1 Overview of the Immune System 1 2 and Organs of the Immune System 23 3 Innate 52

Transcription

1 ι introduction 1 Overview of the Immune System 1 2 and Organs of the Immune System 23 3 Innate 52 PART il Generation of B-Cell and Responses 4 Antigens and Antibodies 76 5 Organization and Expression of Immunoglobulin Genes 6 Antigen-Antibody Interactions: Principles and Applications The System The Major Complex and Antigen Presentation 9 T-Cell T-Cell Maturation,Activation, and Differentiation B-Cell Generation, and Differentiation 271 PART II! PART IV Immune Effector 12 Cytokines Activation and Migration Cytotoxic Responses Hypersensitivity Reactions 371 The Immune System in Health and Disease 16 Tolerance and Transplantation Immune Response to Infectious Diseases 447 ' AIDS and Other Cancer and the Immune System Systems 546 Appendix I: CD Antigens Appendix II: Cytokines A-27 Glossary Answers Kindt, Thomas J. Kuby immunology 2007 digitalisiert durch: IDS Basel Bern

2 Preface Part I Introduction 2 and Organs of the Immune System Regulated at the Level 24 Involves Many Factors 26 1 Overview of the Immune System 1 Cell Death an Essential Homeostatic 26 Historical Perspective 2 Hematopoietic Stern Cells Can Be Enriched 28 Immunology 2 Cells of the Immune System 30 Vaccination an Enterprise 3 Lymphoid Cells 30 Studies of Humoral and Cellular 4 CLINICAL FOCUS USES AND POTENTIAL 32 Theoretical Challenges 5 Β (B Cells) 34 Τ Lymphocytes (T Cells) 34 Infection and Immunity 7 Subpopulations of Clones 35 and Adaptive Immunity 8 Natural Killer Cells 35 Phagocytes 36 Phagocytic Cells Are a Barrier to Infection 9 Phagocytosis Followed by Digestion Soluble Molecules Contribute to Innate Immunity 9 and Presentation of Antigen 36 Collaboration between Innate and Adaptive Cells 37 Immunity Increases Immune Responsiveness 9 Mast Cells 38 Adaptive Immunity Highly Specific 10 Dendritic Cells 38 Lymphocytes and Antigen-Presenting Cells Cooperate Follicular Dendritic Cells 40 in Adaptive Immunity 12, Cells 14 Organs of the Immune System 40 Humoral and Cellular Immune Responses Exhibit Primary Lymphoid Organs 40 Different Effector Functions 14 Secondary Lymphoid Organs 43 The Antigen Receptors of Β and Τ Lymphocytes Are Diverse 14 Lymphoid Cells and The Major Histocompatibility Molecules Bind Comparisons 49 Antigenic Peptides 16 Antigenic Selection of Lymphocytes Causes " ~" ~" Expansion 16 Innate Immunity 52 Immune Dysfunction and Consequences CLINICAL FOCUS AND ASTHMA ARE SERIOUS PUBLIC HEALTH PROBLEMS 20 Connections between Innate and Adaptive Immunity 55

3 XIV Inflammation 57 There Are Five Major Classes of Heavy Chains 87 Immunoglobulins Possess Multiple Domains Leukocyte Extravasation a Highly Regulated, Immunoglobulin 87 Process 59 Antibody Binding Site 89 Soluble Molecules and Membrane-Associated Receptors 59 CDRs Bind Antigen 90 Conformational Changes May Be Induced Peptides Contribute to the Innate by Antigen Binding 92 Defense against Bacteria and Fungi 59 Domains 93 Proteins of the Acute Phase Response to Innate Immunity 61 Antibody-Mediated Functions 94 Immunity Uses a Variety of Receptors Opsonization Promoted by Antibody 94 Infection 61 Activate 95 Receptors 62 Antibody-Dependent Cytotoxicity (ADCC) Cells 95 Cell Types of Innate Immunity 65 Antibodies Can Cross Epithelial Layers Neutrophils Are Specialized for by Transcytosis 95 and Killing 65 Antibody Classes and Activity 95 CLINICAL FOCUS PROTEIN Α KEY MARKER Immunoglobulin G 95 OF CARDIOVASCULAR 66 Immunoglobulin Μ 96 Macrophages Deploy a of Antipathogen Devices 66 CLINICAL FOCUS PASSIVE ANTIBODY THERAPY 98 Κ Cells Are an First Line of Defense,..,... Immunoglobulin Α 99 against Viruses and a....,, Immunoglobulin Ε 100 Signa to