IMMUNOLOGY ForElsevier: AcquisitionEditor:MadeleneHyde DevelopmentalEditor:AndreaVosburgh EditorialAssistant:MargaretNelson ProjectManager:LucyBoon DesignManager:KirsteenWright IllustrationsManager:GillianRichards MarketingManager:JasonOberacker EIGHTH EDITION IMMUNOLOGY David Male PhD MA Professor of Biology Department of Life Sciences The Open University Milton Keynes, UK Jonathan Brostoff MA DM DSc FRCP FRCPath FIBiol Professor Emeritus of Allergy and Environmental Health School of Biomedicaland HealthSciences King’s College London London, UK David B Roth MD PhD SimonFlexner Professor and Chair ofPathology and Laboratory Medicine Department of Pathologyand Laboratory Medicine University of Pennsylvania Philadelphia, Pennsylvania, USA Ivan M Roitt MADSc (Oxon)Hon FRCP (Lon)FRCPath FRS Director,CentreforInvestigative and Diagnostic Oncology MiddlesexUniversity London, UK Copyright#2013,2006,2001byElsevierLtd. 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The Publisher's policy is to use paper manufactured from sustainable forests Contents Preface vii 11 Regulation of theImmune Response 183 David Bending List of Contributors ix 12 Immune Responses in Tissues 199 SECTION 1 David Male Components of theImmune System 1 1 Introduction totheImmune System 3 SECTION 3 David Male Defense AgainstInfectiousAgents 209 2 Cells, Tissues, and Organsof the 13 Immunity to Viruses 211 Immune System 17 Persephone Borrow and AnthonyANash PeterM Lydyard and NinoPorakishvili 14 Immunity to Bacteria and Fungi 223 3 Antibodies 51 GregoryJ Bancroft RoyJefferis 15 Immunity to Protozoaand Worms 243 4 Complement 71 Richard J Pleass B Paul Morgan 16 Primary Immunodeficiencies 263 5 TCell Receptors and MHC Molecules 89 LuigiDNotarangelo David B Roth 17 AIDS, SecondaryImmunodeficiency and Immunosuppression 277 SECTION 2 Dean HKedes and Lisa ANichols Modes of Immune Response 107 18 Vaccination 289 ColinCasimir 6 Mechanisms of Innate Immunity 109 David Male SECTION 4 7 Mononuclear Phagocytes in Immune Immune Responses AgainstTissues 305 Defense 125 Luisa Martinez-Pomares and 19 Immunological Tolerance 307 Siamon Gordon Thomas Kamradt 8 Antigen Presentation 143 20 Autoimmunity and Autoimmune David Male Disease 323 James EPetersand David AIsenberg 9 Cell Cooperation in the Antibody Response 157 21 Transplantation andRejection 341 JosephC Marini and Kalpit AVora Andrew J TGeorge 10 Cell-mediated Cytotoxicity 171 22 Immunity to Cancers 355 VictoriaMale Pramod K Srivastava v Contents Appendices online SECTION 5 1. Major Histocompatibility Complex Hypersensitivity 369 2. CD System 23 Immediate Hypersensitivity (Type I) 371 3. The Major Cytokines Thomas AEPlatts-Mills 4. Human Chemokines and Their Receptors 24 Hypersensitivity(Type II) 393 Critical thinking: Explanations 433 David Male Glossary 445 25 Hypersensitivity(Type III) 405 Index 455 David P D’Cruz 26 Hypersensitivity(Type IV) 419 Warwick J Britton vi Preface InpreviouseditionsofImmunology,wehaveusedthepref- system–cells,organs,complement,andthemajorreceptor acetooutlinethemajorimmunologicaladvancesthathave molecules,includingantibodies,Tcellreceptors,andMHC taken place since the previous edition. Recently, however, molecules. The second section deals with the initiation of advances in the teaching of biomedical science have been the immune response starting with innate defenses and just as striking as advances in immunology. Students now mononuclearphagocytes.Theunitonantigenpresentation, learnfromavarietyofinterlinkedmedia,includingbooks, costimulation and cell activation pathways precedes units DVDs, and websites. This edition of Immunology reflects on the principal effector arms of the immune response, these changes in science teaching. We have produced this TH2 responses with antibody production, TH1 responses edition as an integrated teaching package, which is pre- andmononuclearphagocytes,TH17cellsandinflammation sentedin twoformats. Inboth casesthey can beread asa andthefunctionsofcytotoxicTcellsandNKcells.Thefinal continuous narrative but they have slightly different unitsinthissectionlookintotheregulationoftheimmune content: response, and there is an expanded unit on the distinctive typesofimmuneresponsethatdevelopindifferenttissues (cid:129) thebookcontainswhatweconsidertobethecoreareas of the body. Although it has long been recognized that andconceptsofimmunology immune responses in tissues vary, the underlying reasons (cid:129) theelectronicteachingpackageincludesallthematerial forthedifferencesareonlyjustbeingelucidated. inthebook,plusadditionalsectionswithinthechapters, Section three describes the immune responses that de- whichexpandonthecorematerialandprovide velopagainstdifferenttypesofinfection,andhowimmuno- backgroundonimmunologicalmethods.Italsoprovides deficiency leads to increased susceptibility to particular activelinkstothepublisher’swebsiteandexternal infections. Indeed the diversity and complexity of the websites,andallowsmoreinnovativeuseofvideoand immune system can only be understood in relation to the questionswithinthetextandattheendofthechapters. diversity of the pathogens whichit protects against. In re- Moreover, the availability of much essential information cent years, the devious strategies employed by pathogens onlinemeansthatitisnowbettertoprovidelinkstoweb- toevadeimmuneresponseshaveprovidedsomequitestar- sitesthatareupdatedregularly,ratherthanrelyonprinted tlingrevelations,bothontheadaptabilityofthepathogens tablesof,forexample,CDmoleculesandcytokines. and on the flexibility of the