Clinical Immunology E-Book

Robert R. Rich; Thomas A. Fleisher; William T. Shearer; Harry W. Schroeder Jr.; Anthony J. Frew; Cornelia M. Weyand

BOOK

Clinical Immunology E-Book

(2018)

Additional Information

Book Details

ISBN: 978-0-7020-7039-6
Edition: 5
Language: English
Pages: 1323
Subjects: Infectious & contagious diseases
Immunology
Mathematics

Abstract

Keep abreast of the latest advances in this complex field with the 5th Edition of Clinical Immunology: Principles and Practice. This substantially revised edition by Drs. Robert R. Rich, Thomas A. Fleisher, William T. Shearer, Harry W. Schroeder, Jr., Anthony J. Frew, and Cornelia M. Weyand, offers authoritative guidance from some of the most respected global leaders in immunology, helping you navigate today’s latest knowledge and evidence-based practices that result in improved patient care. This trusted resource features sweeping content updates, rewritten chapters, a highly clinical perspective, and an easy-to-use organization designed to enhance your diagnosis and management skills in daily practice.

Includes new chapters on the Microbiota in Immunity and Inflammation, Immune Responses to Fungi, and Genetics and Genomics of Immune Response.

Features extensive revisions to many chapters, including the Major Histocompatibility Complex, Multiple Sclerosis, Diabetes and Related Autoimmune Diseases, Biologic Modifiers of Inflammation and Tumor Immunotherapy.

Covers hot topics such as the role of genetics and genomics in immune response and immunologic disease, atherosclerosis, recurrent fever syndromes, aging and deficiencies of innate immunity, the role of microbiota in normal immune system development and the pathogenesis of immunologic and inflammatory diseases, and novel therapeutics.

Addresses notable advances in key areas such as the importance of the microbiota to normal immune system development and to the pathogenesis of immunologic and inflammatory diseases; relationships between the innate and adaptive immune systems; progress in rapid and cost-effective genomics; cell signaling pathways and the structure of cell-surface molecules; and many more.

Summarizes promising research and development anticipated over the next 5-10 years with "On the Horizon" boxes and discussion of translational research.