Other 68,..,, Immunoglobulin D 100 Dendritic Cells Engage Pathogens and Invoke Adaptive Immune Responses by Activating Τ Cells 68 Antigenic Determinants on Pathways 69 Immunoglobulins 100 Isotype 101 TLR Signaling Typical of Signal Transduction Pathways Ubiquity of Innate Immunity 71 Idiotype 101 Part II Generation of B-Cell and T-Cell Responses The B-Cell Receptor 102 Receptors Bind to Regions of Antibodies 102 The Immunoglobulin Superfamily 103 Monoclonal Antibodies 105 Antibodies Have Important Clinical Uses 106 Antigens and Antibodies 76 Are Monoclonal Antibodies Catalyze Reactions 106 Immunogenicity Versus Antigenicity 77 Haptens Are Valuable Research and Diagnostic 5 Organization and Expression of Tools 77 Immunoglobulin Genes 111 Properties of the Contribute to Immunogenicity 78 The Biological System Contributes to Devising a Heterogenicity 80 with Ig Model Compatible Epitopes 81 Germ-Line and Contended B-Cell Epitopes Have Characteristic to Explain Antibody Diversity Properties 81 Dreyer and Bennett Proposed a Revolutionary... Two-Gene Model 113 Basic Structure Antibodies 84,,.- Tonegawa s Are 85 Genes Rearrange 114 and Methods Revealed Basic Multigene Organization of Ig Genes 115 Antibody Structure 85 Sequences Revealed Constant and Each Multigene Family Has Distinct Features Variable Regions 87 Heavy-Chain Multigene Family

4 C O N T E N T S XV Variable-Region Gene Rearrangements 116 Light-Chain DNA UndergoesV-J Rearrangements Heavy-Chain DNA Undergoes V-D-J Rearrangements 6 Antigen-Antibody Interactions: and Applications Strength of Antigen-Antibody Interactions 145 Mechanism of Variable-Region Gene Rearrangements 119 Affinity a Quantitative Measure Signal Sequences Direct of Binding Strength 145 Antibody Avidity Incorporates Affinity 119 of Multiple Binding Sites 148 Gene Segments Are Joined by 119 Rearrangements May Be Productive Cross-Reactivity 149 or Nonproductive 121 Plasmon Resonance (SPR) 149 Allelic Exclusion Ensures a Single Antigenic Specificity 121 SPR Can Be Used to Characterize the Epitope Generation of Antibody Diversity 123 Specificities of Collections of Antibodies Precipitation Reactions 151 There Are Germ-Line V, D, and J Gene Segments 123 Precipitation Reactions in Visible and V-D-J Joining Precipitin Lines 151 Generates Diversity 123 Combines Electrophoresis Junctional Flexibility Adds Diversity 123 and Double Immunodiffusion 152 P-Addition Adds Diversity at Sequences 125 N-Addition Adds Considerable Diversity Agglutination Reactions 153 by Addition of 125 Used in Typing 153 Adds Diversity Bacterial Agglutination Used to Diagnose in Already-Rearranged Gene Segments 125 Infection 154 Α Final Source of Diversity Agglutination Useful with Soluble Antigens Association of Heavy and Light Chains Agglutination Inhibition, Absence of Immunoglobulin Gene Diversification Agglutination Diagnostic of Antigen Differs Among Species Radioimmunoassay 154 Among Constant-Region Genes 128 Assay 155 AID Cytidine There Are Numerous Variants of Mediates Both Somatic Hypermutation Western Blotting 158 and Class Switching 128 Expression of Ig Genes 130 Immunoprecipitation 158 Heavy-Chain Primary Transcripts Undergo Immunofluorescence 160 Differential RNA Processing 130 and Fluorescence 161 Synthesis, and Secretion CLINICAL FOCUS FLOW CYTOMETRY AND LEUKEMIA TYPING 163 of Immunoglobulins 133 Alternatives to Antigen-Antibody Reactions Transcription 133 Microscopy 164 DNA Greatly Accelerates Transcription 135 Expression Inhibited Cells 135 J The Complement System 168 Antibody Genes and Antibody Engineering The Functions of Complement 168 Monoclonal Antibodies Have Potent Clinical Potential 136 The Components of Complement 169 Mice Have Been Engineered with Human Immunoglobulin Loci 137 Complement Activation 169 Phage Display Libraries the Derivation classical Pathway Begins with of Monoclonal Antibodies without 137 Antigen-Antibody Binding 170 CLINICAL FOCUS THERAPY FOR The Alternative Pathway LYMPHOMA AND OTHER DISEASES WITH GENETICALLY The Lectin Pathway Originates with Host Proteins ENGINEERED ANTIBODIES 140 Binding Surfaces 175

