154

E Chapter 3 The Induced Responses of Innate Questions. 121 Immunity 75 General references. 122 Section references. 122 Pattern recognition by cells of the innate immune system. 75 3-1 After entering tissues, many pathogens are recognized, � THE RECOGNITION OF ANTIGEN ingested, and killed by phagocytes. 76 3-2 G-protein-coupled receptors on phagocytes link microbe recognition with increased efficiency of intracellular killing. 78 3-3 Pathogen recognition and tissue damage initiate an Chapter 4 Antigen Recognition by 8-cell inflammatory response. 82 and T-cell Receptors 127 3-4 Toll-like receptors represent an ancient pathogen-recognition system. 85 The structure of a typical antibody molecule. 128 3-5 Mammalian Toll-like receptors are activated by many different 4-1 lgG antibodies consist of four polypeptide chains. 129 pathogen-associated molecular patterns. 85 4-2 Immunoglobulin heavy and light chains are composed 3-6 TLR-4 recognizes bacterial lipopolysaccharide in association of constant and variable regions. 130 with the host accessory proteins MD-2 and CD14. 88 4-3 The antibody molecule can readily be cleaved into 3-7 TLRs activate the transcription factors NFKB, AP-1, functionally distinct fragments. 130 and IRF to induce the expression of inflammatory 4-4 The immunoglobulin molecule is flexible, especially at cytokines and type I interferons. 89 the hinge region. 131 3-8 The NOD-like receptors act as intracellular sensors of 4-5 The domains of an immunoglobulin molecule have bacterial infection. 92 similar structures. 132 3-9 The RIG-1-Iike helicases detect cytoplasmic viral RNAs Summary. 133 and stimulate interferon production. 94 3-10 Activation ofTLRs and NLRs triggers changes in gene The interaction of the antibody molecule with expression in macrophages and dendritic cells that have 96 specific antigen. 134 far-reaching effects on the immune response. 3-11 TLR signaling shares many components with Toll signaling 4-6 Localized regions of hypervariable sequence form the in Drosophila. 97 antigen-binding site. 134 3-12 TLR and NOD genes have undergone extensive 4-7 Antibodies bind antigens via contacts with amino acids in diversification in both invertebrates and some CDRs, but the details of binding depend upon the size primitive chordates. 98 and shape of the antigen. 135 Summary. 98 4-8 Antibodies bind to conformational shapes on the surfaces of antigens. 136 Induced innate responses to infection. 99 4-9 Antigen-antibody interactions involve a variety of forces. 136 3-13 Macrophages and dendritic cells activated by pathogens Summary. 138 secrete a range of cytokines that have a variety of local and distant effects. 99 Antigen recognition byT cells. 138 3-14 Chemokines released by macrophages and dendritic cells 4-10 The T-cell receptor is very similar to a Fab fragment of recruit effector cells to sites of infection. 102 immunoglobulin. 139 3-15 Cell-adhesion molecules control interactions between 4-11 AT-cell receptor recognizes antigen in the form of a leukocytes and endothelial cells during an inflammatory complex of a foreign peptide bound to an MHC molecule. 140 response. 103 4-12 There are two classes of MHC molecules with distinct 3-16 Neutrophils make up the first wave of cells that cross the subunit compositions but similar three-dimensional blood vessel wall to enter an inflamed tissue. 105 structures. 141 3-17 TN F-a is an important cytokine that triggers local 4-13 Peptides are stably bound to MHC molecules, and also containment of infection but induces shock when serve to stabilize the MHC molecule on the cell surface. 142 released systemically. 107 4-14 MHC class I molecules bind short peptides of 8-10 amino 3-18 Cytokines released by macrophages and dendritic cells acids by both ends. 143 activate the acute-phase response. 109 4-15 The length of the peptides bound by MHC class II 3-19 Interferons induced by viral infection make several molecules is not constrained. 145 contributions to host defense. 111 4-16 The crystal structures of several peptide:MHC:T-cell 3-20 NK cells are activated by interferon and macrophage-derived receptor complexes show a similar orientation of the cytokines to serve as an early defense against certain T-cell receptor over the peptide:MHC complex. 147 intracellular infections. 113 4-17 The CD4 and COB cell-surface proteins ofT cells are 3-21 NK cells possess receptors for self molecules that prevent required to make an effective response to antigen. 