Janeways immunobiology 9th edition

USA JANEWAY’S JANEWAY’S JANEWAY’S 9TH EDITION 9TH EDITION KENNETH MURPHY & CASEY WEAVER Janeway’s Immunobiology is a textbook for students studying immunology at the undergraduate, graduate, and medical school levels As an introductory text, students will appreciate the book's clear writing and informative illustrations, while advanced students and working immunologists will appreciate its comprehensive scope and depth Immunobiology presents immunology from a consistent point of view throughout—that of the host’s interaction with an environment full of microbes and pathogens The Ninth Edition has been thoroughly revised bringing the content up-to-date with significant developments in the field, especially on the topic of innate immunity, and improving the presentation of topics across chapters for better continuity Kenneth Murphy is the Eugene Opie First Centennial Professor of Pathology and Immunology at Washington University School of Medicine in St Louis and Investigator at the Howard Hughes Medical Institute He received his MD and PhD degrees from The Johns Hopkins University School of Medicine.  Casey Weaver is the Wyatt and Susan Haskell Professor of Medical Excellence in the Department of Pathology at the University of Alabama at Birmingham, School of Medicine He received his MD degree from the University of Florida His residency and post-doctoral training were completed at Barnes Hospital and Washington University Praise for the previous edition: “…this is an excellent overview of immunology placed in a biological context….both the style of writing and the use of figures mean that complicated concepts are put across very well indeed…” IMMUNOLOGY NEWS “This is one of the best basic immunology textbooks available Materials are well organized and clearly presented It is a must-have… The chapters are well ordered and the language is clear and succinct Ample, well-designed diagrams and tables illustrate complex ideas.” DOODY REVIEWS   “This is the only immunology text I would need, as all the important topics are given detailed coverage; the diagrams, tables, and videos rapidly get across important concepts in an easily understood way.” OXFORD MEDICAL SCHOOL GAZETTE Diseases and immunological deficiencies are cross-referenced to Case Studies in Immunology: A Clinical Companion, Seventh Edition by Raif Geha and Luigi Notarangelo (ISBN 978-0-8153-4512-1) 9TH EDITION MURPHY & WEAVER ISBN 978-0-8153-4505-3 780815 345053 imm_cover.indd KENNETH MURPHY & CASEY WEAVER 29/01/2016 11:41 Icons used throughout the book degranulation smooth muscle cell diapedesis phagocytosis blood vessel macrophage mast cell natural killer (NK) cell basophil eosinophil active neutrophil neutrophil erythrocyte monocyte fibroblast Student and Instructor Resources Websites: Accessible from www.garlandscience.com, these Websites contain over 40 animations and videos created for Janeway’s Immunobiology, Ninth Edition These movies 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 infected cell Movie thymic thymic cortical medullary epithelial epithelial cell cell T cell dendritic cell immature dendritic cell activated T cell plasma cell B cell follicular dendritic cell antigen-presenting cell (APC) antibody (IgG, IgD, IgA) endothelial cell antibody (IgM, IgE) M cell epithelial cell goblet cell apoptotic cell pentameric IgM HEV T-cell receptor antibody SH2 domain B-cell receptor complex α3 α2 CD40L selectin integrin CD8 ζ light chain MASP-2 C-type ICAM-1 chemokine cytokine receptor receptor lectin Igβ Igα peptide TNF-family receptor e.g CD40 MHC class II MHC class I viruses FasL C3 C3a C4 C4a C5 C5a calreticulin ERp57 kinase IRAK1 γ (NEMO) ubiquitin β α IMM9 Inside front pages.indd Lymph Node Development 9.2 Lymphocyte Trafficking 3.1 Phagocytosis 9.3 Dendritic Cell Migration 3.2 Patrolling Monocytes 9.4 Visualizing T Cell Activation 3.3 Chemokine Signaling 9.5 TCR-APC Interactions 3.4 Neutrophil Extracellular Traps 9.6 Immunological Synapse 3.5 Pathogen Recognition Receptors 9.7 T Cell Granule Release 3.6 The Inflammasome 9.8 Apoptosis 3.7 Cytokine Signaling 9.9 T Cell Killing 3.8 Chemotaxis 10.1 Germinal Center Reaction 3.9 Lymphocyte Homing 10.2 Isotype Switching 3.10 Leukocyte Rolling 11.1 The Immune Response 3.11 Rolling Adhesion 11.2 Listeria Infection 3.12 Neutrophil Rolling Using Slings 11.3 Induction of Apoptosis 3.13 Extravasation 13.1 Antigenic Drift 5.1 V(D)J Recombination 13.2 Antigenic Shift 6.1 MHC Class I Processing 13.3 Viral Evasins 6.2 MHC Class II Processing 13.4 HIV Infection 7.1 TCR Signaling 14.1 DTH Response 7.2 MAP Kinase Signaling Pathway 15.1 Crohn’s Disease 7.3 CD28 and Costimulation 16.1 NFAT Activation and Cyclosporin 8.1 T Cell Development active Ras GTP:Ras FADD C8 death domain C9 GDP:Ras C7 membraneactivated attack complement complex protein death effector domain (DED) activated calmodulin inactive Ras degraded IκB tapasin C6 IRAK4 TRAF-6 UBC13, Uve1A IKK C5b Fc receptor MAL MyD88 9.1 Complement System TAP transporter Fas Toll receptor Innate Recognition of Pathogens 2.1 C2/factor B C1s bacterium PIP3 CD80 heavy chain C1q C1r CD28 CD4 chemokine γ ε ITAMs MBL CD45 T-cell receptor cytokine α β ζ phosphorylation kinase domain SH2 domain cell membrane T-cell receptor complex εδ lymph node ZAP-70/Syk tyrosine kinase MHC class I β2microglobulin α1 protein antigen dimeric IgA antibody production 1.1 procaspase active calcineurin protein proteasome transcription factor NFκB peptide fragments AP-1 NFAT Ca2+ gene NFAT active gene pseudogene (being transcribed) 01/03/2016 14:00 IMM9 FM.indd 24/02/2016 15:56 This page intentionally left blank to match pagination of print book Kenneth Murphy Washington University School of Medicine, St Louis Casey Weaver University of Alabama at Birmingham, School of Medicine With contributions by: Allan Mowat University of Glasgow Leslie Berg University of Massachusetts Medical School David Chaplin University of Alabama at Birmingham, School of Medicine With acknowledgment to: Charles A Janeway Jr Paul Travers MRC Centre for Regenerative Medicine, Edinburgh Mark Walport IMM9 FM.indd 24/02/2016 15:56 Vice President: Denise Schanck Development Editor: Monica Toledo Associate Editor: Allie Bochicchio Assistant Editor: Claudia Acevedo-Quiñones Text Editor: Elizabeth Zayetz Production Editor: Deepa Divakaran Typesetter: Deepa Divakaran and EJ Publishing Services Illustrator and Design: Matthew McClements, Blink Studio, Ltd Copyeditor: Richard K Mickey Proofreader: Sally Livitt Permission Coordinator: Sheri Gilbert Indexer: Medical Indexing Ltd © 2017 by Garland Science, Taylor & Francis Group, LLC This book contains information obtained from authentic and highly regarded sources Every effort has been made to trace copyright holders and to obtain their permission for the use of copyright material Reprinted material is quoted with permission, and sources are indicated A wide variety of references are listed Reasonable efforts have been made to publish reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequences of their use All rights reserved No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means—graphic, electronic, or mechanical, including photocopying, recording, taping, or information storage and retrieval systems—without permission of the copyright holder ISBN 978-0-8153-4505-3 978-0-8153-4551-0 (International Paperback) Library of Congress Cataloging-in-Publication Data Names: Murphy, Kenneth (Kenneth M.), author | Weaver, Casey, author Title: Janeway's immunobiology / Kenneth Murphy, Casey Weaver ; with contributions by Allan Mowat, Leslie Berg, David Chaplin ; with acknowledgment to Charles A Janeway Jr., Paul Travers, Mark Walport Other titles: Immunobiology Description: 9th edition | New York, NY : Garland Science/Taylor & Francis Group, LLC, [2016] | Includes bibliographical references and index Identifiers: LCCN 2015050960| ISBN 9780815345053 (pbk.) | ISBN 9780815345510 (pbk.-ROW) | ISBN 9780815345503 (looseleaf) Subjects: | MESH: Immune System physiology | Immune System physiopathology | Immunity | Immunotherapy Classification: LCC QR181 | NLM QW 504 | DDC 616.07/9 dc23 LC record available at http://lccn.loc.gov/2015050960 Published by Garland Science, Taylor & Francis Group, LLC, an informa business, 711 Third Avenue, New York, NY, 10017, USA, and Park Square, Milton Park, Abingdon, OX14 4RN, UK Printed in the United States of America 15 14 13 12 11 10 Visit our web site at http://www.garlandscience.com IMM9 FM.indd 24/02/2016 15:56 Preface Janeway’s Immunobiology is intended for undergraduate and graduate courses and for medical students, but its depth and scope also make it a useful resource for trainees and practicing immunologists Its narrative takes the host's perspective in the struggle with the microbial world—a viewpoint distinguishing ‘immunology’ from ‘microbiology’ Other facets of immunology, such as autoimmunity, immunodeficiencies, allergy, transplant rejection, and new aspects of cancer immunotherapy are also covered in depth, and a companion book, Case Studies in Immunology, provides clinical examples of immunerelated disease In Immunobiology, symbols in the margin indicate where the basic immunological concepts related to Case Studies are discussed The ninth edition retains the previous organization of five major sections and sixteen chapters, but reorganizes content to clarify presentation and eliminate redundancies, updating each chapter and adding over 100 new figures The first section (Chapters 1–3) includes the latest developments in innate sensing mechanisms and covers new findings in innate lymphoid cells and the concept of ‘immune effector modules’ that is used throughout the rest of the book Coverage of chemokine networks has been updated throughout (Chapters and 11) The second section (Chapters 4–6) adds new findings for γ:δ T cell recognition and for the targeting of activationinduced cytidine deaminase (AID) class switch recombination The third section (Chapters and 8) is extensively updated and covers new material on integrin activation, cytoskeletal reorganization, and Akt and mTOR signaling The fourth section enhances coverage of CD4 T cell subsets (Chapter 9), including follicular helper T cells that regulate switching and affinity maturation (Chapter 10) Chapter 11 now organizes innate and adaptive responses to pathogens around the effector module concept, and features new findings for tissue-resident memory T cells Chapter 12 has been thoroughly updated to keep pace with the quickly advancing field of mucosal immunity In the last section, coverage of primary and secondary immunodeficiencies has been reorganized and updated with an expanded treatment of immune evasion by pathogens and HIV/AIDS (Chapter 13) Updated and more detailed consideration of allergy and allergic diseases are presented in Chapter 14, and for autoimmunity and transplantation in Chapter 15 Finally, Chapter 16 has expanded coverage of new breakthroughs in cancer immunotherapy, including ‘checkpoint blockade’ and chimeric antigen receptor (CAR) T-cell therapies End-of-chapter review questions have been completely updated in the ninth edition, posed in a variety of formats, with answers available online Appendix I: The Immunologist's Toolbox has undergone a comprehensive IMM9 FM.indd revitalization with the addition of many new techniques, including the CRISPR/Cas9 system and mass spectrometry/proteomics Finally, a new Question Bank has been created to aid instructors in the development of exams that require the student to reflect upon and synthesize concepts in each chapter Once again, we benefited from the expert revision of Chapter 12 by Allan Mowat, and from contributions of two new contributors, David Chaplin and Leslie Berg David's combined clinical and basic immunologic strengths greatly improved Chapter 14, and Leslie applied her signaling expertise to Chapters and 8, and Appendix I, and her strength as an educator in creating the new Question Bank for instructors Many people deserve special thanks Gary Grajales wrote all end-of-chapter questions New for this edition, we enlisted input from our most important audience and perhaps best critics—students of immunology-in-training who provided feedback on drafts of individual chapters, and Appendices II–IV We benefitted from our thoughtful colleagues who reviewed the eighth edition They are credited in the Acknowledgments section; we are indebted to them all We have the good fortune to work with an outstanding group at Garland Science We thank Monica Toledo, our development editor, who coordinated the entire project, guiding us gently but firmly back on track throughout the process, with efficient assistance from Allie Bochicchio and Claudia Acevedo-Quiñones We thank Denise Schanck, our publisher, who, as