5 XVI Complement Pathways Converge and Immune Responsiveness 206 at the Complex Restriction of Τ Cells 207 Regulation of the Complement System of Antigen-Presenting Cells 207 Biological Consequences of Complement Activation 180 Processing of Antigen Required for Recognition by Τ Cells 208 The Membrane-Attack Complex Can Lyse Most Cells Can Present Antigen with Class I MHC; a Broad Spectrum of Cells 180 Presentation with Class II MHC Restricted to APCs 209 Cleavage Products of Complement Components Mediale 182 Evidence for Different Antigen-Processing and Presentation Pathways 209 CLINICAL FOCUS PAROXYMAL NOCTURNAL Α DEFECT IN REGULATION Endogenous Antigens: 183 The Cytosolic Pathway 210 C3b and C4b Binding Facilitates Opsonization 184..,»,, Peptides for Presentation Are Generated The Complement System Also,,, by Protease Called 211 Viral Infectivity 184 Peptides Are Transported from the Cytosol The Complement System Clears Immune Complexes to the Rough from Circulation 185 Peptides with Class I Complement Deficiencies 185 Chaperone Molecules The Major Complex and Antigen Presentation CLINICAL FOCUS DEFICIENCY IN TRANSPORTERS ASSOCIATED WITH ANTIGEN PROCESSING (TAPS) LEADS Α DIVERSE DISEASE SPECTRUM Exogenous Antigens: The Endocytic Pathway 214 General Organization and Inheritance Peptides Are Generated from MHC 190 Molecules in Endocytic Vesicles 214 The Invariant Chain Guides Transport of The MHC Encodes Three Major Classes Class II MHC Molecules to Endocytic Vesicles 214 of Molecules Peptides Assemble with Class II MHC Molecules Allelic MHC Genes Are Inherited by Displacing CLIP 215 in Linked Groups Called Haplotypes 191 Inbred Mouse Strains Have Aided the Study Cross-Presentation of Exogenous MHC 193 Antigens 217 MHC Molecules and Genes Controversy Exists over the Cell Types in Which Cross-Presentation Can Occur 217 Class I Molecules Have a Glycoprotein Heavy Chain and a Protein Light Chain 193 Antigens 217 Class II Molecules Nonidentical Glycoprotein Chains 195 The Arrangement of Class I and II 9 T-Cell Receptor 223 Genes Reflects Their Domain Structure 196 Class I and II Molecules Exhibit Studies of the T-Cell Receptor 223 in the Region That Binds to Peptides 197 Class I and Class II Molecules Exhibit Diversity Classic Experiments the within a Species, and Multiple Occur Self-MHC Restriction of the T-Cell Receptor 224 in an Individual T-Cell Receptors Isolated by Using Clonotypic Antibodies 224 Detailed Map of MHC Genes 201 The TCR ß-Chain Gene Was Cloned by Use The Human Class I Region Spans about 2000 kb of Subtractive Hybridization 224 at End of the HLA Complex 202 The Class II MHC Genes Are Located the Centromeric HLA 203 Structures and 226 Human MHC Class III Genes Are between Organization and II 203 TCR Genes 228 Cellular Expression of MHC Molecules 203 Variable-Region Genes Rearrange Regulation of MHC Expression 204 Antibody Genes 229 Mechanism of TCR DNA Rearrangements 230 MHC and Disease Susceptibility 205 Allelic Exclusion TCR Genes 231