148 their activation by uninfected cells. 113 4-18 The two classes of MHC molecules are expressed 3-22 NK cells bear receptors that activate their effector function differentially on cells. 150 in response to ligands expressed on infected cells or 117 4-19 A distinct subset ofT cells bears an alternative receptor tumor cells. made up of y and o chains. 151 3-23 The NKG2D receptor activates a different signaling pathway Summary. 152 from that of the other activating NK receptors. 117 3-24 Several lymphocyte subpopulations behave as innate-like Summary to Chapter 4. 152 lymphocytes. 118 Questions. 153 Summary. 120 General references. 154 Summary to Chapter 3. 120 Section references. 154

Chapter 5 The Generation of Lymphocyte 522 Antigen Receptors 5 190 158 523 51 5-24 52 8ohcrBaniriTcelteceptosarepresentn 525 159 53 Summan 用 Summary to Chapter 5. 54 yagng0tonandJgenesegmenissguded Questions 5-5 General NA-moditying enzymes 162 56 inrepertoines Chapter 6 Antigen Presentation to T Lymphocytes 201 168 The generation receptor ligands 202 anebeadionandstbtactionofnucleotidesnathe 61 Summary. 6-2 166 Tcell receptor gene rearrangment. 169 63 高 59 南 510 anged 169 6-4 ersiy in the thrd 171 65 Many viruse 511 raemeposaneakogeneatedbygene 209 172 6-6 class are Summary. d endocytic vesicles 173 6-7 Srctration inmmnobi 月 173 6-8 22 512 174 Cross-presentati sexogenosDotetnstbb 5-13 senting cel 175 214 5-14 Mature naive Bcells express bothMand gDat their 610 eaotantigen-p 176 Summary. 515 216 77 The major histocompatibility complex and its function. 516 loM and loA can form po 78 217 Summary 6-11 179 wayDpotensnoednangenprocesngadc 217 Secondary diversification of the antibody repertoire. 612 products of MHC class l es 220 517 180 6-13 th 182 6-14 519 molecules o be 6-15 Man I cells respond to sun antioens 26 6-16 Summary. 27 6-17 Evolution of the adaptive immune response 186 A variety of gene ialized functions in immunity 228 520 Some 187 618 d MH sact as ligandsfor epe on and bition of NK cell 521 Agn 6-19 189 231

3 Chapter 5 The Generation of Lymphocyte 5-22 RAG-dependent adaptive immunity based on a diversified Antigen Receptors 157 repertoire of immunoglobulin-like genes appeared abruptly in the cartilaginous fishes. 190 Primary immunoglobulin gene rearrangement. 158 5-23 Different species generate immunoglobulin diversity in 5-1 Immunoglobulin genes are rearranged in antibody- different ways. 192 producing cells. 158 5-24 Both a:� and y:o T-cell receptors are present in 5-2 Complete genes that encode a variable region are cartilaginous fish. 194 generated by the somatic recombination of separate 5-25 MHC class I and class II molecules are also first found gene segments. 159 in the cartilaginous fishes. 195 5-3 Multiple contiguous V gene segments are present at Summary. 195 each immunoglobulin locus. 160 Summary to Chapter 5. 196 5-4 Rearrangement of V, D, and J gene segments is guided Questions. 197 by flanking DNA sequences. 161 General references. 198 5-5 The reaction that recombines V, D, and J gene segments Section references. 198 involves both lymphocyte-specific and ubiquitous DNA-modifying enzymes. 162 5-6 The diversity of the immunoglobulin repertoire is Chapter 6 Antigen Presentation to generated by four main processes. 166 T Lymphocytes 201 5-7 The multiple inherited gene segments are used in different combinations. 166 The generation ofT-cell receptor ligands. 202 5-8 Variable addition and subtraction of nucleotides at the 6-1 The MHC class I and class II molecules deliver peptides junctions between gene segments contributes to the to the cell surface from two intracellular compartments. 202 diversity of the third hypervariable region. 167 Summary. 168 6-2 Peptides that bind to MHC class I molecules are actively transported from the cytosol to the endoplasmic T-cell receptor gene rearrangment. 169 reticulum. 204 6-3 Peptides for transport into the endoplasmic reticulum 5-9 The T-cell receptor gene segments are arranged in a are generated in the cytosol. 205 similar pattern to immunoglobulin gene segments and are 6-4 Newly synthesized MHC class I molecules are retained rearranged by the same enzymes. 169 in the endoplasmic reticulum until they bind a peptide. 207 5-10 T-cell receptors concentrate diversity in the third 6-5 Many viruses produce immunoevasins that interfere with hypervariable region. 171 antigen presentation by MHC class I molecules. 