Section Title	Page	Action	Price
Front Cover	cover
Inside Front Cover	ifc1
Clinical Immunology	i
Copyright Page	ii
Table Of Contents	iii
Preface to the First Edition	vi
Preface to the Fifth Edition	viii
List of Contributors	ix
Dedication	xviii
One Principles of Immune Response	1
1 The Human Immune Response	3
The Host–Microbe Interaction	3
Adaptive and Innate Immunity	3
Cells of the Immune System	4
Granulocytes	4
Lymphocytes	4
Antigen-Presenting Cells	5
Basis of Adaptive Immunity	5
Clonal Basis of Immunological Memory	6
Antigen-Binding Molecules	6
Immunoglobulins and T-Cell Receptors	7
Receptor Selection	7
Immunoglobulin Class Switching	8
Major Histocompatibility Complex	9
Antigen Presentation	9
Lymphocyte Adhesion and Trafficking	10
Lymphocyte Activation	10
Cell-Mediated Immune Responses	11
T-Cell Subsets	11
CD4 T Cells, Cytokines, and Chemokines	11
CD8 T Cells	12
Antibody-Mediated Immune Responses	12
Complement and Immune Complexes	13
Apoptosis and Immune Homeostasis	13
Mechanisms of Immunological Diseases	13
Host Immune Defenses Summarized	14
Multiple-Choice Questions	17.e1
References	16
2 Organization of the Immune System	19
Immune Cell Development	19
Ontogeny of the Cells of the Immune System	19
Tools Essential to an Understanding of Immune Cell Biology	19
Hematopoiesis and Lymphopoiesis	19
Characteristics of Hematopoietic Stem Cells	19
Regulation of Hematopoietic and Lymphopoietic Cell Growth and Differentiation	20
Cytokines That Affect the Growth and Maintenance of Pluripotent and Multipotent Stem Cells	22
Cytokines That Inhibit Hematopoietic Stem Cell Growth	23
Cytokines Affecting Development and Differentiation of Specific Cell Lineages	23
Mature Cells of the Immune System	23
Antigen-Presenting Cells	23
Monocytes–Macrophages	23
Dendritic Cells	24
Polymorphonuclear Granulocytes	24
Neutrophils	24
Eosinophils	25
Basophils and Mast Cells	25
Platelets and Erythrocytes	25
Lymphocytes	25
T Lymphocytes	26
Subpopulations of T Cells	26
B Cells and Plasma Cells	26
Innate Lymphoid Cells	27
Natural Killer Cells	27
Noncytotoxic Innate Immune Cells	27
Major Lymphoid Organs	28
Bone Marrow	28
Thymus	29
Development of Hematopoietic and Lymphoid Cells	30
Secondary Lymphoid Organs	30
Systemic Immune System	30
Spleen	30
Lymph Nodes and Lymphatics	32
Adipose Tissue	32
Mucosal Immune System	33
Gastrointestinal Tract	33
Respiratory Tract	34
Genital Tract	34
Skin	35
Commensal Organisms/Toll-Like Receptors	36
Acknowledgments	36
References	37
Multiple-Choice Questions	38.e1
3 Innate Immunity	39
Barriers to Infection	39
Skin and Mucosa	39
Antimicrobial Proteins and Peptides	40
Humoral Innate Immunity	40
The Acute Phase Response	40
The Complement System	41
Complement Deficiency Diseases	42
Cellular Innate Immunity	42
Polymorphonuclear Leukocytes	42
Intraepithelial Lymphocytes, Innate Lymphoid Cells, B1 and MZ B Cells, and Mast Cells	45
Activating Innate Immunity	46
Pattern Recognition Receptors	46
Toll-Like Receptors	47
NOD-Like Receptors	50
RIG-I–Like Receptors	50
C-Type Lectin Receptors	51
Scavenger Receptors	51
Inflammasomes	51
Innate Immunity in Clinical Practice	52
Multiple-Choice Questions	53.e1
References	52
4 Antigen Receptor Genes, Gene Products, and Coreceptors	55
Paratopes and Epitopes	55
The BCR and TCR Antigen Recognition Complex	55
Immunoglobulins and TCR Structures	56
The Ig Domain, the Basic IgSF Building Block	56
Idiotypes and Isotypes	56
The V Domain	56
Antigen Recognition and Fab	56
Effector Function and Fc	56
Gm Allotype System	57
Ig Classes and Subclasses	57
IgM	58
IgG	58
IgA	58
IgE	58
IgD	58
TCR αβ and γδ	59
TCR αβ	59
TCR γδ	59
Ligand Recognition	59
Binding to pMHC	60
TCR Binding Affinity	60
Atypical Antigens	60
Superantigens	60
Immunoglobulin Gene Organization	60
The κ Locus	63
The λ Locus	63
The H Chain Locus	63
Class-Switch Recombination	64
Somatic Hypermutation	65
Activation-Induced Cytidine Deaminase	65
Diversity and Constraints on Immunoglobulin Sequence	65
The TCR αδ Chain Locus	65
The TCR β Chain Locus	65
The TCR γ Chain Locus	66
Allelic Exclusion	66
B Cell Receptor Complex: Structure and Function	67
Membrane-Bound Immunoglobulin	67
Signal Transduction and the Ig-α/β (CD79a/CD79b) Heterodimer	67
Clinical Consequences of Disruptions in BCR Signaling	68
BCR Coreceptors	69
Coreceptors That Positively Regulate BCR Signaling	69
CD21	69
CD19	69
CD21–CD19 Coreceptor Complex	69
Coreceptors That Negatively Regulate BCR Signaling	70
FcγRIIB	70
CD22	70
The TCR–CD3 Complex	71
CD3 Proteins	71
Stoichiometry of the TCR–CD3 Complex	72
Assembly and Cell-Surface Expression of the TCR–CD3 Complex	72