always, contributed her guidance, support, and wisdom We thank Adam Sendroff, who is instrumental in relaying information about the book to immunologists around the world As in all previous editions, Matt McClements has contributed his genius—and patience—re-interpreting authors' sketches into elegant illustrations We warmly welcome our new text editor Elizabeth Zayetz, who stepped in for Eleanor Lawrence, our previous editor, and guiding light The authors wish to thank their most important partners—Theresa and Cindy Lou—colleagues in life who have supported this effort with their generosity of time, their own editorial insights, and their infinite patience As temporary stewards of Charlie’s legacy, Janeway’s Immunobiology, we hope this ninth edition will continue to inspire—as he did—students to appreciate immuno­ logy's beautiful subtlety We encourage all readers to share with us their views on where we have come up short, so the next edition will further approach the asymptote Happy reading! Kenneth Murphy Casey Weaver 24/02/2016 15:56 vi Resources for Instructors and Students The teaching and learning resources for instructors and students are available online The homework platform is available to interested instructors and their students Instructors will need to set up student access in order to use the dashboard to track student progress on assignments The instructor's resources on the Garland Science website are password-protected and available only to adopting instructors The student resources on the Garland Science website are available to everyone We hope these resources will enhance student learning and make it easier for instructors to prepare dynamic lectures and activities for the classroom Online Homework Platform with Instructor Dashboard Instructors can obtain access to the online homework platform from their sales representative or by emailing science@garland.com Students who wish to use the platform must purchase access and, if required for class, obtain a course link from their instructor The online homework platform is designed to improve and track student performance It allows instructors to select homework assignments on specific topics and review the performance of the entire class, as well as individual students, via the instructor dashboard The user-friendly system provides a convenient way to gauge student progress, and tailor classroom discussion, activities, and lectures to areas that require specific remediation The features and assignments include: • Instructor Dashboard displays data on student performance: such as responses to individual questions and length of time spent to complete assignments • Tutorials explain essential or difficult concepts and are integrated with a variety of questions that assess student engagement and mastery of the material The tutorials were created by Stacey A Gorski, University of the Sciences in Philadelphia Instructor Resources Instructor Resources are available on the Garland Science Instructor's Resource Site, located at www.garlandscience com/instructors The website provides access not only to the teaching resources for this book but also to all other Garland Science textbooks Adopting instructors can obtain access to the site from their sales representative or by emailing science@garland.com Art of Janeway's Immunobiology, Ninth 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, by figure name, or by keywords used in the figure legend from the book Figure-Integrated Lecture Outlines The section headings, concept headings, and figures from the text have been integrated into PowerPoint® IMM9 FM.indd presentations These will be useful for instructors who would like a head start creating lectures for their course Like all of our PowerPoint® presentations, the lecture outlines can be customized For example, the content of these presentations can be combined with videos and questions from the book or Question Bank, in order to create unique lectures that facilitate interactive learning Animations and Videos The animations and videos that are available to students are also available on the Instructor's Website 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 using the ‘download’ button on the movie preview page The movies are related to specific chapters and callouts to the movies are highlighted in color throughout the textbook Question Bank Written by Leslie Berg, University of Massachusetts Medical School, the Question Bank includes a variety of question formats: multiple choice, fill-in-the-blank, truefalse, matching, essay, and challenging synthesis questions There are approximately 30–40 questions per chapter, and a large number of the multiple-choice questions will be suitable for use with personal response systems (that is, clickers) The Question Bank provides a comprehensive sampling of questions that require the student to reflect upon and integrate information, and can be used either directly or as inspiration for instructors to write their own test questions Student Resources The resources for students are available on the Janeway's Immunobiology Student Website, located at students garlandscience.com Answers to End-of-Chapter Questions Answers to the end-of-chapter questions are available to students for self-testing Animations and Videos There are over 40 narrated movies, covering a range of immunology topics, which review key concepts and illuminate the experimental process Flashcards Each chapter contains flashcards, built into the student website, that allow students to review key terms from the text Glossary The comprehensive glossary of key terms from the book is online and can be searched or browsed 24/02/2016 15:56 vii Acknowledgments We would like to thank the following experts who read parts or the whole of the eighth edition chapters and provided us with invaluable advice in developing this new edition Chapter 2: Teizo Fujita, Fukushima Prefectural General Hygiene Institute; Thad Stappenbeck, Washington University; Andrea J Tenner, University of California, Irvine Chapter 3: Shizuo Akira, Osaka University; Mary Dinauer, Washington University in St Louis; Lewis Lanier, University of California, San Francisco; Gabriel Nuñez, University of Michigan Medical School; David Raulet, University of California, Berkeley; Caetano Reis e Sousa, Cancer Research UK; Tadatsugu Taniguchi, University of Tokyo; Eric Vivier, Université de la Méditerranée Campus de Luminy; Wayne Yokoyama, Washington University Chapter 4: Chris Garcia, Stanford University; Ellis Reinherz, Harvard Medical School; Robyn Stanfield, The Scripps Research Institute; Ian Wilson, The Scripps Research Institute Chapter 5: Michael Lieber, University of Southern California Norris Cancer Center; Michel 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 6: Sebastian Amigorena, Institut Curie; 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, National Jewish Health; Hans-Georg Rammensee, University of Tuebingen, Germany; Jose Villadangos, University of Melbourne; Ian Wilson, The Scripps Research Institute Chapter 7: Oreste Acuto, University of Oxford; Francis Chan, University of Massachusetts Medical School; Vigo Heissmeyer, Helmholtz Center Munich; Steve Jameson, University of Minnesota; Pamela L Schwartzberg, NIH; Art Weiss, University of California, San Francisco Chapter 8: Michael Cancro, University of Pennsylvania School of Medicine; Robert Carter, University of Alabama; Ian Crispe, University of Washington; Kris Hogquist, University of Minnesota; Eric Huseby, University of Massachusetts Medical School; Joonsoo Kang, University of Massachusetts Medical School; Ellen Robey, University of California, Berkeley; Nancy Ruddle, Yale University School of Medicine; Juan Carlos Zúñiga-Pflücker, University of Toronto Chapter 9: Francis Carbone, University of Melbourne; Shane Crotty, La Jolla Institute of Allergy and Immunology; Bill Heath, University of Melbourne, Victoria; Marc Jenkins, University of Minnesota; Alexander Rudensky, Memorial Sloan Kettering Cancer Center; Shimon Sakaguchi, Osaka University Chapter 10: Michael Cancro, University of Pennsylvania School of Medicine; Ann Haberman, Yale University IMM9 FM.indd School of Medicine; John Kearney, University of Alabama at Birmingham; Troy Randall, University of Alabama at Birmingham; Jeffrey Ravetch, Rockefeller University; Haley Tucker, University of Texas at Austin Chapter 11: Susan Kaech, Yale University School of Medicine; Stephen McSorley, University of California, Davis Chapter 12: Nadine Cerf-Bensussan, Université Paris Descartes-Sorbonne, Paris; Thomas MacDonald, Barts and London School of Medicine and Dentistry; Maria Rescigno, European Institute of Oncology; Michael Russell, University at Buffalo; Thad Stappenbeck, Washington University Chapter 13: Mary Collins, University College London; Paul Goepfert, University of Alabama at Birmingham; Paul Klenerman, University of Oxford; Warren Leonard, National Heart, Lung, and Blood Institute, NIH; Luigi Notarangelo, Boston Children’s Hospital; Sarah RowlandJones, Oxford University; Harry Schroeder, University of Alabama at Birmingham Chapter 14: Cezmi A Akdis, Swiss Institute of Allergy and Asthma Research; Larry Borish, University of Virginia Health System; Barry Kay, National Heart and Lung Institute; Harald Renz, Philipps University Marburg; Robert Schleimer, Northwestern University; Dale Umetsu, Genentech Chapter 15: Anne Davidson, The Feinstein Institute for Medical Research; Robert Fairchild, Cleveland Clinic; Rikard Holmdahl, Karolinska Institute; Fadi Lakkis, University of Pittsburgh; Ann Marshak-Rothstein, University of Massachusetts Medical School; Carson Moseley, University of Alabama at Birmingham; Luigi Notarangelo, Boston Children's Hospital; Noel Rose, Johns Hopkins Bloomberg School of Public Health; Warren Shlomchik, University of Pittsburgh School of Medicine; Laurence Turka, Harvard Medical School Chapter 16: James Crowe, Vanderbilt University; Glenn Dranoff, Dana–Farber Cancer Institute; Thomas Gajewski, University of Chicago; Carson Moseley, University of Alabama at Birmingham; Caetano Reis e Sousa, Cancer Research UK Appendix I: Lawrence Stern, University of Massachusetts Medical School We would also like to specially acknowledge and thank the students: Alina Petris, University of Manchester; Carlos Briseno, Washington University in St Louis; Daniel DiToro, University of Alabama at Birmingham; Vivek Durai, Washington University in St Louis; Wilfredo Garcia, Harvard University; Nichole Escalante, University of Toronto; Kate Jackson, University of Manchester; Isil Mirzanli, University of Manchester; Carson Moseley, University of Alabama at Birmingham; Daniel Silberger, University of Alabama at Birmingham; Jeffrey Singer, University of Alabama at Birmingham; Deepica Stephen, University of Manchester; Mayra Cruz Tleugabulova, University of Toronto 02/03/2016 15:58 This page intentionally left blank to match pagination of print book Index initiating phagocytosis 63–64, Fig. 2.31 on pathogen surface 58 ORAI1 273, Fig. 7.17 Oral administration antigens 529, 651, 714, 751, Fig. 12.19 vaccines 736 Oral cavity see Mouth Oral tolerance 519–520, Fig. 12.19 induced Treg cells 651 Original antigenic sin 484–485, Fig. 11.34 Ornithine 464 Outer surface protein E (OspE) Fig. 2.38 Ovalbumin memory CD8 T-cell response 482, 485, Fig. 11.32 MHC allelic variants binding Fig. 6.22 oral tolerance 519, Fig. 12.19 Ovarian cancer 722, Fig. 16.17, Fig. 16.20 Owen, Ray 16, 816 OX40 (CD134) 286, 370, 798 OX40 ligand (OX40L) 370 Oxygen radicals see Reactive oxygen species Ozone, atmospheric 611 P P1 bacteriophage 788, Fig. A.46 P2X7 purinergic receptor 99, Fig. 3.19 p40 see under Interleukin-12 p47phox deficiency 83 p150,95 see CR4 PA28 proteasome-activator complex 217–218, Fig. 6.6 PADGEM see P-Selectin PAMPs see Pathogen-associated molecular patterns Pancreas transplantation Fig. 15.53 Pancreatic β-cells selective destruction 665, Fig. 15.27 viruses inducing autoimmunity 681, Fig. 15.43 Paneth cells antimicrobial proteins 45, 47, 48 microbial responses 517, Fig. 12.21 NOD2 function 98, 679 TLR-4 signaling 95 Papain allergic reactions 606–607 antibody cleavage 144, Fig. 4.4 Paracrine action 107 Paramagnetic beads/particles, antibody‑coated 770, Fig. A.22 Parasites 3, Fig. 1.4 genetically attenuated 734–735, Fig. 16.26 IgE-mediated responses 437–438, 602 type responses 451, 462–464, 604, Fig. 11.15 see also Helminths; Protozoa Paroxysmal nocturnal hemoglobinuria 71, 553, Fig. 13.12 Passive immunization 428, 782–783 Pasteur, Louis 1–2, 729–730, 816 Pathogen-associated molecular patterns (PAMPs; MAMPs) 9, 77 activation of dendritic cells Fig. 9.17 activation of macrophages 364 IMM9 Index.indd 891 adjuvants 751 differential activation of ILC subsets 448, Fig. 11.3 inducing TH17 cell development 