6 XVII Rearranged TCR Genes Are from Segments 231 and CLINICAL FOCUS T-CELL REARRANGEMENTS AS MARKERS Differentiation 271 FOR CANCEROUS CELLS 232 TCR Diversity Generated Like Antibody Diversity B-Cell Maturation 271 but without Somatic Mutation 232 Progenitor Β Cells Proliferate in Bone Marrow 272 T-Cell Receptor Complex: TCR-CD3 235 Produces T-Cell Accessory Membrane Molecules 236 Β Cells 273 The Receptor Essential for CD4 and CD8 Coreceptors Bind to Conserved B-Cell Development 274 Regions of MHC Class II or I Molecules 236 Knockout Experiments Identified Essential Affinity Complexes Transcription Factors 275 Enhanced by Coreceptors 238 Markers Identify Stages 275 Structures of Are a B-Cell Subset 275 TCR-Peptide-MHC Complexes 240 Β Cells Are Selected Against....,, in Bone Marrow 276 TCRs Interact Class I and.,....,,.. Se Β Ce s May Be Rescued by Class II Molecules 241,... of Genes 278 of Τ Cells 241 and 10 T-Cell Maturation, Activation, Antigen Have Different for Response 278 and Differentiation 245 _ and through the Cell Cycle 279 Transduction of Activating Signals Involves T-Cell Maturation and the Thymus Repertoire 248 Signaling Initiated Antigen and Induces Many Signal Transduction Pathways 281 Positive Selection Ensures MHC Restriction 249 Complex Can Enhance Negative Selection Ensures 250 B-Cell Responses and CD22 Can Inhibit 281 Experiments Revealed the Essential Elements,...,. of Positive and Negative Selection 250.,.. Α FAILURE IN AND B-CELL DEVELOPMENT 284 Central Issues Thymic Selection Unresolved 251 Essential in Most B-Cell Responses 285 T-Cell Activation 254 Mature Self-Reactive Β Cells Can Be Negatively,,.... Multiple Signaling Pathways Are, Selected in the Periphery 287 by TCR Engagement 254 The Humoral Response 289 How TCR Complexes Must Be Engaged to Trigger T-Cell Activation? 258 Primary and Secondary Responses Signals Are Required Significantly 289 for T-Cell Activation 259 Helper Cells Play a Critical in the Clonal Anergy Ensues a Costimulatory Humoral Response to Hapten-Carrier Conjugates 290 s sen vivo Sites for Induction of Humoral Responses 292 Superantigens T-Cell Activation by Binding the TCR and MHC II 260 Centers and T-Cell Differentiation 261 B-Cell Differentiation 292 Activated Τ Cells Effector and Memory Maturation the Result τ 262 Mutation and Selection 293 Α Subpopulation of Τ Cells Memory Β Cells and Plasma Cells Are Generated Negatively Regulates Immune Responses 263 in Germinal Centers 296 Antigen-Presenting Cells Have Characteristic Regulation of the Immune Effector Costimulatory Properties 263 Response 297 Cell Death and T-Cell Populations 264 Different Antigens Can with Each Other 297 CLINICAL FOCUS FAILURE OF APOPTOSIS CAUSES The Presence of Antibody Can Suppress DEFECTIVE LYMPHOCYTE HOMEOSTASIS 266 the Response to Antigen 297

7 XVIII C O N T E N T S Part III Immune Effector Sites of Extravasation 334 Directed by Receptor Mechanisms Profiles and Signals 336 Naive Lymphocytes Recirculate to Secondary Lymphoid Tissue 336 Effector and Memory Lymphocytes Adopt 12 Cytokines 302 Trafficking 337 Other Mediators of Inflammation 338 Properties of Cytokines 302 The System Tissue 338 Cytokines Belong to Four Families 305 System Yields Fibrin-Generated Cytokines Have Numerous Biological Functions 306 Mediators of Inflammation 338 Cytokine Receptors 307 System Yields Plasmin-Generated Mediators of Inflammation 338 Cytokine Receptors Fall within Five Families 308 The Complement System Produces Anaphylotoxins 338 of Class I Cytokine Receptors Lipids Act as Mediators 339 Have Signaling Subunits in Common 309 Cytokines Are Important IL-2R the Most Thoroughly Inflammatory Mediators 339 Cytokine Receptor 311 Cytokine Receptors Initiate The Inflammatory Process 340 Signaling 312 Neutrophils Play an and Important Cytokine Antagonists 314 in Inflammation 340 Inflammatory Responses May be Localized Cytokine Secretion Subsets CLINICAL FOCUS ADHESION The Development of and Subsets DEFICIENCY (LAD) IN HUMANS AND CATTLE 343 Determined by the Cytokine Environment 316 Cytokine Profiles Are Inflammation The Balance Disease 