209 5-11 y: o T-cell receptors are also generated by gene 6-6 Peptides presented by MHC class II molecules are rearrangement. 172 generated in acidified endocytic vesicles. 210 Summary. 173 6-7 The invariant chain directs newly synthesized MHC class II molecules to acidified intracellular vesicles. 211 Structural variation in immunoglobulin 6-8 A specialized MHC class ll-like molecule catalyzes constant regions. 173 loading of MHC class II molecules with peptides. 212 5-12 Different classes of immunoglobulins are distinguished by 6-9 Cross-presentation allows exogenous proteins to be the structure of their heavy-chain constant regions. 174 presented on MHC class I molecules by a restricted 5-13 The constant region confers functional specialization set of antigen-presenting cells. 214 on the antibody. 175 6-10 Stable binding of peptides by MHC molecules provides 5-14 Mature naive B cells express both lgM and lgD at their effective antigen presentation at the cell surface. 215 surface. 176 Summary. 216 5-15 Transmembrane and secreted forms of immunoglobulin are generated from alternative heavy-chain transcripts. 177 The major histocompatibility complex and its function. 217 5-16 lgM and lgA can form polymers. 178 6-11 Many proteins involved in antigen processing and Summary. 179 presentation are encoded by genes within the MHC. 217 Secondary diversification of the antibody repertoire. 179 6-12 The protein products of MHC class I and class II genes are highly polymorphic. 220 5-17 Activation-induced cytidine deaminase (AID) introduces 6-13 MHC polymorphism affects antigen recognition byT cells mutations into genes transcribed in B cells. 180 by influencing both peptide binding and the contacts 5-18 Somatic hypermutation further diversifies the rearranged V between T-cell receptor and MHC molecule. 222 regions of immunoglobulin genes. 182 6-14 Alloreactive T cells recognizing nonself MHC molecules 5-19 Class switching enables the same assembled V H exon are very abundant. 223 to be associated with different CH genes in the course of 6-15 Many T cells respond to superantigens. 226 an immune response. 184 6-16 MHC polymorphism extends the range of antigens to Summary. 186 which the immune system can respond. 227 6-17 A variety of genes with specialized functions in immunity Evolution of the adaptive immune response. 186 are also encoded in the MHC. 228 5-20 Some invertebrates generate extensive diversity in a 6-18 Specialized MHC class I molecules act as ligands for repertoire of immunoglobulin-like genes. 187 the activation and inhibition of NK cells. 230 5-21 Agnathans possess an adaptive immune system that 6-19 The CD1 family of MHC class 1-like molecules is encoded uses somatic gene rearrangement to diversify receptors outside the MHC and presents microbial lipids to built from LRR domains. 189 CD1 -restricted T cells. 231

7-20 oearmya 2834 266 eral references 235 721 Section references 235 7-2 西 Part lTHE DEVELOPMENT OF 7-23 MATURE LYMPHOCYTE Summarv RECEPTOR REPERTOIRES Summary to Chapter7. 271 Questions. Chapter7 mmne-ysim General reference 239 239 Chapter 8 The Development and Survival of 7-1 Lymphocytes 275 240 nceltrsbnalpropagaionisme ted by larce Development of B lymphocytes 276 242 8-1 73 276 ent signaling pathways 243 8-2 ted to the membrane by 278 244 8-3 75 inscan both activate The pre-Bcp 245 B cell stao 8-4 Pre-B-cell recep 246 283 Summary. 247 85 86 电 Antigen receptor signaling and lymphocyte activation. 247 11 285 Summary 280 247 7-8 The development ofT lvmphocytes in the thymus but all 7.10 21 8-8 foelpoe xtensively in the thymus, 71 294 econd mess 89 294 7.12 NEAT 8-10 7.13 opmental stages are ound ) stimulate 动 8-11 7-14 256 8-12 7.15 an ord 257 8-13 7-16 a pre ocB-ce r sign hain g nensgrg 7-17 2358 8-14 ha5aasotundnohereceptorsonleukogytes nmpsitnes8lectonOrc3aheeegrangement 304 260 Summary 305 7.18 0 Positive and negative selection ofT cells Summary 26 8-15 Othe r receptors and signaling pa hways 264 306 7-19 8-16 sel-peptide