465 recognition by TLRs 88–91, Fig. 3.10 shielding or inhibition 560–562, Fig. 13.17 Pathogenesis, disease 38–42, Fig. 2.4 Pathogens 38–42, Fig. 2.2 categories 3, Fig. 1.4, Fig. 1.26 enteric see Intestinal pathogens evasion/subversion of host defenses 560–573 extracellular see Extracellular pathogens intestinal see Intestinal pathogens intracellular see Intracellular pathogens modes of transmission Fig. 2.2 opportunistic Fig. 2.2 protective immunity see Protective immunity routes of entry 44, Fig. 2.2 surfaces see Microbial surfaces tissue damage mechanisms 40–41, Fig. 2.4 see also Antigen(s); Infection(s) Pattern-recognition receptors (PRRs) 8–9, 77–107, Fig. 1.9 antigen-specific receptors vs Fig. 3.1 avoiding detection by 560–562 classes 78 dendritic cells 361, Fig. 9.17 evolution 106 genetic defects in signaling 555 intestinal epithelial cells 516–517, Fig. 12.15 lectin pathway 54–55 see also Mannose-binding lectin; NOD-like receptors; Toll-like receptor(s); other specific types Pax5 expression by developing B cells 299–301, Fig. 8.3 plasma-cell differentiation 419 PD-1 (programmed death-1) knockout mouse Fig. 15.33 regulation of T-cell activation 286–287, 288 tumor immunotherapy targeting 728 virus-mediated blockade 571 PDK1 (phosphoinositide-dependent protein kinase-1) 277, Fig. 7.22, Fig. 7.29 PD-L1 (programmed death ligand-1) 288 therapeutic targeting 728 tumor cells 719, 728 PD-L2 (programmed death ligand-2) 288 PDZ domains Fig. 7.2 Peak expiratory flow rate (PEFR) Fig. 14.11 Peanut allergy 621, 624–625 PECAM see CD31 Pembrolizumab 728 Pemphigus foliaceus 659 Pemphigus vulgaris epitope spreading 658–659, Fig. 15.18 HLA associations Fig. 15.37 immunopathogenic mechanism Fig. 15.19 placental transfer Fig. 15.13 Penicillin allergy 621 Pentraxin proteins 120, Fig. 3.34 891 Pepsin, antibody cleavage 144, Fig. 4.4 Peptide(s) amino acid sequencing 765–766, Fig. A.17 defective ribosomal products (DRiPs) 218, Fig. 6.8 editing 221, 228 generation in cytosol 216–218, Fig. 6.5 in endocytic vesicles Fig. 6.10 MHC class I ligands see under MHC class I molecules MHC class II ligands see under MHC class II molecules MHC complexes see Peptide:MHC complexes presentation see Antigen presentation transport into endoplasmic reticulum 218–219, Fig. 6.7 vaccines 738–739 see also Antigen(s) Peptide-binding cleft (or groove) allelic variation 235–236, Fig. 6.21 MHC class I molecules 156–157, Fig. 4.17 MHC class II molecules 157, Fig. 4.18 Peptide-loading complex (PLC), MHC class I 220–221, Fig. 6.8 antigen cross-presentation 223 structure Fig. 6.9 viral immunoevasins targeting Fig. 13.25 Peptide:MHC class I complexes 157–160, Fig. 4.19 generation 220–222, Fig. 6.8 molecular interactions 158–160, Fig. 4.20 stability 158, 228–229 TCR binding 161–162, Fig. 4.24 transport to cell surface 221, Fig. 6.8 virus immunoevasins targeting 568–569, Fig. 13.24, Fig. 13.25 see also MHC class I molecules, peptide ligands Peptide:MHC class II complexes 157, Fig. 4.19 generation 223–229 endosomal compartments 226, Fig. 6.12 regulation 226–229, Fig. 6.13, Fig. 6.14 molecular interactions 160–161, Fig. 4.22 naive B-cell activation 400, 401, Fig. 10.2 stability 158, 228–229 TCR binding 162, Fig. 4.25 see also MHC class II molecules, peptide ligands Peptide:MHC complexes 155, 157, Fig. 4.19 encounter by naive T cells 351–352, Fig. 9.4 generation 213 initiation of TCR signaling 267–268, Fig. 7.11 pseudo-dimeric 268 stability 158, 228–229 TCR binding interactions 161–163, Fig. 4.24, Fig. 4.25 29/02/2016 14:59 892 Index see also Peptide:MHC class I complexes; Peptide:MHC class II complexes; Self‑peptide:self-MHC complexes Peptide:MHC tetramers 776, Fig. A.30 memory T-cell responses 477–478, Fig. 11.26 primary CD8 T-cell responses 470–471 Peptidoglycan digestion by lysozyme 45, Fig. 2.9 Drosophila proteins recognizing 105, Fig. 3.24 inhibition of recognition 560–561 recognition by NODs 96–98, Fig. 3.17 Peptidoglycan-recognition proteins (PGRPs) 105, Fig. 3.24 Peptidyl arginine deiminase Fig. 15.30 Perforin 390, Fig. 9.44 directed release Fig. 9.45 inherited deficiency 549, Fig. 13.9 tumor immunity 717 Periarteriolar lymphoid sheath (PALS) 21, 348, Fig. 1.23 Peridinin chlorophyll protein (PerCP) 760, Fig. A.11 Periodic fever syndromes, hereditary see Autoinflammatory diseases Peripheral blood mononuclear cells (PBMCs), isolation 766, Fig. A.18 Peripheral lymphoid tissues 17–23, 347–366, Fig. 1.18 antigen delivery to 19, 357–358, 404–405 antigen-presenting cells 20, 358, Fig. 9.13 B cells see B cell(s), peripheral lymphoid tissues dendritic cell migration to 361–362, Fig. 9.17 development 349–350, Fig. 9.2 role of chemokines 350–351, Fig. 9.3 gastrointestinal see Gut-associated lymphoid tissue HIV reservoir 585 lymphocytes chemokine-mediated partitioning 350–351, Fig. 9.3 encounter and response to antigen 19–21, Fig. 1.21 localization 347–348, Fig. 9.1 proliferation after activation 23–24 sources 295 T cells see T cell(s), peripheral lymphoid tissues see also Lymph nodes; Mucosaassociated lymphoid tissue; Spleen Peripheral tolerance 645 B cell 308–309, Fig. 8.11 mechanisms 645, Fig. 15.2 oral 519–520, Fig. 12.19 T cell 336 Peripherally derived regulatory T cells (pTreg) see Regulatory T cells (Treg), peripherally derived Pertussis (whooping cough) Fig. 10.31 mortality 495, 736–737, Fig. 12.3 see also Bordetella pertussis Pertussis toxin 736, Fig. 10.31 adjuvant properties 739–740 Pertussis vaccines 730, 736–737 IMM9 Index.indd 892 acellular 737 Petromyzon marinus, adaptive immunity 200, Fig. 5.25 Peyer’s patches 22, 497 antigen uptake 499–500, Fig. 12.7 dendritic cells 503 development 349–350, 498, 499, Fig. 9.2 follicle-associated epithelium 498 lymphocytes 348, 501–502, Fig. 9.1, Fig. 12.8 structure 498, Fig. 1.24, Fig. 12.5 subepithelial dome 498, Fig. 1.24 see also Gut-associated lymphoid tissue; Small intestine PGLYRP-2 105 PGRP-SA 105, Fig. 3.24 Phage display libraries 758–759, Fig. A.10 Phagocyte oxidase see NADPH oxidase Phagocytes 78–85 adhesion to endothelium 115, Fig. 3.30 antibody-mediated recruitment 27, Fig. 1.28 antimicrobial proteins 45–48, Fig. 3.4 cell-surface receptors 80–81, Fig. 3.2 complement receptors 63–64, 81, Fig. 10.39 Drosophila 105 evasion mechanisms 85 Fc receptors 433–435, Fig. 10.39 G-protein-coupled receptors 81–82, Fig. 3.3 human blood Fig. A.19 inherited defects 553–556, Fig. 13.1, Fig. 13.13 intracellular pathogens 563–565 microbial killing mechanisms 81–85, Fig. 3.4 parasitic worm responses 435, Fig. 10.41 respiratory burst 83, Fig. 3.5 types 78–79 see also specific types Phagocytic glycoprotein-1 (Pgp1) see CD44 Phagocytosis 80–81, Fig. 3.2 antibody-mediated 433–435, Fig. 10.39 antigen processing after 223–224 apoptotic cells 391, 472 complement-mediated 63–64, Fig. 2.31 dendritic cells 359, Fig. 9.15 intestinal antigens Fig. 12.10 by M cells Fig. 12.7 Phagolysosomes 80, Fig. 3.2 respiratory burst 82, Fig. 3.5 Phagophore 517, Fig. 12.15 Phagosome–lysosome fusion 80, Fig. 3.2 inhibition by pathogens 563 Phagosomes 80, 435, Fig. 3.2, Fig. 6.1 pathogen escape from 563 PH domains Fig. 7.2 Akt activation 277, Fig. 7.22 PIP3 recognition 263, Fig. 7.5 TCR signaling 272–273, Fig. 7.16 Phorbol myristate acetate 273 Phosphatidylinositol 3,4,5-trisphosphate (PIP3) 263, Fig. 7.5 Akt activation 277, Fig. 7.22 B-cell receptor signaling 282, Fig. 7.27 CD28 signaling 283, Fig. 7.29 TCR signaling 272–273, Fig. 7.16 Vav recruitment 279, Fig. 7.24 Phosphatidylinositol 3-kinase (PI 3-kinase) 263, Fig. 7.5 activation by CD28 283, 369, Fig. 7.29 activation by TNF receptors 285, Fig. 7.31 B-cell receptor signaling 282, 402, Fig. 7.27 mast-cell activation 614 NKG2D signaling 131 TCR signaling 272, 277, Fig. 7.22 Phosphatidylinositol 4,5-bisphosphate (PIP2) 263 cleavage 273, Fig. 7.17 Phosphatidylinositol kinases 263 Phosphatidylserine (PS) annexin V assay for apoptosis 779–780, Fig. A.36 apoptotic cells 391, 472 exploitation by Listeria 563 Phosphocholine, C-reactive protein binding 120, Fig. 3.34 Phospholipase A2, secretory 45 Phospholipase C-γ (PLC-γ) activation 272–273, Fig. 7.16 B-cell receptor signaling 281, Fig. 7.27 co-stimulation via CD28 284, Fig. 7.29 PKC-θ activation 276–277, Fig. 7.21 Ras activation 274–276, Fig. 7.19 second messengers 273, Fig. 7.17 stimulation of Ca2+ entry 273–274, Fig. 7.18 TCR signaling module 272–277 Phosphorylation, protein 258–259, 263 see also Tyrosine phosphorylation Phycoerythrin (PE) 248, 760, Fig. 6.29, Fig. A.11 Phytohemagglutinin (PHA) Fig. A.32 PIAS proteins 111 Pi-cation interactions, antigen–antibody binding 150, Fig. 4.9 Picryl chloride 633 PIGA gene mutations 71 Pig xenografts 688 Pili 562 Pilin 428, 562 PIP2 see Phosphatidylinositol 4,5-bisphosphate PIP3 see Phosphatidylinositol 3,4,5-trisphosphate PKC-θ see Protein kinase C-θ PKR kinase 122 Placenta autoantibody transfer 655–656, Fig. 15.13, Fig. 15.14 IgG transport 426, Fig. 10.29 role in fetal tolerance 693–694 Plague 729 Plants defensins 46–47 pattern recognition receptors 88, 96 Plasma 752 Plasmablasts 407, 408, Fig. 10.5, Fig. 10.9 Plasma cells 12, 23, 407–408 bone marrow 419 differentiation germinal centers 419, Fig. 10.10 29/02/2016 14:59 Index mucosal tissues 507 primary focus 407 emigration from germinal centers 419, Fig. 10.10 IgA-secreting 506–507, 518 medullary cords in lymph nodes 419, Fig. 1.22 properties 407–408, Fig. 10.9 Plasmacytoid dendritic cells see under Dendritic cells Plasmapheresis 656, Fig. 15.14 Plasmodium falciparum 90, 734–735, 739 Plasmodium infections see Malaria Platelet-activating factor (PAF) 86 Platelet precursors Fig. 1.3 Pleckstrin homology domains see PH domains Pluripotent stem cells 3, Fig. 1.3 induced (iPS) cells 558 Pneumococcal surface protein C (PspC) Fig. 2.38 Pneumococcus see Streptococcus pneumoniae Pneumocystis jirovecii (formerly P carinii) 121, 461–462, 587 P-nucleotides Ig gene rearrangements 185–186, Fig. 5.11 TCR gene rearrangements 188 Poison ivy 632, Fig. 14.23 Pokeweed mitogen (PWM) Fig. A.32 Pol gene/protein 576, Fig. 13.30, Fig. 13.31 Polio vaccination 730, 731, Fig. 1.36 Polio vaccine, Sabin 733, 736 Polio virus, protective immunity 469 Pollution, allergic disease and 610–611 Polyacrylamide gel electrophoresis (PAGE) 762–763, Fig. A.13 Polyclonal activation, B cells 419–420, Fig. 10.24 Polyclonal mitogens 778, Fig. A.32 Polymerase stalling, class switching 417, Fig. 10.21 Polymeric immunoglobulin receptor (pIgR) 425, 507, Fig. 12.11 Polymorphonuclear leukocytes see Granulocytes Polymorphonuclear neutrophilic leukocytes (PMNs) see Neutrophils Polysaccharide A, Bacteroides fragilis 523, Fig. 12.23 Polysaccharides, capsular see Capsules, bacterial polysaccharide Polyubiquitin chains NOD signaling 97, Fig. 3.17 RIG-I-like receptor signaling 103, Fig. 3.21 targeting proteins for degradation 217, 264, Fig. 7.6 TLR signaling 94, Fig. 3.15, Fig. 3.16 PorA 72, Fig. 2.38 Porphyromonas gingivalis Fig. 13.17 Porter, Rodney 13, 816 Positive selection 295, 328–332 affinity hypothesis 334–335, Fig. 8.31 CD4 and CD8 T-cell development 330–331, Fig. 8.27 fate of thymocytes failing 329 generating alloreactive T cells 239 IMM9 Index.indd 893 germinal center B cells 410–413, Fig. 10.15 self-peptide:self-MHC complex–TCR interactions 328–329, Fig. 8.26 specificity of TCRs for MHC molecules 329–330 thymic cells mediating 331–332, Fig. 8.28 Treg cells 335 Post-translational modifications, protein regulation by 263–264 Post-transplant lymphoproliferative disorder 718 Potassium efflux, NLRP3 activation 99, Fig. 3.19 Poxviruses, subversion of host defenses 568–571, Fig. 13.23 Pre-B-cell receptors (pre-BCR) 302–304 assembly 302–303, Fig. 8.5 genetic defects 542 heavy-chain allelic exclusion 303–304, Fig. 8.7 signaling 303, Fig. 8.6 see also B-cell receptors Pre-B cells 304–305, Fig. 8.3, Fig. 8.5 expressed proteins Fig. 8.4 large 304, Fig. 8.4 light-chain rearrangements 304–305, Fig. 8.8 small 304, Fig. 8.4 Prednisone 702–703 Pregnancy autoantibody transfer 655–656, Fig. 15.13, Fig. 15.14 fetal tolerance 693–694, Fig. 15.56 HIV transmission 579–580 see also Placenta Pre-T-cell receptors (pre-TCR) assembly 320, 325–326, Fig. 8.24 genetic defects in signaling 539 signaling 326 Prevotella copri 523 PREX1 82 PrgJ 100 Primary antibody response 24, Fig. 1.25, Fig. A.2 Ig production and affinity 476, Fig. 11.25 secondary antibody response vs 475, Fig. 11.24 Primary focus formation 407, Fig. 10.5 vs germinal center reaction 408 Primary immune response 445 Primary lymphoid follicles see Lymphoid follicles, primary Pro-B cells 298, 299–302 early 299–301, Fig. 8.3, Fig. 8.4 expressed proteins Fig. 8.4 heavy-chain rearrangements 299–302, Fig. 8.5 late 301–302, Fig. 8.3, Fig. 8.4 regulation of survival 302 transition to pre-B cells 302–303 Probiotics 523 Procainamide, autoantibodies 682 Pro-caspase 1, NLRP3 inflammasome 99–100, Fig. 3.20 893 Pro-caspase 