318 of IFN-7 and TNF-α in Chronic Diseases 318 Inflammation 344 HEV-Like Structures Appear in Septic Shock Common and Potentially Lethal 318 Chronic Inflammatory Disease 346 Bacterial Toxic Shock Caused by Superantigens 319 Agents 346 Activity in Lymphoid.,, and Myeloid Cancers 319 Chagas's Disease Caused by a Parasite 320 Extravasation 346 Corticosteroids Are Powerful Anti-Inflammatory Cytokine-Based Therapies NSAIDs Combat Pain and Inflammation 347 Cytokines in Hematopoiesis 321 CLINICAL FOCUS THERAPY WITH INTERFERONS Cytotoxic Responses Leukocyte Activation and Effector Responses 351 Migration 327 General of Effector Τ Cells 352 Cell Adhesion Molecules 327 The Activation Requirements of Τ Cells Differ 352 Chemokines 329 Molecules Facilitate TCR-Mediated Interactions 352 Mediate Effector Τ Cells Express a Variety Leukocyte Activity 331 of Effector Molecules 353 Leukocyte Extravasation Cytotoxic Τ Cells 353 The 332 from Lymphocyte Recirculation 334 with Technology 355 Lymphocyte Extravasation 334 CTLs Kill Cells in Two Ways 355

8 C O N T E N T S Natural Killer Cells 360 Type IV or Hypersensitivity (DTH) 393 NK Cells and Τ Cells Share Some Features 361 There Are Several Phases of the DTH Response 394 Killing by NK Cells Numerous Cytokines Participate in the DTH Reaction 395 to CTL-Mediated Killing 361 The DTH Reaction Detected with a η Test 396 NK Cells Have Both Activation Contact Dermatitis a Type of DTH Response 396 and Inhibition Receptors 362 CLINICAL FOCUS GENE INFLUENCE HEALTH 364 KT Cells 364 Antibody-Dependent Cytotoxicity 366 Part IV The Immune System in Health and Disease Experimental Assessment 16 Tolerance 401 of Cell-Mediated Cytotoxicity 366 Τ Cells with Foreign Cells Establishment and Maintenance of Tolerance 402 MLR 366 Central Tolerance Limits Development of Autoreactive CTL Activity Can Be by CML The GVH Reaction an Indication Peripheral Tolerance Regulates Autoreactive Cells of Cell-Mediated Cytotoxicity 367 Circulation 404 Cells Are a Component of Peripheral Tolerance Hypersensitivity Reactions 371 Antigen Sequestration a Means - to Protect Antigens 407 Failure of Tolerance Leads to Autoimmunity 407 Gell and Coombs Classification 371 Autoimmune Diseases 407 (Type I) Hypersensitivity 372 Some Autoimmune Diseases Are Mediated There Are Several Components by Direct Cellular 407 of Type I Reactions 373 Autoimmune Diseases Are Mediated Receptors 376 by or 409 Initiates Degranulation 377 Intracellular Events Trigger Autoimmune Diseases 410 Degranulation 377 Systemic Lupus Erythematosus Attacks Agents 410 Type I Reactions _ Multiple Attacks the Type Reactions Can Be Systemic or ,...,., Central Nervous System 411 Reactions Induce Localized Rheumatoid Arthritis Attacks Joints Inflammatory Reactions 383 Type I Responses Are Regulated for Autoimmune by Many Factors 383 Diseases CLINICAL FOCUS THE GENETICS ASTHMA Autoimmunity Can Develop Spontaneously Several Clinical Methods Are Used 412 to I Hypersensitivity Reactions 386 Autoimmunity Can Be Induced Type I Hypersensitivities Can Be Controlled Medically 386 inanimals 413 Antibody-Mediated Cytotoxic Evidence the Τ Cell, MHC, (Type II) Hypersensitivity 388 TCR in Autoimmunity 413 Transfusion Reactions Are Type II Reactions 388 Τ Cells and Balance Play Disease of the Newborn an Important in Autoimmunity Caused Type II Reactions 389 in Some Animal 414 Hemolytic Autoimmunity Can Be Associated with the a Type II Response 391 MHC or with Particular T-Cell Receptors 414 Immune (Type III) Proposed Mechanisms Hypersensitivity 391 for Induction of Autoimmunity 414 Type III Reactions Can Be Localized 392 Release of Sequestered Antigens Type III Reactions Can Also Be Generalized 392 Can Induce Autoimmune Disease