Early Events in TCR–CD3 Signaling	73
T-Cell Coreceptors: CD4 and CD8	73
CD4: Structure and Binding to MHC Class II Molecules	73
CD8: Structure and Binding to MHC Class I Molecules	73
Costimulatory and Inhibitory T-Cell Molecules: the CD28 Family	74
CD28 and CTLA-4	75
PD-1	75
Multiple-Choice Questions	77.e1
References	76
5 The Major Histocompatibility Complex	79
Genomic Organization of the MHC	79
Structure and Function of the HLA Molecules	80
Classic HLA Class I Molecules	81
MICA and MICB	82
Nonclassic HLA-E, HLA-F, and HLA-G	82
Classic Class II HLA Molecules	83
Nonclassic HLA-DM and HLA-DO	83
Proteosome Elements Within the Class II Region	83
Principles of Peptide Presentation	83
Selection by Self Peptides in the Thymus	84
Evolutionary Considerations Driving the Separate Functions of Class I and Class II	84
Generation and Selection of Polymorphisms: Biological Consequences	85
Hlas in Infections, Transplantation, Autoimmunity, and Cancer	85
HLA in Infections	85
HLA in Transplantation	86
HLA in Autoimmunity	86
HLA in Cancer	86
HLA and Disease Associations	86
Ankylosing Spondylitis	87
Narcolepsy	87
Type 1 Diabetes	88
Rheumatoid Arthritis	88
Multiple Sclerosis	88
Celiac Disease	88
Drug Hypersensitivity and Pharmacogenomics	89
Carbamazepine	89
Nevirapine	89
Abacavir	89
Methods of Detecting HLA Polymorphisms: HLA Typing	89
DNA-Based Typing Techniques: SSO, SSP, and SBT	89
Next-Generation Sequencing	90
HLA Nomenclature	91
Future Learning and Resources	92
Multiple-Choice Questions	92.e1
References	92
6 Overview of T-Cell Recognition	93
Antigens	93
Antibodies and T-Cell Receptors Recognize Antigens	93
Innate Receptors Recognize Pathogen-Associated Molecular Patterns or Danger Signal Ligands	93
The Nature of Antigen Recognition by Immunoglobulin and T-Cell Receptor Differs	94
Antigens for B Cells	94
Coupling of B-Cell and T-Cell Epitopes Permits Highly Focused Adaptive Responses	95
Superantigens	95
Antigen-Presenting Cells	96
Cells That Present Antigens to B Cells: Follicular Dendritic Cells	96
Cells That Present Antigens to T Cells	96
MHC-Restricted Recognition of Antigen	96
Class I MHC	96
Class II MHC	97
MHC Class II Antigen Presentation	97
Invariant Chain	98
Class II Peptide Loading	99
HLA-DM and Peptide Exchange	99
Selection of Immunodominant Peptides	99
HLA-DO	100
Targeting of Antigen into the MHC Class II Processing Pathway	100
MHC Class I–Restricted Antigen Presentation	101
The Proteasome	101
Import of Antigenic Peptides Into the Endoplasmic Reticulum and Final Trimming	102
The Peptide Loading Complex	102
Cross-Presentation of Antigens for Recognition by CD8 T Cells	102
The MHC-Presented Peptidome	103
Cryptic Viral or Tumor-Associated Peptides Presented by MHC Class I Molecules	104
Pathogen Evasion Strategies	104
Tumor Escape From Immune Surveillance	105
Potential Role of “Peptide Editing” of Presented Peptides on Self Tolerance and Autoimmunity	105
Summary	105
Acknowledgement	105
Multiple-Choice Questions	106.e1
References	105
7 B-Cell Development and Differentiation	107
B-Cell Development Begins in the Primary Lymphoid Organs	109
Generation of a Functioning Antigen Receptor Is Key to the Viability of a B Cell	109
Tyrosine Kinases Play Key Roles in B-Cell Development	109
Cell Surface Antigens Associated With B-Cell Development	109
Transcription Factors Controlling B-Cell Differentiation	111
MicroRNAs and B-Cell Development	112
Modulation of B-Cell Development by Chemokines, Cytokines, and Hormones	112
B-Cell Development in the Periphery	113
BAFF and APRIL Can Play Key Roles in the Development of Mature B Cells	113
B Cells and the Response to Antigen	113
T Cell–Independent Antigens	113
T Cell–Dependent Antigens	113
Organization of Peripheral Lymphoid Tissues	113
The Spleen	114
B-1 Cells	114
Germinal Centers	115
B-Cell Functions in Addition to Antibody Production	115
Molecular Mechanism of Somatic Hypermutation and Class-Switch Recombination	115
Somatic Hypermutation	115
Class-Switch Recombination	115
Both SHM and CSR Require Activation-Induced Cytidine Deaminase	116
B-Cell Memory	117
Memory B Cells	117
Plasma Cells	117
Ectopic Lymphoid Tissue and B-Cell Development	117
Multiple-Choice Questions	118.e1
References	118
8 T-Cell Development	119
Thymus: the Site of T-Cell Development	119
Lineage Commitment	120
The Common Lymphoid Progenitor	120
The Early Thymic Progenitor	120
Double-Negative Thymocytes	120
Fate Commitment	121
Transcriptional Regulation of Commitment to T-Cell Lineage	121
Notch	121
Notch Ligand	121
T-Cell Factor 7	121
Enhancer Binding Protein GATA-3	121
B-Cell Chronic Lymphocytic Lymphoma/ Lymphoma 11B (Bcl11b)	122