8, Fas-mediated apoptosis 471, Fig. 11.22 Pro-caspase 9, intrinsic pathway of apoptosis 389, Fig. 9.42 Pro-caspase 10, Fas-mediated apoptosis 471 Pro-caspases 388 Profilin 90–91, Fig. 3.10 Programmed cell death 387 see also Apoptosis; Autophagy Programmed death-1 see PD-1 Programmed death ligand-1 see PD-L1 Progressive multifocal leukoencephalopathy (PML) 712–713 Properdin (factor P) 59, 60, Fig. 2.25, Fig. 2.26 deficiency 59, 552, Fig. 13.11, Fig. 13.12 Prostaglandin D2 463, 615 Prostaglandin E2, fever 119–120 Prostaglandins 86, 615 Prostate cancer 727, Fig. 16.15, Fig. 16.20 Prostatic acid phosphatase (PAP) 727 Protease inhibitors allergic disorders 606–607 HIV infection 588, Fig. 13.39 resistance 590, Fig. 13.40 Proteases allergenicity 606–607, Fig. 14.5 antibody cleavage 144, Fig. 4.4 antimicrobial protein activation 47, Fig. 2.11 complement system 49 HIV 576 invariant chain cleavage 226 mast cell secretion 615, Fig. 14.9 processing vesicular antigens 224 thymic cortical epithelial cells 332 Proteasomes 216–218, Fig. 6.5 PA28 proteasome activator 217–218, Fig. 6.6 protein targeting 217, 264, Fig. 7.6 thymic cortical epithelial cells 217, 332 Protectin see CD59 Protective immunity 12 effector mechanisms 469 mucosal immune system 503, 515–519, Fig. 12.18 transfer 782–785, Fig. A.40 transplantable tumors 716, Fig. 16.12 vaccination 729–730, 731–732 see also Memory Protein(s) dephosphorylation 259, 263, Fig. 7.6 targeting for degradation 217, 263–264, Fig. 7.6 see also Peptide(s) Protein A, Staphylococcus aureus 72, 762 Protein inhibitors of activated STAT (PIAS) proteins 111 Protein-interaction domains (or modules) 260, Fig. 7.2 Protein kinase(s) 258–259 cascades, signal amplification Fig. 7.7 nonreceptor 258, Fig. 7.1 receptor-associated 258, Fig. 7.1 Protein kinase B see Akt 29/02/2016 14:59 894 Index Protein kinase C-θ (PKC-θ) 276–277 activation of AP-1 277, Fig. 7.20 activation of NFκB 276–277, Fig. 7.21 recruitment and activation 276, Fig. 7.17 Protein phosphatases 259 termination of signaling 263, Fig. 7.6 Protein phosphorylation 258–259, 263 Protein tyrosine phosphorylation see Tyrosine phosphorylation Proteolipid protein (PLP) 666 Protozoa (parasitic) 560 immune evasion 565–566 intracellular, role of TH1 cells 458 TLRs recognizing 90–91 Prox1 349 P-selectin (CD62P) 115, 795, Fig. 3.29 leukocyte recruitment 116, 352–353 ligands, effector T cells 370–371, Fig. 9.27 P-selectin glycoprotein ligand-1 (PSGL‑1; CD162) 454, 799, Fig. 9.27, Fig. 11.6 see also Cutaneous lymphocyte antigen Pseudomonas aeruginosa Fig. 13.17 Pseudomonas toxin, antibody-conjugated 725 PSGL-1 see P-selectin glycoprotein ligand-1 PSMB (LMP) genes 217, 232, Fig. 6.16, Fig. 6.17 Psoriasis Fig. 15.1 biologic agents 713, Fig. 16.8, Fig. 16.11 genetic factors Fig. 15.35, Fig. 15.37 immunopathogenesis Fig. 15.19 Psoriatic arthropathy 711 PSTPIP1 gene mutations 557, Fig. 13.14 pTα 320, 325–326, Fig. 8.18, Fig. 8.24 Pten, heterozygous deficiency Fig. 15.33 PTGDR gene polymorphism 615 PU.1 298, 299, 312, Fig. 8.3 PUMA 390 Purine nucleotide phosphorylase (PNP) deficiency 538 Purine salvage pathway, inherited defects 538 Pus 83 PX domains 263, Fig. 7.2 PYHIN proteins 100–101 Pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) 557, Fig. 13.14 Pyogenic bacteria 83 Pyogenic bacterial infections antibody deficiencies 541 complement deficiencies 552, Fig. 13.11 phagocyte defects 554–555, Fig. 13.13 recurrent 534 Pyrexia (fever) 118–120, Fig. 3.33 Pyrin 557 Pyrin domains 98, Fig. 3.18 NLRP3 inflammasome 99, Fig. 3.19, Fig. 3.20 Pyrogens endogenous 119–120, Fig. 3.33 exogenous 119–120 Pyroptosis 100 Q Qa-1 129, 245–246, Fig. 6.26 Qa-1 determinant modifiers (Qdm) 245–246 IMM9 Index.indd 894 Quasi-species, HIV 590 R RAB27a 549, Fig. 13.9 Rabbit myxoma virus Fig. 13.23 Rabbits, antibody diversification 204–205 Rabies vaccine Rac 82, 262, Fig. 3.3 Rac1 704 Rac2 Fig. 3.5 Radiation bone marrow chimeras 784 Radiation-sensitive severe combined immunodeficiency (IR-SCID or R-SCID) 183, 538–539 Radioimmunoassay (RIA) 753–755 Radioisotope-linked antibodies, tumor therapy 724, 726, Fig. 16.19 Rae1 (retinoic acid early inducible 1) 130, 245, Fig. 6.26 RAET1 proteins 245 activation of NK cells 130, Fig. 3.43 see also ULBP4 Raf 275, Fig. 7.19 Raf/Mek/Erk kinase cascade Fig. 7.7 T-cell activation 275–276, Fig. 7.19, Fig. 7.20 RAG1/RAG2 genes 180 evolutionary origins 202–203, Fig. 5.26 hypomorphic mutations 538 mutations 183, 538 RAG1/RAG2 proteins binding of RSSs 182, Fig. 5.10 developing B cells 299, 304, 307, Fig. 8.4 developing T cells 326, Fig. 8.18 heterotetramer complex Fig. 5.9 tumor immunity 717 V(D)J recombination 180, 182, Fig. 5.8 Ragweed pollen allergy 622 allergen dose 605 genetic factors 608, 611 RANK ligand (RANK-L) 813 M-cell development 498 rheumatoid arthritis 667, Fig. 15.29 RANTES see CCL5 Rap1 278, Fig. 7.23 Rapamycin (sirolimus) 704, 705–706, Fig. 16.2 mode of action 705–706, Fig. 15.52, Fig. 16.6 Raptor 706, Fig. 16.6 Ras 262 activation 262, Fig. 7.4 mutations in cancer cells 262 recruiting proteins to membrane 262–263, Fig. 7.5 TCR signaling 272, 274–276, Fig. 7.17 activation 274–275, Fig. 7.19 downstream actions 275–276, Fig. 7.19, Fig. 7.20 RasGRP 274, Fig. 7.19 Raxibacumab Fig. 16.8 Reactive oxygen species (ROS) 81, 82, Fig. 3.4 asthma exacerbation 611 defects in production 556 NLRP3 activation 99 respiratory burst 83, Fig. 3.5 Receptor editing, immature B cells 307, Fig. 8.10 Receptor–ligand interactions, biosensor assays 777–778, Fig. A.31 Receptor-mediated endocytosis 80 extracellular antigens 215, 223, Fig. 6.2 Receptors associated protein kinases 258–259, Fig. 7.1 autoantibodies 662–663, Fig. 15.23 intracellular signaling 257–290 recruitment of signaling proteins 262–263, Fig. 7.5 see also specific receptors Receptor serine/threonine kinases 258 Receptor tyrosine kinases 258, Fig. 7.1 B-cell receptor signaling Fig. 7.26 multiprotein signaling complexes Fig. 7.3 TCR signaling 268–269, Fig. 7.12 Recessive lethal genes 788 Recombinant DNA technology humanization of monoclonal antibodies 707–708, Fig. 16.7 monoclonal antibody production 758–759, Fig. A.10 vaccine development 733–735, Fig. 16.25, Fig. 16.26 Recombination signal sequences (RSSs) enzymatic mechanisms 179, Fig. 5.8 evolution 202, 203, Fig. 5.26 Ig gene rearrangements 178–179, 189, Fig. 5.6 mechanism of DNA rearrangement Fig. 5.7 RAG1/RAG2 binding 182, Fig. 5.10 TCR gene segments 187–188, 189, Fig. 5.14 Red blood cells Fig. 1.3 autoantibodies 661, Fig. 15.20 clearance of immune complexes 430–431, Fig. 10.37 disposal in spleen 20 MHC molecules 166, Fig. 4.30 RegIIIα (HIP/PAP) 48, Fig. 2.12 RegIIIβ 466 RegIIIγ 48, 466 RegIII proteins 48, Fig. 2.11 Regulatory B cells 651 Regulatory T cells (Treg cells) 13, 379–380 allergen desensitization inducing 626 allergic/atopic responses 610, 611 alloreactive responses 692–693 CD8+CD28- 693 Crohn’s disease pathogenesis 678, Fig. 15.41 effector functions 374–375, 379–380, Fig. 9.30 self tolerance 650–651, Fig. 15.9 suppression of TH1 and TH2 cells 377, Fig. 9.34 effector molecules Fig. 9.39 FoxP3-negative 380, 651 gene defects causing autoimmunity 674–675, Fig. 15.33 IL-2 receptors 369 29/02/2016 14:59 Index induced/peripherally derived (iTreg/pTreg) 375, 379–380 development 377, Fig. 9.31, Fig. 9.32 developmental link with TH17 cells 377, Fig. 9.33 fetal tolerance 693–694 plasticity Fig. 11.20 self-tolerance 651, Fig. 15.9 mucosal/intestinal 510, 522 control by dendritic cells 503–504 induction by gut microbiota 523, Fig. 12.23 suppressing inflammation Fig. 9.33 natural/thymus-derived (nTreg/tTreg) 375, 379 development 335, 379 self-tolerance 650–651, Fig. 15.9 oral antigen administration inducing 651, 714 self-tolerance 650–651, Fig. 15.2, Fig. 15.9 tumor proliferation and 719 Regulatory tolerance 650–651, Fig. 15.9 Relish 105 Rel proteins 276–277 Renal cell carcinoma 728 Reporter mice, cytokine gene 774–775, Fig. A.28 Reproductive tract, pathogens Fig. 2.2 Resistance Respiratory burst 83, Fig. 3.5 Respiratory infections, mortality 495, Fig. 12.3, Fig. 16.22 Respiratory syncytial virus (RSV) 610, 732 Respiratory tract 493, Fig. 12.1 allergen exposure 621–622, Fig. 14.12 barriers to infection 42, Fig. 2.5, Fig. 2.6, Fig. 2.7 humoral immunity 425 infection via Fig. 2.2 Restriction factors, HIV 579, 589 Retinoic acid control of iTreg cell/TH17 cell balance 379–380, Fig. 9.33 intestinal dendritic cells 504, 505 Retinoic acid early inducible see Rae1 Retinoic acid-inducible gene I see RIG-I Retrotranslocation complex 221–222 Retroviruses 575 REV1 Fig. 10.19 Reverse immunogenetics 722–723, 730, 739 Reverse transcriptase 575, 590, Fig. 13.29 transcription of HIV RNA 576, Fig. 13.30 Reverse transcriptase inhibitors, HIV 588, Fig. 13.39 prophylactic use 593 resistance 590 Reverse transcriptase–polymerase chain reaction (RT–PCR) 782 Rev gene/protein, HIV 576, 579, Fig. 13.30, Fig. 13.31 Rev response element (RRE) 579 RFX5 gene mutations 540 RFXANK gene mutations 540 RFXAP gene mutations 540 RFX complex 540 IMM9 Index.indd 895 Rheb 278, 706, Fig. 7.22 Rhesus (Rh) blood group antigens IgG antibodies against 756–757 matching 683 Rhesus (Rh) incompatibility detection 756–757, Fig. A.8 prevention 484 Rheumatic fever 681–682, Fig. 15.19, Fig. 15.44 Rheumatoid arthritis (RA) 667–668, Fig. 15.1 anti-TNF-α therapy 711, 785, Fig. 16.9, Fig. A.42 autoantibody targets 667, Fig. 15.30 biologic agents 702, 710, 712, Fig. 16.8, Fig. 16.11 genetic factors 672, Fig. 15.35 gut microbiota 523 HLA associations Fig. 15.37 pathogenesis 660, 667–668, Fig. 15.19, Fig. 15.29 Rheumatoid factor 648, 667 Rhinitis, allergic 621–622, Fig. 14.12 Rhinoconjunctivitis, allergic 621–622 genetic factors 607 perennial 622 seasonal (hay fever) 601, 621–622, Fig. 14.1 treatment 626 Rho 82, 262, Fig. 3.3 Rhodamine 760, Fig. A.11 RIAM 278, Fig. 7.23 Ribonucleoprotein complex, autoimmune responses 647–648, 664 Rickettsia 469 Rictor 706, Fig. 16.6 RIG-I (retinoic acid-inducible gene I) 102–103, Fig. 3.21 RIG-I-like receptors (RLRs) 101–103, Fig. 3.21 RIP2 (RIPK2; RICK), NOD signaling 97, Fig. 3.17 Riplet 103 RISC complex 790, Fig. A.48 Rituximab (anti-CD20 antibody) Fig. 16.8 autoimmune disease 710, Fig. 16.11 lymphoma 725 R-loops, class switching 417 RNA (viral) absence of 5’ cap 102 cytoplasmic sensors 101–103, Fig. 3.21 inhibition of translation by IFIT 122–123, Fig. 3.36 recognition by TLRs 91, Fig. 3.10, Fig. 3.16 RNA exosome 417, Fig. 10.22 RNA helicase-like domain 101 RNA interference (RNAi) 790, Fig. A.48 RNA polymerase class switching 417, Fig. 10.22 stalling 417, Fig. 10.21 RNA viruses, evasion of host responses 566–568, 571 Ro autoantigen 664 RORγT effector T cell plasticity 468 intestinal innate lymphoid cells 510 895 TH17 cell development 376, Fig. 9.32, Fig. 11.9 RSS see Recombination signal sequences Runx3 331, Fig. 8.18 Ruxolitinib 706 S S1PR1 see Sphingosine 1-phosphate receptors S100A8/S100A9 466 Sabin polio vaccine 733, 736 Salivary glands 493, 502, Fig. 12.1 Salmonella adherence to host cells 428 dendritic cell responses 503 immune evasion strategies 563, Fig. 13.17 plasticity of T-cell responses 468–469 Salmonella enterica serotype Typhi (Salmonella typhi) 44, 499 Salmonella enterica serovar Typhimurium (Salmonella typhimurium) 92 activation of MAIT cells 248 inflammasome activation 100 routes of entry Fig. 12.16 SAMHD1 579 Sandwich ELISA 754, 782 SAP (SLAM-associated protein) 131 gene defects 406, 550–551, Fig. 13.10 TFH cell–B cell interactions 406, Fig. 10.8 Sarcoidosis, early-onset 98 SARS (severe acute respiratory syndrome) 42 SARS coronavirus 42, 123 Scaffold proteins, multiprotein signaling complexes 260–261, Fig. 7.3 Scarlet fever Fig. 10.31 Scavenger receptors 80–81, Fig. 3.2 invertebrates 106 Schistosoma mansoni 438, 741, Fig. 10.41 Schistosomiasis Fig. 16.22 SCID see Severe combined immunodeficiency scid mice 183 scurfy mouse 675, Fig. 15.33, Fig. 15.36 SDS-PAGE 763, 764, Fig. A.13 Sea anemone 202 Seasonal allergic rhinoconjunctivitis see Hay fever Sea urchin 106, 203 Sec61 complex 221 Secondary antibody response 24, Fig. 1.25, Fig. A.2 additional somatic hypermutation 476–477 antibody amount and affinity 476, Fig. 11.25 generation 475–476, Fig. 11.24 Secondary immune response 446, 473, 476–477, 484–485 Secondary lymphoid chemokine (SLC) see CCL21 Secondary lymphoid follicles 408, Fig. 1.22, Fig. 10.10 Secondary lymphoid tissue chemokine (SLC) see CCL21 Secondary lymphoid tissues see Peripheral lymphoid tissues 29/02/2016 14:59 896 Index Second messengers 264–265, Fig. 7.7 heterotrimeric G proteins 82 TCR signaling pathway 272–273, Fig. 7.17 Secretion-coding (SC) sequence, IgM synthesis Fig. 5.22 Secretory component (SC) 425, 507, Fig. 12.11 Segmented filamentous bacteria (SFB) 523, 670, Fig. 12.23 Selectins 114, Fig. 3.29 activated endothelial cells 115 inducing leukocyte rolling 