9 XX C O N T E N T S CLINICAL ARE MORE Clinical Transplantation 440 SUSCEPTIBLE ΜΕΝ AUTOIMMUNITY? GENDER DIFFERENCES IN AUTOIMMUNE DISEASE Transplanted Organ,,, the Kidney 441 Molecular May Contribute to Autoimmune Disease 416 for 441 There Evidence for Mimicry between MBP Operation 442 and Viral Peptides 418 Lung Transplants Are on the Increase 442 Expression of Class II MHC Molecules Defects Can Sensitize Autoreactive Τ Cells 418 Polyclonal B-Cell Activation Can Lead Autoimmune Disease 419 Transplantation of Pancreatic Cells Offers a Cure for Diabetes Mellitus 442 Autoimmune Diseases 419 Skin Grafts Are Used Treat 443 Xenotransplantation May Be the Answer Treatment of Human Autoimmune Disease to the Shortage of Donor Organs 443 Poses Special Challenges 420 Inflammation Target for Treatment of Autoimmunity 420 Activated Τ Cells Are a Possible Therapeutic Target 421 Oral Antigens Can Induce Tolerance Immune Response to Diseases 447 Transplantation Immunology 425 Viral Infections 448 Viruses Are by Antibodies 449 Basis of Graft Rejection 426 Cell-Mediated Immunity Important for Viral Control and Clearance 450 Allograft Rejection Displays Specificity Viruses Can Evade Host Defense 450 and Memory 426 Influenza Has Been Responsible for Some Τ Cells Play a Key in Allograft Rejection 426 of the Worst in History Antigenic Foster The Humoral Response to Influenza Strain Specific 454 Allograft Acceptance 428 Avian H5N1 Presents the Threat Graft Donors and Recipients Are Typed for RBC of a Pandemic 454 and MHC Antigens 428 Cell-Mediated Graft Rejection Occurs 431 Clinical Manifestations of Graft Rejection 433 Bacterial Infections 454 Immune Responses to Extracellular and Intracellular Bacteria Can Differ 455 Bacteria Can Effectively Evade Host Preexisting Recipient Antibodies Mediate Defense Mechanisms 455 Hyperacute Rejection 433 Immune Responses Can Contribute Acute Rejection Mediated T-Cell Responses 434 to Bacterial Pathogenesis 457 Chronic Rejection Occurs Months Diphtheria diphtheriae) or Years 434 Can Be Controlled by with Inactivated Toxoid 458 General Therapy 434 Tuberculosis (Mycobacterium tuberculosis) T-Cell Proliferation 434 Controlled by Cells 458 CLINICAL FOCUS THERE Α CLINICAL FUTURE Parasitic Diseases 460 FOR XENOTRANSPLANTATION? 435 Protozoan Diseases Affect Worldwide 460 Corticosteroids Suppress Inflammation 436 Malaria (Plasmodium Species) Infects 600 Million Metabolites People Worldwide 460 Are Immunosuppressants 436 Total Lymphoid Irradiation Lymphocytes 436 Two Species of Trypanosoma Cause Therapy 436 a Useful Model for Differences in Host Responses 462 Antibodies Can Suppress Graft Rejection Responses 437 Α Variety of Diseases Are Caused Blocking Costimulatory Signals Can Induce Anergy 438 by Parasitic Worms (Helminths) 462 Immune Tolerance to Allografts 439 Fungal Diseases 465 Privileged Antigenic 439 Innate Immunity Controls Most Fungal Infections 466 Exposure to Immunity against Fungal Pathogens Can Induce Specific Tolerance 439 Can Be Acquired 466

10 XXI Emerging Infectious Diseases 467 AIDS and Other Acquired or Secondary,. Immunodeficiencies 504 Diseases May Re-emerge Reasons 467 CLINICAL FOCUS THE THREAT OF INFECTION HIV/AIDS Has Millions of Lives Worldwide 505 FROM POTENTIAL OF BIOTERRORISM 468 Spreads by Sexual Contact, by Infected and from Mother to Infant 505 Some Fatal Diseases Have Appeared Recently 470 The SARS Outbreak a CLINICAL FOCUS PREVENTION OF INFANT Rapid International Response 470 HIV INFECTION TREATMENT 507 The Retrovirus the Causative Agent Vaccines 475 Studies Revealed the Replication Cycle 509 HIV-1 Infection Leads to Opportunistic Infections 512 CLINICAL FOCUS VACCINATION: CHALLENGES THE Therapeutic Agents Inhibit Retrovirus UNITED STATES AND