immune system. Ultimately Inthepast5years,therehavealsobeenmajoradvancesin the immune system can only be understood in relation to immunology, particularly in our understanding of innate itsprincipalfunction–defenseagainstpathogens. immunedefenses,andimmunerecognitionsystems.These Sectionfourdescribesimmuneresponsesagainsttissues, evolutionarily ancient mechanisms for recognizing patho- and section five hypersensitivity. These areas are of great gen, have been retained in mammals and indeed have clinical importance. One aim of this book is to provide developed alongside the adaptive immune system. In the readerswithasoundunderstandingoftheimmunerespon- eightheditionofImmunology,wehaveexpandedoninnate ses which underlie clinically important areas including immunity throughoutthe text.Thistrulyreflectsthe way hypersensitivitystatesandallergy,immunopathology,tumor theimmunesystemoperateswiththeintegrationofancient immunotherapy, and transplantation. In these sections, we andrecently-evolvedimmunedefenses. havemaintainedwhatwebelievetobeanimportantfeature Other areas that receive greater coverage are tissue- of the book, namely a clear description of the scientific specific immune defenses, T cell subsets and the use of principlesofclinicalimmunology,integratedwithhistology, monoclonalantibodiesindiseasetherapy.Itisveryexciting pathology,andclinicalexamples. toseehowadvancesinantibodytechnologyhavenowcom- Afeatureofthetextistheinclusionofin-textquestions. binedwithourknowledgeoftheimmunesystemtoprovide Thesearedesignedtocheckthatthereaderunderstandsthe effective treatments for a number of diseases, including implicationsoftheprecedingparagraphsorcanrelatethat multiplesclerosisandrheumatoidarthritis. material to information in earlier units. Another useful Despitethesechanges,wehaveretainedtheoverallorga- learningaidisthecriticalthinkingsectionsattheendofeach nization of the subject material within five sections. The unit.Finally,wehaveputalotofcareintothesummaries, openingsectiondescribesthebuildingblocksoftheimmune ensuring that they really do distil the key aspects, into a vii Preface manageable overview. The summaries make an excellent biochemistry, genetics, cell biology, structural biology and revision guide for exams, in addition to setting the frame- molecular biology. For the past century, immunology has workforeachsubjectarea. fascinated and inspired some of the greatest scientific Thecontributorstothisvolumeincludemanyexpertsin thinkers of our time. We wish our readers well in their differentareasofimmunology,including14newcontribu- study of immunology, a subject which continues to excite torswhohavebroughtnewperspectivesontheirownareas and surprise us, and which underpins many other areas of of expertise. We also greatly appreciate the hard work of biologyandbiomedicalsciences. our publishers and their colleagues, particularly, Andrea DavidMale Vosburgh,LucyBoonandMadeleneHydefromElsevier. JonathanBrostoff Immunology bridges basic sciences and medicine and DavidRoth encompasses approaches from numerous fields, including IvanRoitt2012 The following are standard shapes which are used consistently throughout the book complement lymphocyte basophil antibodies system molecules plasma cell megakaryocyte LFA-I MHC class I antigen- APC presenting cell mast cell ICAM-I MHC class II macrophage platelets B7 CD8 complement control protein (CCP) domains antigen erythrocyte CD28 tyrosine CD4 processed kinase antigen neutrophil TNF receptor T-cell family domains bacteria receptor eosinophil virus Fc receptor Ig super family domains becomes stimulates/enhances inhibits/kills –wherethisiconisfoundinthemargin,itindicatesmorematerialisavailableonstudentconsult.com viii List of Contributors Gregory J Bancroft BSc(Hons)PhD AndrewJTGeorgeMAPhDFRCPathFHEAFRSA Reader Professor of MolecularImmunology Department of Immunology and Infection Department of Immunology, Division of Medicine LondonSchoolof Hygieneand TropicalMedicine ImperialCollege London London, UK London, UK David Bending MA PhD SiamonGordon MBDhBPhD ArthritisResearchUK Foundation Fellow GlaxoWellcome Professor of Cellular Pathology UCL, Instituteof ChildHealth Emeritus London, UK Sir William DunnSchoolof Pathology PersephoneBorrowPhD OxfordUniversity Oxford,UK Reader Nuffield Department of Clinical Medicine David AIsenberg University of Oxford The Centre for Rheumatology Research Oxford,UK Department of Medicine Warwick J Britton PhD MB BSBScMedFRACP University College London FRCP FRCPA DTM&H London, UK Bosch Professor of Medicine and Professor Roy JefferisBSc PhD FRSC CChem MRCP of Immunology FRCPath DSc Department of Medicine Professor Emeritus Sydney MedicalSchool School of Immunityand Infection University of Sydney; University of Birmingham Head, Mycobacterial ResearchProgram Birmingham, West Midlands,UK Centenary Institute Sydney,NSW, Australia Thomas KamradtDr med Jonathan Brostoff MADM DScFRCP Professor FRCPath FIBiol Instituteof Immunology ProfessorEmeritusofAllergyandEnvironmentalHealth University of Jena School of Biomedicaland HealthSciences Jena, Germany King’s College London Dean HKedes BScPhD MD London, UK Associate Professor Colin Casimir BSc PhD Myles HThalerCenter for AIDS and Senior Lecturer Retrovirology Research Department of NaturalSciences Departments of Microbiology and Medicine MiddlesexUniversity University of Virginia London, UK Charlottesville, Virginia,USA David PD’CruzMD FRCP Consultant Rheumatologist and Reader The Louise Coote LupusUnit St Thomas’Hospital London, UK ix