116, Fig. 3.31 naive T-cell homing 352–353 see also E-selectin; L-selectin; P-selectin Self discrimination from nonself 643–645 dysregulated 126 ignorance see Ignorance, immunological missing 126, 127 stress-induced 126, 127 Self antigens 16 adaptive immune responses 652–653 autophagy 216, 224–225, Fig. 6.4 B cells specific for activation requirements 647–648, Fig. 15.5 central elimination 305–308, Fig. 8.9 elimination in germinal centers 648, Fig. 15.6 peripheral elimination 308–309, Fig. 8.11 see also B cell(s), autoreactive/ self‑reactive immunologically privileged sites 648–649, Fig. 15.8 lymphocyte receptors specific for 16 molecular mimicry 680–682, Fig. 15.42 post-translational modifications 668, Fig. 15.30 presentation 222, 362 sequestration Fig. 15.2 failure 648, 657, Fig. 15.16 infections disrupting 680, Fig. 15.42 see also Immunologically privileged sites T cells specific for deletion in thymus 332–334, Fig. 8.29 peripheral elimination 336 regulation by Treg cells 650–651, Fig. 15.9 see also T cell(s), autoreactive/ self‑reactive thymic expression 333, Fig. 8.30 TLR-mediated recognition 647–648, Fig. 15.5 tumor antigens recognized as 718, Fig. 16.14 see also Autoantigens Self-peptide:self-MHC complexes memory T-cell survival 479, Fig. 11.29 negative selection of thymocytes 332–333, Fig. 8.29 positive selection of thymocytes 328–329, Fig. 8.26 Self peptides; self proteins see Self antigens IMM9 Index.indd 896 Self-tolerance 643–652 central mechanisms see Central tolerance gene defects causing autoimmunity Fig. 15.33 immunologically privileged sites Fig. 15.7 infectious agents breaking 680–682, Fig. 15.42 mechanisms 645–651, Fig. 15.2 role of linked recognition 402 Treg cells 650–651, Fig. 15.9 see also Autoimmunity; Tolerance Semmelweis, Ignác 816 Sensitization, allergic see Allergens, sensitization to Sensor cells, innate see Innate sensor cells Sepsis 92, 118, Fig. 3.32 Septic shock 92, 118, Fig. 3.32 Serglycin 390, Fig. 9.45 Serine/threonine kinases 258 Serological assays 752–753 Serology 752 Serotypes 562, Fig. 13.18 Serpins (serine protease inhibitors) 68 Serum 749 Serum amyloid A (SAA) protein Fig. 12.23 Serum amyloid protein (SAP) Fig. 3.34 Serum response factor (SRF) 276, Fig. 7.20 Serum sickness 629–630, 664, 707, Fig. 14.18 Severe acute respiratory syndrome see SARS Severe combined immunodeficiency (SCID) 535–541, Fig. 13.2 autosomal recessive 538–539 gene therapy 558 hematopoietic stem cell transplantation 557–558 Jak3 mutations 110, 535 purine salvage pathway defects 538 radiation-sensitive (RS-SCID or IR-SCID) 183, 538–539 RAG1/RAG2 gene mutations 183, 538 TCR signaling defects 273, 539 X-linked (XSCID) 109, 535–538 Severe congenital neutropenia (SCN) 553–554 Sex differences, autoimmune disease incidence 669, Fig. 15.31 SGT1 99, Fig. 3.19 SH2D1A gene mutations 550–551 SH2 domains 260, Fig. 7.2 adaptor proteins 261, Fig. 7.3 B-cell receptor signaling 280, Fig. 7.26 cytokine receptor signaling 110, 111 Lck 269, Fig. 7.12 PLC-γ activation 272–273 recruitment by ITAMs 267, Fig. 7.9 ZAP-70 270, Fig. 7.13 SH3 domains Fig. 7.2 adaptor proteins 261, Fig. 7.3 Lck 269, Fig. 7.12 PLC-γ activation 272–273 Sharks see Cartilaginous fish Shear-resistant rolling, neutrophils 116 Sheep, immunoglobulin diversification 205 Shigella flexneri Fig. 3.6, Fig. 12.17 Shingles 572, 587 SHIP (SH2-containing inositol phosphatase) 287, 288, Fig. 7.34 Short-chain fatty acids (SCFAs) 520, 523, Fig. 12.23 Short consensus repeat (SCR) 71 SHP (SH2-containing phosphatase) 287, 288, Fig. 7.6 SHP-1 110–111, 128 deficiency 129 knockout mouse Fig. 15.33 SHP-2 110–111, 128 Sialic-acid-binding immunoglobulin-like lectins (SIGLECs) Fig. 3.40 Sialyl-Lewisx (CD15s) 792 deficiency 115, 554 leukocyte recruitment 115, 116, Fig. 3.31 naive T-cell homing 353, Fig. 9.7, Fig. 9.10 Signaling, intracellular 257–290 amplification 265, Fig. 7.7 cytokine receptors 109–111, Fig. 3.26 general principles 257–265 G-protein-coupled receptors 81–82, Fig. 3.3 lymphocyte antigen receptors 265–282 membrane recruitment of proteins 262–263, Fig. 7.5 post-translational modifications regulating 263–264 propagation via multiprotein complexes 260–261, Fig. 7.3 role of protein phosphorylation 258–259, 263 second messengers 264–265 small G protein switches 262, Fig. 7.4 termination mechanisms 263, Fig. 7.6 Toll-like receptors 92–96, Fig. 3.15 variations in strength 258–259 Signaling scaffold, TLRs 94 Signal joint, V(D)J recombination 179, 182, Fig. 5.7, Fig. 5.8 Signal transducers and activators of transcription see STAT(s) Simian immunodeficiency virus (SIV) 573–574, 579, 580 immune response 583 vaccine development 592 Sindbis virus 123 Single-chain antibody 152 Single-nucleotide polymorphisms (SNPs), autoimmune diseases 671–672 Single-positive thymocytes see Thymocytes, single positive Single-stranded RNA (ssRNA) recognition by TLRs 91, Fig. 3.10, Fig. 3.16 sensing by RIG-I 102 systemic lupus erythematosus Fig. 15.25 Sipuleucel-T (Provenge) 727 Sirolimus see Rapamycin SIV see Simian immunodeficiency virus Sjögren’s syndrome 653, 656, Fig. 15.1 SKAP55 278, Fig. 7.23 Skin antigen uptake 360, Fig. 9.16 barriers to infection 47, Fig. 2.5, Fig. 2.6 29/02/2016 14:59 Index blistering, pemphigus vulgaris 659, Fig. 15.18 grafts, mouse studies 683–684, Fig. 15.45 T-cell homing 455–456, Fig. 11.7 Skin prick testing 619, Fig. 14.11, Fig. 14.12 Skint-1 250, Fig. 6.29 SLAM (CD150) 799 TFH cell–B cell interactions 406, Fig. 10.8 SLAM-associated protein see SAP SLAM family receptors 131 TFH cell–B cell interactions 406, 413, Fig. 10.8 SLE see Systemic lupus erythematosus Sleeping sickness 565–566 Slings, neutrophil rolling 116 SLP-65 (BLNK) B-cell receptor signaling 281, Fig. 7.27 deficiency 303, 542 expression in developing B cells 299–301 pre-B-cell receptor signaling 303 SLP-76 271–272, Fig. 7.15, Fig. 7.16 SMAC see Supramolecular adhesion complex Small G proteins (small GTPases) 82, 262 recruiting proteins to membrane 262–263, Fig. 7.5 switch function 262, Fig. 7.4 Small hairpin RNAs (shRNAs) 790, Fig. A.48 Small interfering RNAs (siRNA) 790, Fig. A.48 Small intestine antigen-presenting cells 503–506 antigen uptake 498, 499–500, Fig. 12.7, Fig. 12.10 dendritic cells 503–505 effector lymphocytes 500–501, Fig. 12.8 intraepithelial lymphocytes 511–514, Fig. 12.13 lymphocyte homing 500–502, Fig. 12.9 lymphoid tissues and cells 498–499, Fig. 12.5 surface area 494 Smallpox eradication 729, Fig. 1.2 vaccination 1, 729–730 duration of immunity 474, Fig. 11.23 variolation 729 Smcx (Kdm5c) gene 686 Smcy (Kdm5d) gene 686 Smoking, rheumatoid arthritis pathogenesis 668 SNARE proteins 549, Fig. 13.9 Snell, George 32, 816 SOCs proteins 111 Sodium dodecyl sulfate (SDS) 762–763, Fig. A.13 Somatic diversification theory 174 Somatic DNA recombination 173 agnathans 200–202, Fig. 5.25 Ig genes 175 see also V(D)J recombination Somatic gene rearrangements see Gene rearrangements Somatic hypermutation 399, 408, 410–415 accumulation of mutations 410, Fig. 10.14 antibody diversification 174, 184, 410, Fig. 10.13 in different species 205 IMM9 Index.indd 897 DNA repair mechanisms 414–415, Fig. 10.19, Fig. 10.20 generating autoreactive B cells 648, Fig. 15.6 initiation by AID 413–414, Fig. 10.18 secondary antibody response 476–477 selection of high-affinity B cells 410–413, Fig. 10.15 Sos Ras activation 262, 272, 275 recruitment by Grb2 261 Soybeans, genetically engineered 607 Spacers, recombination signal sequences 178–179, Fig. 5.6 SP-A; SP-D see Surfactant proteins Spätzle protein 88–89, 105, Fig. 3.24 Sphingolipids 247 Sphingosine 1-phosphate (S1P) T-cell exit from lymph nodes 355–356, Fig. 9.11 thymocyte emigration from thymus 336, Fig. 8.32 Sphingosine 1-phosphate (S1P) receptors (S1PR1) agonist see Fingolimod B-cell exit from bone marrow 306 downregulation, activated naive T cells 453–454, Fig. 9.27 mature thymocytes 336, Fig. 8.32 memory T cells 481, Fig. 11.31 naive B cells 403 naive T cells 355–356, 403, Fig. 9.11 SPINK5 gene mutations 606, Fig. 14.5 Spleen 17, 20–21 absent/non-functional 559 B-cell survival and maturation 310–312, Fig. 8.12 development 350, Fig. 9.2 lymphocyte locations 347–348, Fig. 9.1 marginal sinus 348, 404 marginal zone 21, Fig. 1.23 naive B-cell activation 404–405, Fig. 10.5 organization 20–21, Fig. 1.23 perifollicular zone (PFZ) Fig. 1.23 primary focus formation 407, Fig. 10.5 red pulp 20–21, 348, Fig. 1.23 plasma cells 419 white pulp 21, 347–348, Fig. 1.23 S-protein (vitronectin) 71, Fig. 2.36 Spt5 417 SR-A I/II scavenger receptors 81, Fig. 3.2 Src homology domains see SH2 domains; SH3 domains Src tyrosine kinases B-cell receptor signaling 279–280, Fig. 7.26 NK receptors 128 TCR signaling 268–269, Fig. 7.12 triple knockout mouse Fig. 15.33 see also Csk; Lck Staphylococcal complement inhibitor (SCIN) 72, Fig. 2.38 Staphylococcal enterotoxins (SE) 241, Fig. 6.25, Fig. 10.31 Staphylococcus aureus chronic eczema and 606 immune evasion strategies Fig. 13.17 897 inhibition of complement activation 72, Fig. 2.38 protein A (Spa) 72, 762, Fig. 2.38 toxins Fig. 10.31 Staphylokinase (SAK) 72, Fig. 2.38 STAT(s) 110–111, Fig. 3.26 antiviral effects 122 CD4 T-cell subset development 375–376, Fig. 9.32 see also JAK/STAT signaling pathway STAT1 110 gain-of-function mutations 547–548, Fig. 13.8 loss-of-function mutations 547, Fig. 13.7 TH1 cell development 375, 376, Fig. 9.32 tumor immunity 717 STAT3 autoimmunity and Fig. 15.32 IL-23/IL-12 signaling 467, Fig. 11.17 inherited deficiency 546, Fig. 13.8 naive B-cell activation 401, 406, Fig. 10.3 TFH cell development 376, Fig. 9.32 TH17 cell development 376, Fig. 9.32 STAT4 autoimmunity and Fig. 15.32 IL-12/IL-23 signaling 467, Fig. 11.17 TH1 cell development 375, 376, Fig. 9.32 STAT5, Treg cell development Fig. 9.32 STAT6 110 IgE class switching 418, 604 TH2 cell development 376, Fig. 9.32 Statins 713, Fig. 16.11 Status asthmaticus 616–617 Steinman, Ralph 8, 816 Stem-cell factor (SCF) B-cell development 299, Fig. 8.3 mast-cell development 614 Stem cells, hematopoietic see Hematopoietic stem cells Steric constraints, antibody–antigen binding 150–151, Fig. 4.11 Sterile injury 87 Sterilizing immunity 446 STIM1 273, Fig. 7.17 STING (stimulator of interferon genes) 103–104, Fig. 3.22 Streptavidin 776, Fig. A.30 Streptococcus pneumoniae (pneumococcus) 41 antigenic variation 562, Fig. 13.18 B-1 B cell response 312 immune subversion Fig. 2.38, Fig. 13.17 immunodeficiency diseases 541, 552, 559 Streptococcus pyogenes rheumatic fever 681–682, Fig. 15.44 toxins Fig. 10.31 Stress-induced self 126, 127 Stromal cell-derived growth factor (SDF-1) see CXCL12 Strongylocentrotus purpuratus, innate receptors 106 Strongyloides 438 Subacute sclerosing panencephalitis (SSPE) Fig. 1.36 Subcutaneous (s.c.) antigen injection 751 Subversion of host defenses see Evasion/ subversion of host defenses 29/02/2016 14:59 898 Index Sulfated sialyl-Lewisx see Sialyl-Lewisx Superantigens 240–241, Fig. 6.25 Superoxide anion 82, 83, Fig. 3.5 Superoxide dismutase (SOD) 83, Fig. 3.5 Suppressor of cytokine signaling (SOCS) 111 Supramolecular adhesion complex (SMAC) 381–382, Fig. 9.37 central (c-SMAC) 382, Fig. 9.37 peripheral (p-SMAC) 382, Fig. 9.37 see also Immunological synapse Surface plasmon resonance (SPR) 777–778, Fig. A.31 Surfactant proteins (SP-A and SP-D) 56 acute-phase response 120–121, Fig. 3.34 Sushi domain 71 Switch regions 415–417, Fig. 10.21 AID recruitment 417, Fig. 10.22 Syk B-cell maturation 311–312 B-cell receptor signaling 280, Fig. 7.26, Fig. 7.27 IgE-mediated signaling 613, 614 phosphorylation of targets 281 recruitment by ITAMs 267, 270–271, Fig. 7.9 thymocyte subpopulations 326, Fig. 8.18 Symbiosis 520 Sympathetic ophthalmia 649, Fig. 15.8 Synapse, immune see Immunological synapse Syngeneic grafts 683, Fig. 15.45 Syntaxin 11, inherited deficiency 549, Fig. 13.9 Systemic immune system 494 Systemic lupus erythematosus (SLE) 653, Fig. 15.1 activation of autoreactive B cells 648, Fig. 15.5 autoantigens 664 biologic agents 710, Fig. 16.8, Fig. 16.11 epitope spreading 658, Fig. 15.17 genetic factors 91, 664, Fig. 15.33, Fig. 15.35, Fig. 15.36 HLA associations Fig. 15.37 immune complexes 431, 664–665 defective clearance 664, Fig. 15.25 tissue-injury mechanisms 664–665, Fig. 15.26 immune effector pathways Fig. 15.15 neonatal disease 656, Fig. 15.13 T T10 protein (CD38) 243, 793, Fig. 6.26, Fig. 6.29 T22 protein 243, Fig. 6.26 γ:δ TCR binding 167, Fig. 4.31 recognition by γ:δ T cells 248, Fig. 6.29 TAB1/TAB2 94, Fig. 3.15, Fig. 7.21 TACE (TNF-α-converting enzyme) 118 TACI 310, 404, Fig. 10.6 gene defects in TNFRSF13B 545 Tacrolimus (FK506) 704–705, Fig. 16.2 immunological effects 704, Fig. 16.4 mode of action 274, 704–705, Fig. 15.52, Fig. 16.5 Tada, Tomio 816 TAK1 NOD signaling 97, Fig. 3.17 IMM9 Index.indd 898 TCR signaling 277, Fig. 7.21 TLR signaling 94, Fig. 3.15 Talin immunological