COUNTRIES 476 Replication 515 Active and Passive 477 Vaccine May Be the Way to Stop the HIV/AIDS 518 Passive Immunization Involves Transfer of Antibodies 477 Active Immunization Elicits Long-Term Protection Cancer and the Immune System 525 Vaccines for Active Immunization 481 Vaccines 481 Cancer: Origin and 525 Inactivated or Vaccines 484 Malignant Transformation of Cells 526 Vaccines 484 Oncogenes and Cancer Induction 527 Vaccines 485 Genes Have Many Functions 527 Bacterial Polysaccharide Capsules Are Used as Vaccines 485 Proto-Oncogenes Can Be Converted to Oncogenes 529 Viral Glycoproteins Are Candidate Vaccines 485 induction of Cancer a Process 530 Pathogen Proteins Are Manufactured by Recombinant Techniques 485 Tumors of the Immune System 530 Use of Synthetic Peptides as Vaccines Has Progressed Slowly 485 Conjugate Vaccines 486 Some Antigens Are 532 CLINICAL FOCUS Α VACCINE THAT PREVENTS CANCER 534 One Polysaccharide Confers Protection 535 against Several Fungi 486 Multivalent Subunit Vaccines Confer Tumor Cells 536 Both Cellular and Humoral Immunity DNA Vaccines 488 Important in Tumor Recognition 537 Recombinant Vector Vaccines 488 Tumor Evasion of the Immune System 538 Antibodies Can Tumor Growth AIDS and Other Antibodies Can Antigens 538 Immunodeficiencies 493 Tumor Cells Frequently Express Low Levels of Class I MHC Molecules 538 Tumor Cells May Provide Poor Primary Immunodeficiencies 493 Signals 538 Lymphoid Immunodeficiencies May Involve Β Cells, Cancer 539 Τ Cells, or Both 495 Immunodeficiencies of the Myeloid Lineage Manipulation of Signals Affect Innate Immunity 500 Can Enhance Immunity 539 Complement Defects Result in Immunodeficiency Enhancement of APC Activity or Disease 502 Can Modulate Tumor Immunity 540 Immunodeficiency Disorders Are Treated Cytokine Therapy Can Augment by of the Defective Element 502 Immune Responses to Tumors 540 of Immunodeficiency Monoclonal Antibodies Are Effective Include 503 in Treating Some Tumors 542

11 XXII chain Reaction 22 Systems 546 Quantities of DNA 559 Animal Methods 546 Analysis of DNA Regulatory Sequences 560 DNA Footprinting Identifies the Sites Inbred Strains Can Reduce Experimental Variation 547 Where Proteins Bind DNA 560 Adoptive-Transfer Systems the,.,.....,... Analysis Identifies DNA-Protein Complexes ,...,. Luciferase Assays Measure Activity 562 Cell Culture Systems 547 Gene Transfer into Cells 562 Primary Lymphoid Cell Cultures Are Derived Cloned Genes Transferred into Cultured Cells from or Lymphoid Organs 547,....,, Allow Vitro Analysis of Gene Function 562 Cloned Lymphoid Cell Lines Are Important Tools,,... Cloned Genes Transferred Mouse Embryos ,..,.,,, Allow Analysis of Gene Function 563 Hybrid Lymphoid Cell Lines 550,., Knockout Targeted Are 564 Protein 551 Allows the of an Endogenous Gene 565 RadiolabelingTechniques Allow Sensitive Detection Inducible Gene Targeting, the System, Antibodies 551 Targets Gene Deletion 565 Biotin Labels Facilitate Detection of of Proteins 551 Approach Gel Electrophoresis Separates Proteins for Analyzing of Gene Expression 567 by Size and Charge 551 CLINICAL FOCUS MICROARRAY ANALYSIS X-Ray Crystallography Provides TOOL FOR HUMAN DISEASES 568 Structural Information 553 for Vivo Imaging Recombinant DNA Technology 555 of the Immune System 570 Restriction Cleave DNA Advances in Technology 571 at Precise Sequences 555 DNA Sequences Are Cloned into Vectors 556 Appendix I: CD Antigens Useful to Replicate Defined Sequences of DNA 556 Appendix II: Cytokines A-27 Cloning of cdna and DNA Allows the Isolation of Defined Sequences 556 Glossary DNA Clones Are Selected by Hybridization 558 Answers to Study Questions Southern Blotting Detects DNA of a Given Sequence 559 Northern Blotting Detects 559