Summary. 233 7-20 Cytokine receptors of the hematopoietin family are Summary to Chapter 6. 233 associated with the JAK family of tyrosine kinases, Questions. 234 which activate STAT transcription factors. 266 General references. 235 7-21 Cytokine signaling is terminated by a negative feedback mechanism. 267 Section references. 235 7-22 The receptors that induce apoptosis activate specialized intracellular proteases called caspases. 267 I Part Ill I THE DEVEL OPMENT OF 7-23 The intrinsic pathway of apoptosis is mediated by the release of cytochrome c from mitochondria. 270 MATURE LYMPHOCYTE Summary. 270 RECEPTOR REPERTOIRES Summary to Chapter 7. 271 Questions. 272 Chapter 7 Signaling Through Immune-System General references. 272 Receptors 239 Section references. 272 General principles of signal transduction and propagation. 239 Chapter 8 The Development and Survival of 7-1 Transmembrane receptors convert extracellular signals Lymphocytes 275 into intracellular biochemical events. 240 Development of B lymphocytes. 276 7-2 Intracellular signal propagation is mediated by large multiprotein signaling complexes. 242 8-1 Lymphocytes derive from hematopoietic stem cells in 7-3 Small G proteins act as molecular switches in many the bone marrow. 276 different signaling pathways. 243 8-2 B-cell development begins by rearrangement of the 7-4 Signaling proteins are recruited to the membrane by heavy-chain locus. 278 a variety of mechanisms. 244 8-3 The pre-B-cell receptor tests for successful production 7-5 Ubiquitin conjugation of proteins can both activate of a complete heavy chain and signals for the transition and inhibit signaling responses. 245 from the pro-B cell to pre-B cell stage. 282 7-6 The activation of some receptors generates 8-4 Pre-B-cell receptor signaling inhibits further heavy-chain small-molecule second messengers. 246 locus rearrangement and enforces allelic exclusion. 283 Summary. 247 8-5 Pre-B cells rearrange the light-chain locus and express cell-surface immunoglobulin. 284 Antigen receptor signaling and lymphocyte activation. 247 8-6 Immature B cells are tested for autoreactivity before they 7-7 Antigen receptors consist of variable antigen-binding leave the bone marrow. 285 chains associated with invariant chains that carry out Summary. 290 the signaling function of the receptor. 247 7-8 Antigen recognition by the T-cell receptor and its co-receptors The development ofT lymphocytes in the thymus. 290 leads to phosphorylation of ITAMs by Src-family kinases. 249 8-7 T-cell progenitors originate in the bone marrow, but all 7-9 Phosphorylated ITAMs recruit and activate the tyrosine the important events in their development occur in kinase ZAP-70, which phosphorylates scaffold proteins the thymus. 291 that recruit the phospholipase PLC-y. 251 8-8 T-cell precursors proliferate extensively in the thymus, 7-10 The activation of PLC-y requires a co-stimulatory signal. 251 but most die there. 294 7-11 Activated PLC-y generates the second messengers 8-9 Successive stages in the development of thymocytes are diacylglycerol and inositol trisphosphate. 252 marked by changes in cell-surface molecules. 294 7-12 Ca2+ entry activates the transcription factor NFAT. 253 8-10 Thymocytes at different developmental stages are found 7-13 Ras activation stimulates the mitogen-activated protein in distinct parts of the thymus. 297 kinase (M APK) relay and induces expression of the 8-11 T cells with a:� or y:o receptors arise from a common transcription factor AP-1. 253 progenitor. 298 7-14 Protein kinase C activates the transcription factors NFKB 8-12 T cells expressing particular y- and o-chain V regions arise and AP-1. 256 in an ordered sequence early in life. 299 7-15 The cell-surface protein CD28 is a co-stimulatory receptor 8-13 Successful synthesis of a rearranged � chain allows for naive T cells. 257 the production of a pre-T-cell receptor that triggers cell 7-16 The logic of B-cell receptor signaling is similar to that of proliferation and blocks further �-chain gene T-cell receptor signaling, but some of the signaling rearrangement. 301 components are specific to B cells. 258 8-14 T-cell a-chain genes undergo successive rearrangements 7-17 IT AMs are also found in other receptors on leukocytes until positive selection or cell death intervenes. 304 that signal for cell activation. 260 Summary. 305 7-18 Inhibitory receptors on lymphocytes help regulate immune responses. 260 Positive and negative selection ofT cells. 305 Summary. 263 8-15 The MHC type of the thymic stroma selects a repertoire of Other receptors and signaling pathways. 264 mature T cells that can recognize foreign antigens presented by the same MHC type. 306 7-19 Cytokines and their receptors fall into distinct families 8-16 Only thymocytes whose receptors interact with self-peptide: of structurally related proteins. 264 self-MHC complexes can survive and mature. 307