synapse 382, Fig. 9.37 leukocyte migration 115 TANK Fig. 3.16 TAP1/TAP2 MHC class I binding Fig. 6.8 peptide transport 218–219, Fig. 6.7 virus immunoevasins targeting 568, Fig. 13.24, Fig. 13.25 TAP1/TAP2 genes 219 loci 232, Fig. 6.16, Fig. 6.17 mutations 219–220, 221, 540–541 TAPA-1 see CD81 Tapasin (TAPBP) gene locus 232, Fig. 6.16, Fig. 6.17 gene mutations 541 MHC class I peptide-loading complex 221, Fig. 6.8, Fig. 6.9 virus immunoevasins targeting Fig. 13.24, Fig. 13.25 Tat gene/protein 576, 579, Fig. 13.30, Fig. 13.31 T-bet 125 effector T cell plasticity 468 knockout mouse 623–624, Fig. 14.14 TH1 cell development 376, Fig. 9.32, Fig. 11.9 TBK1 RIG-I and MDA-5 signaling 103, Fig. 3.21 STING signaling 103, Fig. 3.22 TLR signaling 96, Fig. 3.16 TBX1 haploinsufficiency 540 T cell(s) 12 activation co-stimulatory receptors 283–284, Fig. 7.29 genetic defects 543–546, Fig. 13.5 immunosuppressive drugs targeting 704–706, Fig. 16.5 inhibitory receptors 286–288, Fig. 7.33 TCR signaling 267–279 see also Naive T cells, priming allograft rejection 683–684, Fig. 15.45 alloreactive alloantigen recognition 686–687, Fig. 15.48, Fig. 15.49 graft-versus-host disease 691, Fig. 15.54 immunosuppressive drug actions 690, Fig. 15.52 mixed lymphocyte reaction 239, 691, Fig. 15.55 processes generating 239–240, Fig. 6.24 α:β antigen recognition 213 development 319–322, 324–327, Fig. 8.18, Fig. 8.20, Fig. 8.33 lineage commitment 322 receptors see T-cell receptors (TCRs), α:β stages of gene rearrangements 324–327, Fig. 8.24, Fig. 8.25 antigen presentation to see Antigen presentation antigen receptors see T-cell receptors antigen recognition 140, 152–168, Fig. 1.15 initiating TCR signaling 267–269, Fig. 7.11 MHC polymorphism and 235–238, Fig. 6.21, Fig. 6.22 MHC restriction 140, 162–163, 237–238 role of CD4 and CD8 163–165 unconventional T-cell subsets 242–250 see also T-cell receptors autoreactive/self-reactive CD4 effector subsets 649–650 elimination in periphery 336 epitope spreading 658, Fig. 15.17 infectious agents inducing 680–681, Fig. 15.43 methods of studying 665 negative selection in thymus 332–334, Fig. 8.29 nonpathogenic/suppressive 649–650 pathogenic role 654–657, 665–668, Fig. 15.15 regulation by Treg cells 650–651, Fig. 15.9 systemic lupus erythematosus 664–665 tissue damage 659–660, 665, Fig. 15.19 transfer studies 654, Fig. 15.12 CD4 see CD4 T cells CD8 see CD8 T cells chimeric antigen receptor (CAR) 723, Fig. 16.18 co-receptors 29 initiation of TCR signaling 268–269, Fig. 7.11 MHC molecule interactions 163–165 positive selection and 330–331, Fig. 8.27 see also CD4; CD8 cytokines 383–386, Fig. 9.40 capture assay 773–774, Fig. A.27 detection methods 773–775, 782 ELISPOT assay 773, Fig. A.25 gene knock-in reporter mice 774–776, Fig. A.28 intracellular staining 773, Fig. A.26 cytotoxic see Cytotoxic T cells cytotoxicity mediated by 387–392 depletion, allogeneic HSCs 558, 692, 708–709 development 315–328, Fig. 8.15, Fig. 8.33 duration 321 inherited defects 535–541, Fig. 13.2 lineage commitment 297–298, 317, Fig. 8.2 nonconventional subsets 335–336 positive and negative selection 328–337 protein expression patterns 319–321, Fig. 8.18 29/02/2016 14:59 Index two distinct lineages 319, Fig. 8.20 see also Thymocytes effector see Effector T cells effector functions 29–31 functional assays 780–782 γδ see γ:δ T cells helper see Helper T cells human blood Fig. A.19 identification of antigen-specific 776, Fig. A.30 immature see Thymocytes immune effector modules 450–452, Fig. 11.5 immunosuppressive drugs targeting 704–706, Fig. 16.5 isolation methods 770–772 mature see Mature T cells memory see Memory T cells naive see Naive T cells negative selection see Negative selection peripheral lymphoid tissues 19–20, 350–356, Fig. 1.22 chemokine-mediated homing 350–351, Fig. 9.3 egress 355–356, 453–454, Fig. 9.11 fates of autoreactive 336 localization 347–348 see also Naive T cells; T-cell zones Peyer’s patches 498, Fig. 1.24, Fig. 12.5 polarization 382, Fig. 9.38 positive selection see Positive selection precursors/progenitors 17, 297, Fig. 1.3, Fig. 8.2 lineage commitment 297–298, 317, Fig. 8.2 migration to thymus 315, 317 proliferation in thymus 317–319 see also Thymocytes proliferation activation-induced 368–369, 370 assays 778–779, Fig. A.34 drugs inhibiting 704–706, Fig. 16.6 polyclonal mitogens 778, Fig. A.32 T-cell clones 771, Fig. A.23 in spleen 21, Fig. 1.23 subset identification methods 773–775 superantigen responses 240–241, Fig. 6.25 tumor antigen recognition 722, 723 tumor immunotherapy 723 T-cell areas see T-cell zones T-cell clones 771, Fig. A.23 T-cell factor-1 (TCF-1) 317, Fig. 8.18 T-cell hybrids 771 T-cell lines 771, Fig. A.23 T-cell-mediated immunity see Cell-mediated immunity T-cell plasticity 468–469, Fig. 11.20 T-cell receptor excision circles (TRECs) 188 T-cell receptors (TCRs) 12, 140 α:β 153–154, Fig. 4.14 complex 266, Fig. 7.8 developing T cells 322 evolution 206 generation of ligands for 214–231 gene rearrangements 187–190, Fig. 5.13 IMM9 Index.indd 899 α chain (TCRα) 153 gene locus 187, Fig. 5.12 mechanics of gene rearrangement 187–189, Fig. 5.13 surrogate see pTα thymocyte subpopulations 320 timing of gene rearrangements 326–327, Fig. 8.24, Fig. 8.25 variable region ( Vα) 154 antigen-binding site 14, 189–190, Fig. 5.16 antigen recognition 14, 155–168, Fig. 1.15 initiation of signaling 267–268, Fig. 7.11 MHC restriction 140, 162–163, 237–238, Fig. 6.23 vs antibodies 155, Fig. 4.16 β chain (TCRβ) 153 gene locus 187, Fig. 5.12 mechanics of gene rearrangement 187–189, Fig. 5.13 pre-T-cell receptor 320, 325–326, Fig. 8.24 stages of gene rearrangements 324–325, Fig. 8.24 thymocyte subpopulations 320 variable region see Vβ complementarity-determining regions see Complementarity-determining regions complex 266, Fig. 7.8 co-receptors see under T cell(s) C regions see Constant regions δ chain 166 deletion 191, Fig. 5.18 gene locus 190–191, Fig. 5.17 gene rearrangements 322, Fig. 8.22 diversity generation 187–191 sources 189–190, Fig. 5.15 effector T cell–target cell interactions 382 evolution 202–203, 206, Fig. 5.26 γ chain 166 gene locus 190–191, Fig. 5.17 gene rearrangements 322–324, Fig. 8.22 γ:δ 153, 166–167 evolution 206 γ:δ T cell subsets 322–324 gene rearrangements 190–191, 322–324, Fig. 8.22 ligands 167, 248–249, Fig. 6.29 role in lineage commitment 322 structure 167, Fig. 4.31 gene rearrangements mechanisms 187–191, Fig. 5.13 nonproductive 324, 327 stages in α:β T cells 324–327, Fig. 8.24 thymocyte subpopulations 320, Fig. 8.18 waves in γ:δ T cells 322–324, Fig. 8.22 gene segments, germline organization 187–188, Fig. 5.12 identification of antigen-specific 776, Fig. A.30 899 immunological synapse 382, Fig. 9.37 inherent specificity for MHC molecules 239, 329–330, Fig. 6.24 ligands assaying binding rates 777–778, Fig. A.31 binding interactions 161–163, Fig. 4.24, Fig. 4.25 generation 214–231 see also Peptide:MHC complexes MAIT cells 248 mediating positive selection 328–330 microclusters 268 signaling 265–279 ADAP module 278, Fig. 7.23 Akt module 277–278, Fig. 7.22 CD4 and CD8 T cell development 330–331 co-stimulating receptors enhancing 283–284 four downstream modules 272, Fig. 7.15 genetic defects 273, 539 initiation 267–269, Fig. 7.11 LAT:Gads:SLP-76 complex formation 271–272, Fig. 7.16 PLC-γ module 272–277 transcription factor activation 273–277 Vav module 279, Fig. 7.24 ZAP-70 activation 270, Fig. 7.13 structure 153–154, Fig. 4.14 three-dimensional 153–154, Fig. 4.15 vs antibody structure 153, Fig. 1.13, Fig. 4.15 vs B-cell receptors 153 vs Fab fragments 153–154, Fig. 4.13 superantigen binding 240–241, Fig. 6.25 thymocyte subpopulations 320, 321 Treg cells 335 V regions see Variable regions T-cell zones (T-cell areas) 20, 348, Fig. 1.22, Fig. 9.1 meeting of B and T cells 403, Fig. 10.5 naive T cell entry 352, Fig. 9.6 naive T cell retention 355, 403, Fig. 10.5 Peyer’s patches 348, Fig. 1.24 role of chemokines 350–351, Fig. 9.3 TCF1 (T cell factor-1) Fig. 8.18 TCP-1 ring complex (TRiC) 219 TCR see T-cell receptors T-DM1 725 TdT see Terminal deoxynucleotidyl transferase Tec kinases B-cell receptor signaling 281, Fig. 7.27 TCR signaling 272–273 Teichoic acid Fig. 2.9 TEP1 protein 61 Teplizumab (OKT3γ1; Ala-Ala) 710 Terminal deoxynucleotidyl transferase (TdT) developing B cells 302, Fig. 8.4 developing T cells 326, Fig. 8.18 N-nucleotide additions 186, Fig. 5.11 TUNEL assay 779, Fig. A.35 V(D)J recombination 183, Fig. 5.8 29/02/2016 14:59 900 Index Tertiary immune response 473 Tetanus 44, Fig. 10.31 toxin 428, Fig. 10.31 vaccine 730, 731, 739 Tetherin 579 Tetrameric peptide:MHC complexes see Peptide:MHC tetramers Texas Red 760, Fig. A.11 TFH cells 30, 373–374 chemoattraction to B-cell follicles 453 development 377, 406, Fig. 9.31, Fig. 9.32 effector functions 374, Fig. 9.30 germinal center formation 351, 408 naive B-cell activation 399, 401, Fig. 10.2 cell adhesion 406, Fig. 10.8 linked recognition of antigen 402, Fig. 10.4 signals involved 401, 406, Fig. 10.3 positive selection of B cells 412–413, Fig. 10.15 regulation of class switching 418, 506 type responses 466 see also Helper T cells T follicular helper cells see TFH cells TGF-β see Transforming growth factor-β TH1 cells 373 activation by IL-12 and IL-18 467, Fig. 11.19 autoimmune disease 649–650 genetic factors 672, Fig. 15.35 immune modulation 650 tissue damage 659, 666 transfer studies Fig. 15.12 continuing regulation 466–467, Fig. 11.17, Fig. 11.18 Crohn’s disease 524, 678, Fig. 15.41 cross-regulation of other CD4 subsets 377–378, Fig. 9.34 cytokines 384, Fig. 9.40 development 375–376, Fig. 9.31, Fig. 9.32 experimental manipulation 378, Fig. 9.35 effector functions 30–31, 374, Fig. 1.34, Fig. 9.30 effector molecules Fig. 9.39 eosinophil actions 617 evasion by intracellular bacteria 564–565 HIV infection 580 homing to sites of infection 457, Fig. 11.9 host–microbiota homeostasis 521–522 hypersensitivity reactions 630–633, Fig. 14.20, Fig. 14.21 inherited defects 546–548, Fig. 13.7 macrophage activation 458–461, Fig. 11.10, Fig. 11.12 granuloma formation 461, Fig. 11.13 regulation 460–461 plasticity and cooperativity 468–469, Fig. 11.20 tuberculoid leprosy 564, Fig. 13.20 type response 451, 458–462, Fig. 11.5, Fig. 11.12 TH2 cells 373 activation by TSLP and IL-23 467, Fig. 11.19 IMM9 Index.indd 900 asthma 622, 623–624, Fig. 14.14 cross-regulation of other CD4 subsets 377, Fig. 9.34 cytokines 384, 386, Fig. 9.40 development 376, Fig. 9.31, Fig. 9.32 experimental manipulation 378, Fig. 9.35 effector functions 31, 374, Fig. 9.30 effector molecules Fig. 9.39 eosinophil actions 617 gnotobiotic animals 522–523 helminth infections 462–464, Fig. 11.15 homing to sites of infection 457, Fig. 11.9 IgE-mediated allergic reactions 604–605, Fig. 14.2 features of allergens driving 605–607, Fig. 14.4 lepromatous leprosy Fig. 13.20 peptide antigens inducing 714 plasticity Fig. 11.20 type response 451, 462–464, Fig. 11.5, Fig. 11.15 TH17 cells 373–374 activation by IL-1 and IL-23 467, Fig. 11.19 asthma 622 autoimmune disease genetic factors 672, Fig. 15.35 tissue damage 659, 666, 667 continuing regulation 466–467, Fig. 11.17 Crohn’s disease 524, 678, Fig. 15.41 cytokines 384, Fig. 9.40 development 376, 452, Fig. 9.31, Fig. 9.32 induction by gut microbiota 523, Fig. 12.23 link with iTreg cells 377, Fig. 9.33 regulation by TH1 and TH2 cells 377, Fig. 9.34 effector functions 31, 374, Fig. 9.30 effector molecules Fig. 9.39 HIV infection 580 homing to sites of infection 457, Fig. 11.9 hyper-IgE syndrome 546 inherited defects 546–548, Fig. 13.7, Fig. 13.8 intestinal lamina propria 510 plasticity 468–469, Fig. 11.20 regulation of microbiota 522, Fig. 9.33, Fig. 12.21 type response 451, 465–466, Fig. 11.5, Fig. 11.16 Thioester proteins (TEPs) 61–62 6-Thioguanine (6-TG) 703–704 Thioredoxin (TRX) 99 Thioredoxin-interacting protein (TXNIP) 99 Thomas, Lewis 717 ThPOK 331, Fig. 8.18 Thrombocytopenia, drug-induced 628 Thrombocytopenic purpura, autoimmune 661, Fig. 15.19 placental transfer Fig. 15.13 Thucydides 729 Thy-1 319 Thymectomy 316 Thymic anlage 316 Thymic cortex 315, 316, Fig. 8.16 thymocyte apoptosis 317–319, Fig. 8.19 thymocyte subpopulations 321–322, Fig. 8.21 Thymic cortical epithelial cells (cTECs) contacts with thymocytes 321–322 mediating negative selection 334, Fig. 8.29 mediating positive selection 331–332, Fig. 8.28 protease expression 332 unique proteasome 217, 332 Thymic epithelial cells mediating negative selection 333, 334, Fig. 8.29 reticular network 316, Fig. 8.17 Thymic medulla 315, 316, Fig. 8.16 negative selection 333, 334, Fig. 8.29 thymocyte subpopulations 322, Fig. 8.21 tissue-specific proteins 333, Fig. 8.30 Thymic stroma 315 role in negative selection 333 role in positive selection 331 Thymic stromal lymphopoietin (TSLP) 813 activation of TH2 cells 467, Fig. 11.19 allergic skin reactions 606 B-cell development 299 ILC2 activation 125, 451 Thymus-derived regulatory T cells (tTreg) see Regulatory T cells (Treg cells), thymically derived Thymidine kinase gene, herpes simplex virus (HSV-tk) 787, Fig. A.44 Thymidine, tritiated (3H-thymidine) antigen-specific T-cell proliferation 779, Fig. A.34 cytotoxic T cell activity 780–781 lymphocyte proliferation 778 Thymocytes 315–328 apoptosis 317–319, Fig. 8.19 cell-surface proteins 319–321, Fig. 8.18 distribution in thymus 316, 321–322, Fig. 8.16, Fig. 8.21 double negative (DN) 319–320, Fig. 8.20 distribution in thymus 321, Fig. 8.21 DN1 320, Fig. 8.21 DN2 320, Fig. 8.21 DN3 320, 326, 328, Fig. 8.21 DN4 320, 326, 328, Fig. 8.21 expressed proteins 319, 326, Fig. 8.18 double positive 320–321, Fig. 8.20 development into nonconventional subsets 335–336 distribution in thymus 321–322, Fig. 8.21 expressed proteins 326, Fig. 8.18 positive and negative selection 328–335 emigration to periphery 336, Fig. 8.32 final maturation 336, Fig. 8.32 γ:δ 322–324, Fig. 8.22 positive and negative selection 328–337 proliferation 317–319, 326 single positive 321, Fig. 8.20 distribution in thymus 322, Fig. 8.21 expressed proteins Fig. 8.18 see also CD4 T cells; CD8 T cells 29/02/2016 14:59 Index thymic epithelial cell interactions 316, 321–322, Fig. 8.17 two distinct lineages 319, Fig. 8.20 see also T cell(s), development Thymoproteasome 217 Thymus 17, 315–317 embryonic development 316, 493 epithelial cells see Thymic epithelial cells expression of tissue-specific antigens 333, Fig. 8.30 genetic defects 539–541 importance 316–317 involution after puberty 317 migration of T-cell progenitors to 315, 317 proliferation of T-cell precursors 317–319, 326 selection of T cells 328–337 self antigen expression 333, 646–647 structure 315–316, Fig. 8.16 T-cell development 315–328, Fig. 8.15 thymocyte subpopulations 321–322, Fig. 8.21 Thymus-dependent (TD) antigens 401, Fig. 10.2, Fig. 10.26 Thymus-independent (TI) antigens 401, 419–421, Fig. 10.2 type (TI-1) 419–420, Fig. 10.24, Fig. 10.26 type (TI-2) 420–421, Fig. 10.25, Fig. 10.26 Thymus leukemia antigen (TL) 513, Fig. 6.26 Thyroid-stimulating hormone (TSH) receptor autoantibodies 662, Fig. 15.14, Fig. 15.21 TI antigens see Thymus-independent (TI) antigens Tick bites IgE-mediated responses 438 pathogen entry via 446, Fig. 2.2 Tight junctions, epithelial barrier against infection 42, 515–516 cleavage by allergens 606, Fig. 14.2 Time-lapse video imaging 761 TIM gene variants, allergic disease 608 Tim proteins 608, 610 Tingible body macrophages 410 TIRAP (MAL) 93–94, Fig. 3.14 TIR domains Fig. 3.18 IL-1 receptors 108 MyD88 94 TLRs 88, 92–93, Fig. 3.12 Tissue damage autoimmune disease mechanisms 659–668, Fig. 15.19 pathogenic role 657, Fig. 15.16 chemokine production 113 immunologically privileged sites 649, Fig. 15.8 infectious disease 40–41, 449, Fig. 2.4 initiating autoimmunity 680, Fig. 15.42 TH1 cell responses 460–461 type responses 464 Tissue-resident memory T cells (TRM) 480–481, Fig. 11.31 Tissue transglutaminase (tTG) autoantibodies 635, Fig. 14.26 IMM9 Index.indd 901 gluten digestion 635, Fig. 14.25 Tissue type 32 TL (thymus leukemia antigen) 513, Fig. 6.26 TLR see Toll-like receptor TLR-1 90, Fig. 3.12 TLR-1:TLR-2 heterodimer Fig. 3.10, Fig. 3.11 adaptor molecules 94, Fig. 3.14 formation 90, Fig. 3.12 TLR-2 90, Fig. 3.12 TLR-2:TLR-6 heterodimer 90, Fig. 3.10, Fig. 3.11 adaptor molecules 94, Fig. 3.14 TLR-3 91, Fig. 3.10, Fig. 3.11 adaptor molecule 94, Fig. 3.14 gene mutations 555 signaling 95–96, Fig. 3.16 TLR-4 92, Fig. 3.10, Fig. 3.11 accessory proteins 92, Fig. 3.13 adaptor molecules 94, Fig. 3.14 evasion strategies of pathogens 560–561 recognition of lipopolysaccharide 92, Fig. 3.13 signaling 95, 96 TLR-5 90, Fig. 3.10, Fig. 3.11 adaptor molecule Fig. 3.14 mucosal immunity 523, Fig. 12.16, Fig. 12.23 TLR-6 90 TLR-7 91, Fig. 3.10, Fig. 3.11 gene polymorphisms 91 interferon production 122 signaling 95–96, Fig. 3.16 TLR-8 91, Fig. 3.10, Fig. 3.11 TLR-9 91, Fig. 3.10, Fig. 3.11 interferon production 122 self antigens as ligands 647, Fig. 15.5 signaling 95–96 TLR-10 91, Fig. 3.10 TLR-11 90, Fig. 3.10 TLR-12 90, Fig. 3.10 TLR-13 Fig. 3.10 T lymphocytes see T cell(s) TNF see Tumor necrosis factor TNFR see Tumor necrosis factor receptor(s) TNF-receptor associated periodic syndrome (TRAPS) 557, Fig. 13.14 TNFRSF13B see TACI Tocilizumab 712, Fig. 16.8 Tofacitinib 706 Tolerance 644–645 central see Central tolerance fetal 693–694, Fig. 15.56 immunological 5, 16 mucosal 519–520, Fig. 12.18 oral see Oral tolerance of pathogens peripheral see Peripheral tolerance regulatory 650–651, Fig. 15.9 see also Self-tolerance Tolerogenic signals, lymphocyte antigen receptors 336 Toll 87–89 deficiency 87–88, Fig. 3.9 signaling 105, Fig. 3.24 Toll-IL-1 receptor domains see TIR domains Toll-like receptor(s) (TLRs) 9, 87–96 adaptor molecules 92–94, Fig. 3.14 901 cells expressing Fig. 3.10 cellular locations 88, Fig. 3.11 evasion strategies of pathogens 560–562 evolution 106 intestinal epithelial cells 516–517, Fig. 12.15 microbial ligands 88, Fig. 3.10 adjuvant activity 740, 752, Fig. A.3 promoting autoimmunity 647–648, 680, Fig. 15.5 naive B-cell activation 401, 420, Fig. 10.2 signaling 92–96, 264, Fig. 3.15 defects 555, Fig. 13.13 dendritic cell maturation 361, Fig. 9.17 vs Drosophila Toll 105, Fig. 3.24 structure 88 see also specific subtypes Tonegawa, Susumu 15, 816 Tonsils 22, 497 lingual 497, Fig. 12.6 palatine 497, Fig. 12.6 Toolbox, immunologist’s 749–790 Toxic epidermal necrolysis 609 Toxic shock syndrome 241, Fig. 10.31 Toxic shock syndrome toxin-1 (TSST-1) 241, Fig. 10.31 Toxins antibody-conjugated, tumor therapy 725, Fig. 16.19 autoimmune reactions 682 bacterial 40–41 adjuvant properties 736 diseases caused Fig. 2.4, Fig. 10.31 neutralization by antibodies 426–428, Fig. 1.28, Fig. 10.32 Toxoid vaccines 428, 730 Toxoplasma gondii 90–91, 467 TR1 cells 380 TRAF-3 BAFF-R signaling 404 TLR-3 signaling 96, Fig. 3.16 TRAF-6 TCR signaling 276, 277, Fig. 7.21 TLR signaling 94, 264, Fig. 3.15 TRAFs MAVS signaling 103, Fig. 3.21 TNF receptor signaling 285–286, Fig. 7.31 TRAIL 125, 813, Fig. 3.39 TRAM 93–94, Fig. 3.14 Transcription factors B-cell development 299, Fig. 8.3 identifying lymphocyte subsets 775 immune effector modules Fig. 11.5 T-cell development 317, Fig. 8.18 TCR signaling 273–277, 284 Transcytosis antibodies across epithelia 425, 507, Fig. 12.11 antigens by M cells 499, Fig. 12.7 HIV across epithelia 580 Transforming growth factor-β (TGF-β) 813 allergic disease 617 autoimmunity and 651, Fig. 15.9, Fig. 15.32 class switching 418, Fig. 10.23 29/02/2016 14:59 902 Index cross-regulation of CD4 T-cell subsets 377, Fig. 9.34 immunologically privileged sites 649 iTreg cell development 377, 379–380, Fig. 9.31, Fig. 9.33 naive B-cell activation 401, Fig. 10.3 natural Treg cells 379 protection against atopy 610 receptor 258 T-cell sources and functions Fig. 9.40 TH17 cell development 376, Fig. 9.31, Fig. 9.33 tumor cell secretion 718–719 Transgenic mice 786, Fig. A.43 Transgenic pigs 688 Transib superfamily of DNA transposons 202–203 Transitional B cells maturation in spleen 311, Fig. 8.12 peripheral tolerance 308–309, Fig. 8.11 Transitional immunity 167 Transplantation 683–694 chronic graft dysfunction 688–689 clinical use 689–690, Fig. 15.53 graft rejection see Graft rejection immunosuppressive therapy 685, 689–690, 704–705, Fig. 15.52 MHC matching 683, 685, Fig. 15.46 monoclonal antibody therapy 708–710, 785, Fig. 16.8 tumor development after 718 Transporters associated with antigen processing see TAP1/TAP2 Transposase 202, Fig. 5.26 Transposons, integration into Ig-like genes 202–203, Fig. 5.26 TRAPS (TNF-receptor associated periodic syndrome) 557, Fig. 13.14 Trastuzumab (Herceptin) 724–725 Treg cells see Regulatory T cells Triacyl lipoproteins 90, Fig. 3.11, Fig. 3.12 TRiC (TCP-1 ring complex) 219 Trichinella spiralis 438 Trichuris trichiura Fig. 11.14 TRIF, TLR signaling 93–94, 96, Fig. 3.14, Fig. 3.16 TRIKA1 (UBC13:Uve1A) 94, Fig. 3.15 TRIM 5α, HIV infection 589 TRIM21 433 TRIM25 103, Fig. 3.21 Trisomy 21, celiac disease 636 Trophoblast, fetal tolerance 693 Tropism, virus 222, 428 TRP2 Fig. 16.17 Trypanosomes 565–566, Fig. 13.21 Tryptase, mast cell 615 TSC complex 278, 706, Fig. 7.22 Tschopp, Jürg 816 TSLP see Thymic stromal lymphopoietin Tuberculin test 630–631 Tuberculosis AIDS-related 587 malnutrition and 558 mortality Fig. 12.3, Fig. 16.22 persistence 741 vaccine development 734 see also Mycobacterium tuberculosis IMM9 Index.indd 902 Tumor(s) 716–729 elimination phase 717, Fig. 16.13 equilibrium phase 717, 718, Fig. 16.13 escape phase 717, 718, Fig. 16.13 evasion/avoidance of immune responses 718–719, Fig. 16.14 immune surveillance 717, Fig. 16.13 immunoediting 717, 718 immunotherapy 723–728 adoptive T-cell therapy 723 checkpoint blockade 727–728 monoclonal antibodies 724–726, Fig. 16.19, Fig. 16.20 vaccination 726–727 NK cell responses 130, 718, Fig. 16.16 prevention, vaccination 726 transplantable 716, Fig. 16.12 Tumor antigens low immunogenicity 718, Fig. 16.14 modulation Fig. 16.14 monoclonal antibodies 724–726, Fig. 16.19, Fig. 16.20 recognized as self antigens 718, Fig. 16.14 vaccines based on 726–727 see also Tumor rejection antigens Tumor necrosis factor-α (TNF-α) 109, 813 acute-phase response 120 autoimmune disease and Fig. 15.32 cytotoxic T cell-derived 392 delayed-type hypersensitivity 631, Fig. 14.21 effector functions 118, Fig. 3.27, Fig. 3.33 endothelial activation 115 gene locus Fig. 6.17 inflammatory response 87 local protective effects 118, Fig. 3.32 macrophage-derived 459, Fig. 11.11 mast-cell release 615 peripheral lymphoid organ development 350, Fig. 9.2 rheumatoid arthritis 667, Fig. 15.29 systemic release 118, Fig. 3.32 T-cell sources and functions 386, Fig. 9.40 TH1 cell-derived 459, Fig. 11.12 therapeutic inhibition see Anti-TNF-α therapy Tumor necrosis factor (TNF) family 109, 813 co-stimulatory signals 370 effector T cells 386, Fig. 9.40 lymphoid tissue development 349–350, Fig. 9.2 Tumor necrosis factor receptor(s) (TNFR) 109, Fig. 3.25 death receptors 125 effector T-cell function 386 Fc-fusion protein 711, 785, Fig. A.42 lymphoid tissue development 349–350, Fig. 9.2 signaling pathway 284–286, Fig. 7.31 Tumor necrosis factor receptor I (TNFR-I; CD120a) 109, 797 gene mutations 557, Fig. 13.14 macrophage activation 459, Fig. 11.10 peripheral lymphoid tissue development 349, 350, Fig. 9.2 Tumor necrosis factor receptor II (TNFR-II; CD120b) 109, 797 Tumor rejection antigens (TRA) 716, 720–723 categories 720–722, Fig. 16.17 recognition by T cells 722, 723 see also Tumor antigens Tumor-specific antigens 720–721, Fig. 16.17 Tumor-specific transplantation antigens see Tumor rejection antigens TUNEL assay 779, Fig. A.35 TWEAK 813 Two-dimensional gel electrophoresis 763, 764, Fig. A.14 Two-photon scanning fluorescence microscopy 761 Tyk2 122, 706 Type diabetes mellitus (T1DM) 653, Fig. 15.1 autoreactive T cells 649–650, 665, Fig. 15.27 biologic agents Fig. 16.11 environmental factors 679, 680 genetic factors 669, Fig. 15.35, Fig. 15.36 gut microbiota and 523 HLA haplotypes 676–678, Fig. 15.37 family studies 677, Fig. 15.39 population studies 676–677, Fig. 15.38 precise definition 677, Fig. 15.40 immune effector pathways Fig. 15.15 insulin allergy 606 tissue-injury mechanisms 659, 660, Fig. 15.19 virus infections triggering 680–681, Fig. 15.43 see also Non-obese diabetic mouse Type immune response 451, Fig. 11.5 activation by cytokines 467–468 autoantibody-mediated tissue damage 659 coordination by TH1 cells 458–462, Fig. 11.12 defects 461–462 effector CD4 T-cell subsets 374 genetic deficiencies 544, 546–548, Fig. 13.7 ILC subsets 26, Fig. 1.27 subversion by Leishmania 566 tuberculoid leprosy 565, Fig. 13.20 Type immune response 451, Fig. 11.5 activation by cytokines 467–468 allergic reactions 601, 604–605, 611 asthma 623–624 chronic allergic inflammation 619 effector CD4 T-cell subsets 374 ILC subsets 26, Fig. 1.27 lepromatous leprosy 565, Fig. 13.20 parasitic infections 451, 462–464, 604, Fig. 11.15 therapeutic manipulation 611 Type immune response 451, 452, Fig. 11.5 activation by cytokines 467–468 autoantibody-mediated tissue damage 659 coordination by TH17 cells 465–466, Fig. 11.16 29/02/2016 14:59 Index effector CD4 T-cell subsets 374 genetic deficiencies 546–548, Fig. 13.7, Fig. 13.8 ILC subsets 26, Fig. 1.27 T-cell plasticity 468–469 Type III secretion systems (T3SS) 100, 563, Fig. 13.19 Type IV secretion systems (T4SS) 563, Fig. 13.19 Tyrosinase, as tumor antigen 722, Fig. 16.17 Tyrosine phosphatases 110–111, 128 downregulating immune responses 287–288 Tyrosine phosphorylation 258 ITAMs of lymphocyte antigen receptors 266–267, Fig. 7.9 Lck regulation 269, Fig. 7.12 recruiting proteins to membrane 262, Fig. 7.5 signaling complex assembly 260–261, Fig. 7.3, Fig. 7.5 TCR signaling 268–269, Fig. 7.11 Tyrosine protein kinases 258 nonreceptor 258, Fig. 7.1 receptor see Receptor tyrosine kinases U UBC13 94, Fig. 3.15 Ubiquitin 263 Ubiquitination regulating signaling responses 263–264, Fig. 7.6 targeting proteins to proteasome 217, 264, Fig. 7.6 TLR signaling 94, 264, Fig. 3.15 Ubiquitin ligases see E3 ubiquitin ligases Ubiquitin–proteasome system 217 UL16-binding proteins (ULBPs; RAET1 proteins) 245, Fig. 6.26 activation of NK cells 130, Fig. 3.43 UL16 protein, cytomegalovirus 130 UL18 protein, cytomegalovirus 569–570 UL49.5 protein, bovine herpes virus Fig. 13.24 ULBP4, activation of γ:δ T cells 249, Fig. 6.29 Ulcerative colitis 524, 654, Fig. 15.35 UNC93B1 91, 555 Unmethylated CpG sequences adjuvant activity 740 allergy therapies 611, 627 dendritic cell activation 362 inducing autoimmunity 647, 680, Fig. 15.5 TLRs recognizing 88, 91, Fig. 3.10 Uracil-DNA glycosylase (UNG) base-excision repair 414, 415, Fig. 10.19, Fig. 10.20 class switch recombination 417, Fig. 10.21 deficiency 417, 545 Urochordates, complement system 62 Urogenital tract 493, Fig. 12.1 Urticaria (hives) 619–620 acute 619, Fig. 14.1 chronic 619–620, 626, Fig. 15.23 familial cold 557, Fig. 13.14 routes of allergen entry 619, Fig. 14.12 IMM9 Index.indd 903 serum sickness 629 treatment 620, 626 Urushiol oil 632 US2 protein, human cytomegalovirus Fig. 13.24 US3 protein, human cytomegalovirus Fig. 13.24 US6 protein, human cytomegalovirus Fig. 13.24, Fig. 13.25 Ustekinumab Fig. 16.8 Uve1A 94, Fig. 3.15 Uveitis, autoimmune Fig. 15.37 V Vaccination 33–34, 729–742, 749 childhood 730 history 1–2, 729–730 immunological memory 474, Fig. 11.23 routes 735–736 therapeutic 739, 741–742, Fig. 16.29 tumors 726–727, Fig. 16.21 in vivo assay of efficacy Fig. A.40 see also Immunization Vaccines 730–735 acellular 737 adjuvants 739–740, 752 antibody induction 731–732 cancer 726–727 conjugate 730, 737–738, Fig. 16.27, Fig. 16.28 criteria for effective 732, Fig. 16.23 development 730 diseases lacking effective 730–731, Fig. 16.22 DNA 740–741 killed 730, 732–733 live attenuated 730 bacteria 734 genetic attenuation 733–735, Fig. 16.25, Fig. 16.26 parasites 734–735 viruses 732–734, Fig. 16.24 peptide-based 738–739 safety 732, 736–737 toxoid/inactivated toxin 428, 730 Vaccinia virus smallpox vaccination 1, 474, 730 subversion of host defenses Fig. 13.23 Vα (variable region of TCR α chain) 154 MAIT cells 248 Van der Waal forces, antibody–antigen binding 149, 150, Fig. 4.9 Vanishing bile duct syndrome 689 Variability plot, antibody V regions 146, Fig. 4.6 Variable (V) domains of T-cell receptors, interactions 154, Fig. 4.15 Variable gene segments see V gene segments Variable (V) immunoglobulin domains 142 evolution 203 flexibility at junction with C region 145 framework regions (FR) 146, Fig. 4.7 regions of hypervariability 146–147, Fig. 4.6 structure 142–144, Fig. 4.3 Variable lymphocyte receptors (VLRs), agnathans 200–202, Fig. 5.25 903 Variable regions (V regions) 13–14, 173, Fig. 1.13 immunoglobulins 139, 173 gene construction 175, Fig. 5.3 gene rearrangements see V(D)J recombination genetically engineered 758–759, Fig. A.10 germline origins 174–175, Fig. 5.2 heavy chains see Heavy (H) chains, V region light chain see Light (L) chains, V region single exon encoding 174, Fig. 5.1 somatic hypermutation see Somatic hypermutation structure 141, 142, Fig. 4.1 theoretical combinatorial diversity 184–185 TCRs 153, 173, Fig. 4.14 α chain (Vα) 154 β chain see Vβ gene construction 187–189, Fig. 5.13 see also V gene segments Variant-specific glycoprotein (VSG), trypanosomal 565–566, Fig. 13.21 Varicella-zoster virus, latent infection 568, 572 Variolation 1, 729 Vascular addressins 353, Fig. 9.7 Vascular endothelial growth factor (VEGF) 618 Vascular permeability, increased allergic reactions 618, Fig. 14.11 inflammatory response 86, 87 Vav 82 B-cell receptor signaling 281, Fig. 7.27 CD28 signaling 283, Fig. 7.29 TCR signaling 279, Fig. 7.24 Vβ (variable region of TCR β chain) 154 contact with pre-T-cell receptor 320 germline specificity for MHC molecules 329–330, Fig. 6.24 MAIT cells 248 superantigen binding 240–241, Fig. 6.25 VCAM-1 (CD106) 797, Fig. 3.29, Fig. 9.9 B-cell development Fig. 8.3 effector T cell guidance 371, 454, Fig. 11.6 V(D)J recombinase 180–182 genetic defects 183–184 see also RAG1/RAG2 proteins V(D)J recombination Ig gene segments 178–184 biases affecting 185 enzymatic mechanisms 179–184, Fig. 5.8 molecular mechanism 179, Fig. 5.7 nonproductive rearrangements 186 pre-B cells 304, Fig. 8.5, Fig. 8.8 pro-B cells 299, 301–302, Fig. 8.5 RSSs guiding 178–179, Fig. 5.6 sequence of events Fig. 8.4, Fig. 8.5 species differences 204–205, Fig. 5.27 inherited defects 183–184, 538–539 TCR gene segments α:β T cells 324–327, Fig. 8.24 29/02/2016 14:59 904 Index γ:δ T cells 322–324, Fig. 8.22 mechanisms 187–189, Fig. 5.13 thymocyte subpopulations 320, Fig. 8.18 V domains see Variable domains Veil cells Fig. 9.12 Venoms, insect or animal 428 Very late activation antigens (VLAs) 354 see also VLA-4; VLA-5 Vesicular compartment, intracellular 214, 215, Fig. 6.1 antigen processing 223–225, Fig. 6.10 pathogens in 215, 223, Fig. 6.2 see also Endosomes; Phagosomes Vesicular stomatitis virus (VSV) 405 V gene segments 173 α:β TCR 187, Fig. 5.12 γ:δ TCR 190–191, Fig. 5.17 immunoglobulin 175–178 biased use 185 construction of V-region genes 175, Fig. 5.3 families 177–178 genetic loci 177, Fig. 5.5 hypervariable regions encoded 175, Fig. 5.2 mechanism of DNA rearrangement 179, Fig. 5.7 numbers of copies 176, 184–185, Fig. 5.4 pseudogenes 176, 185 recombination signal sequences 178, Fig. 5.6 recombination see V(D)J recombination VH see Heavy (H) chains, V region Vibrio cholerae 44, Fig. 10.31 Vif gene/protein 576, 579, Fig. 13.31 Viral entry inhibitors, HIV 589, Fig. 13.39 Viral set point, HIV infection 582 Viruses 3, Fig. 1.4, Fig. 1.26 attenuation 733–734, Fig. 16.24, Fig. 16.25 host defense antibodies 27, 469 cell mediated 29–30, Fig. 1.31, Fig. 1.32 cytotoxic T cells 387–392, Fig. 9.41 dendritic cells 359–360, Fig. 9.15 evasion/subversion 566–573 Fc receptor-mediated 433 integrated responses 469 interferons 121–124, Fig. 3.35 intestinal epithelium 512, Fig. 12.14 neutralizing antibodies 428, Fig. 10.33 NK cells 126, 129–130, Fig. 3.38 phases Fig. 11.35 plasmacytoid dendritic cells 122, 363, 566 TH1 cells 458 see also Type immune response intracellular compartmentalization Fig. 6.2 ITAM-containing receptors 271 lysogenic phase 571 lytic (productive) phase 571 recognition B and T cells 402, Fig. 10.4 IMM9 Index.indd 904 cytotoxic CD8 T cells 29–30, Fig. 1.32 MHC class I molecules 166 RIG-I-like receptors 101–103, Fig. 3.21 sensors acting via STING 103–104, Fig. 3.22 TLRs 88, 91, 122, Fig. 3.10 tropism 222, 428 vaccines 732–734, Fig. 16.24 vaccine vectors 592 Virus infections diagnostics 753 immunodeficiency diseases 541 latent 568, 571–573 recurrent 534 therapeutic vaccination 741–742, Fig. 16.29 triggering autoimmunity 680–681, Fig. 15.43 Vitamin D 679, 713–714 Vitiligo 720 Vitronectin (S-protein) 71, Fig. 2.36 VL see Light (L) chains, V region VLA-4 (integrin α4:β1) Fig. 9.9 B-cell development Fig. 8.3 effector T cells 371, 454, Fig. 9.27, Fig. 11.6 therapeutic inhibition 712, Fig. 16.10, Fig. 16.11 VLA-5 794, Fig. 3.29 VLAs 354 VpreB (CD179a) 800 pre-B-cell receptor 303, Fig. 8.5 signaling function Fig. 8.6 timing of expression 302, Fig. 8.4 Vpr gene/protein 576, 579, Fig. 13.30, Fig. 13.31 Vpu gene/protein 576, 579, Fig. 13.31 V-region genes 175 V regions see Variable regions Vulvar intraepithelial neoplasia 739 cytoskeletal reorganization defects 279, 382 gene therapy 558 Wiskott–Aldrich syndrome protein see WASp Worms, parasitic see Helminths Wounds entry of infection 446, Fig. 2.2, Fig. 11.2 inflammatory response 87 WT1 antigen Fig. 16.17 W/WV mutant mice 438 W Z Waldeyer’s ring 497, Fig. 12.6 Warts, genital 742 WASp (Wiskott–Aldrich syndrome protein) 539 B-cell receptor signaling 281, Fig. 7.27 T-cell polarization 382 TCR-mediated activation 279, Fig. 7.24 Weibel-Palade bodies 115 Western blotting 764, Fig. A.15 West Nile virus 123, 150–151, Fig. 4.11 Wheal-and-flare reaction 618, Fig. 14.11 allergen route of entry and 619, Fig. 14.12 see also Urticaria Whipworm Fig. 11.14 White blood cells see Leukocyte(s) Whooping cough see Pertussis Wiley, Don C 816 Wilms’ tumor antigen Fig. 16.17 WIP 279, Fig. 7.24 Wiskott–Aldrich syndrome (WAS) 539, Fig. 13.1 antibody deficiencies 421 ZAG Fig. 6.26 ZAP-70 (ζ-chain-associated protein-70) activation by Lck 270, Fig. 7.11, Fig. 7.13 B-cell homolog 280 gene defects 539 phosphorylation of LAT and SLP-76 271–272, Fig. 7.15 recruitment by ITAMs 267, 270–271, Fig. 7.9 structure 270, Fig. 7.13 thymocyte subpopulations 326, Fig. 8.18 ζ chain (CD247) 805 FcγRIII signaling 270 TCR complex 266, Fig. 7.8 ZFP318 195 Zidovudine (AZT) 588, 590 Zinkernagel, Rolf 238 Zoonotic infections 42, 574 Zymogens, complement 49 X XBP1, plasma cells 419 X chromosome, inactivation 537–538, 542, Fig. 13.4 XCR1 222–223 Xenografts 688 Xenoimmunity 643 Xeroderma pigmentosum 415 XIAP genetic defects 550, 551, Fig. 13.10 NOD interactions 97, Fig. 3.17 X-linked agammaglobulinemia (XLA) 541–542, Fig. 13.1 defects in B-cell development 303, 542, Fig. 13.4 molecular defect 281, 542 X-linked hypohidrotic ectodermal dysplasia and immunodeficiency 95, 277 X-linked immunodeficiency (xid) 303 X-linked lymphoproliferative (XLP) syndrome 406, 550–551, Fig. 13.1 molecular defects 550–551, Fig. 13.10 X-linked severe combined immunodeficiency (XSCID) 109, 535–538 XRCC4, V(D)J recombination 182, Fig. 5.8 Y Y chromosome, minor H antigens 686 Yeast, innate recognition 53, Fig. 2.18 Yersinia outer proteins (Yops) 563 Yersinia pestis 563, Fig. 13.17 29/02/2016 14:59 Icons used throughout the book degranulation smooth muscle cell diapedesis phagocytosis blood vessel macrophage mast cell natural killer (NK) cell basophil eosinophil active neutrophil neutrophil erythrocyte monocyte fibroblast Student and Instructor Resources Websites: Accessible from www.garlandscience.com, these Websites contain over 40 animations and videos created for Janeway’s Immunobiology, Ninth Edition These movies 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 infected cell Movie thymic thymic cortical medullary epithelial epithelial cell cell T cell dendritic cell immature dendritic cell activated T cell plasma cell B cell follicular dendritic cell antigen-presenting cell (APC) antibody (IgG, IgD, IgA) endothelial cell antibody (IgM, IgE) M cell epithelial cell goblet cell apoptotic cell pentameric IgM HEV T-cell receptor antibody SH2 domain B-cell receptor complex α3 α2 CD40L selectin integrin CD8 ζ light chain MASP-2 C-type ICAM-1 chemokine cytokine receptor receptor lectin Igβ Igα peptide TNF-family receptor e.g CD40 MHC class II MHC class I viruses FasL C3 C3a C4 C4a C5 C5a calreticulin ERp57 kinase IRAK1 γ (NEMO) ubiquitin β α IMM9 Inside front pages.indd Lymph Node Development 9.2 Lymphocyte Trafficking 3.1 Phagocytosis 9.3 Dendritic Cell Migration 3.2 Patrolling Monocytes 9.4 Visualizing T Cell Activation 3.3 Chemokine Signaling 9.5 TCR-APC Interactions 3.4 Neutrophil Extracellular Traps 9.6 Immunological Synapse 3.5 Pathogen Recognition Receptors 9.7 T Cell Granule Release 3.6 The Inflammasome 9.8 Apoptosis 3.7 Cytokine Signaling 9.9 T Cell Killing 3.8 Chemotaxis 10.1 Germinal Center Reaction 3.9 Lymphocyte Homing 10.2 Isotype Switching 3.10 Leukocyte Rolling 11.1 The Immune Response 3.11 Rolling Adhesion 11.2 Listeria Infection 3.12 Neutrophil Rolling Using Slings 11.3 Induction of Apoptosis 3.13 Extravasation 13.1 Antigenic Drift 5.1 V(D)J Recombination 13.2 Antigenic Shift 6.1 MHC Class I Processing 13.3 Viral Evasins 6.2 MHC Class II Processing 13.4 HIV Infection 7.1 TCR Signaling 14.1 DTH Response 7.2 MAP Kinase Signaling Pathway 15.1 Crohn’s Disease 7.3 CD28 and Costimulation 16.1 NFAT Activation and Cyclosporin 8.1 T Cell Development active Ras GTP:Ras FADD C8 death domain C9 GDP:Ras C7 membraneactivated attack complement complex protein death effector domain (DED) activated calmodulin inactive Ras degraded IκB tapasin C6 IRAK4 TRAF-6 UBC13, Uve1A IKK C5b Fc receptor MAL MyD88 9.1 Complement System TAP transporter Fas Toll receptor Innate Recognition of Pathogens 2.1 C2/factor B C1s bacterium PIP3 CD80 heavy chain C1q C1r CD28 CD4 chemokine γ ε ITAMs MBL CD45 T-cell receptor cytokine α β ζ phosphorylation kinase domain SH2 domain cell membrane T-cell receptor complex εδ lymph node ZAP-70/Syk tyrosine kinase MHC class I β2microglobulin α1 protein antigen dimeric IgA antibody production 1.1 procaspase active calcineurin protein proteasome transcription factor NFκB peptide fragments AP-1 NFAT Ca2+ gene NFAT active gene pseudogene (being transcribed) 01/03/2016 14:00