T-Cell Receptor Rearrangement and β Selection	122
γδ T cells	122
αβ T cells	122
β Selection and the Appearance of Double-Positive Thymocytes	122
Positive and Negative Selection	122
Positive Selection	122
Negative Selection	123
Role of the Major Histocompatibility Complex in Negative Selection and Positive Selection	123
CD4 and CD8 T-Cell Determination	123
Transition From Double-Positive to Single-Positive CD4 or CD8 Thymocytes	123
Factors That Dictate CD4 Versus CD8 Commitment	124
Migration of Thymocytes Into the Periphery	124
Multiple-Choice Questions	125.e1
References	124
9 Cytokines and Cytokine Receptors	127
Cytokine Classification	127
Type I and II Cytokine Receptors (Hematopoietin Family and Interferon Receptors)	127
Ligand and Receptor Structure	127
Family Members and Their Actions	131
Homodimeric Receptors	131
Cytokine Receptors Utilizing gp130	132
Interleukin-6.	132
Interleukin-11.	132
Interleukin-27.	132
Cytokine Receptors Utilizing the βc Chain	132
Interleukin-3.	132
Interleukin-5.	132
Granulocyte macrophage–colony-stimulating factor.	132
Cytokine Receptors Utilizing the γc Chain	133
Interleukin-2.	133
Interleukin-4.	133
Interleukin-7.	134
Interleukin-9.	134
Interleukin-15.	134
Interleukin-21.	134
Other Heterodimeric Receptors	134
Interleukin-12.	134
Interleukin-23.	135
Interleukin-35.	135
Interleukin-13.	135
Interleukin-31.	135
Thymic stromal lymphopoietin.	135
Interferons	135
Type I Interferons	135
Interferon-α/β.	135
Interferon-γ.	135
Interleukin-10 and related cytokines.	136
Signaling	136
Janus Kinases	136
Signal Transducer and Activator of Transcription (STAT)	136
Attenuation of Type-I and Type-II Cytokine Signaling	137
The TNF Cytokine and Receptor Superfamily	137
Ligand and Receptor Structure	137
Family Members and Their Actions	138
Tumor Necrosis Factor, Lymphotoxin-α, and Receptors	138
Fas Ligand and Its Receptor Fas/APO-1/CD95	138
CD40 Ligand and CD40	143
Other TNF-Family Cytokines	143
Signaling	143
Death Domains: TNF Receptor-Associated Death Domain and FAS-Associated Death Domain	144
Clinical Relevance	145
Interleukin-1/Toll-Like Receptor Family	145
Ligand and Receptor Structure	145
Family Members and Their Actions	145
Interleukin-1	145
Interleukin-18	146
Interleukin-33	146
Interleukin-36	146
Interleukin-37	146
Interleukin-38	146
Other Members of the Interleukin-1 Family	146
Two Host Defense Mechanisms and Inflammation	221
15 Immunoglobulin Function	223
Antigen Binding and Molecular Identity	223
Physical Aspects of Binding	223
Immunological Specificity	225
Protein Epitopes	226
Carbohydrate Epitopes	227
Immune Complexes in vivo	227
Correlations Between CH Region Structure and Antibody Function	228
Functions Mediated by Antibody Alone	228
Virus Neutralization	228
Neutralization of Toxins and Enzymes	229
Functions Mediated by Antibody and Additional Molecules or Cells	229
Complement Activation	229
Receptors for Fc Regions	230
Antibodies as Surrogate Ligands	230
Functional Properties of Engineered Antibody Molecules	231
Monoclonal Antibodies	231
Recombinant Antibodies	232
Multiple-Choice Questions	233.e1
References	233
16 Helper T-Cell Subsets and Control of the Inflammatory Response	235
Activation	235
Clonal Expansion	236
Trafficking	237
Differentiation of CD4 Th Subsets	237
Naïve T Cells	237
Effector Cell Phenotypes	237
Th1	237
Th2	238
Th17	240
Th9	241
Th22	241
Regulatory T Cells	241
Adaptive Tregs	241
Tr1 Cells	241
Follicular Helper T Cells (Tfh)	242
Memory T Cells	242
General Considerations in Effector T-Cell Differentiation	242
Termination of T-Cell Responses	243
Cell Death Pathways in T-Cell Homeostasis	243
Action of Inhibitory Receptors	244
Cytokine-Mediated Inhibition	244
Summary of Therapeutic Regulation of T-Cell Responses for Treatment of Immune-Mediated Diseases	245
Multiple-Choice Questions	245.e1
References	245
17 Cytotoxic T Lymphocytes and Natural Killer Cells	247
Effector Functions/Mechanisms	247
Cytotoxicity	247
Perforin–Granzyme Pathway	248
Death Receptor–Induced Apoptosis	248
Cytokines	248
Cytotoxic T Cells	249
The Development and Tissue Distribution of CTLs	249
The CTL Response	249
Initial Activation	249
Cross-Presentation and Priming	250
The Contraction of Effector Populations	250
The Long-Term Maintenance of Memory Cells	251
CD4 T-Cell Help	251
Detection and Analysis of CTL Function	251
Natural Killer Cells	251
Properties of NK Cells	251
Tissue Distribution and Diversity of NK Cells	252
Cytokine Regulation of NK-Cell Activation, Function, and Homeostasis	253
NK-Cell Receptors	253
NK-Cell Receptor Signaling	254
NK Receptors That Recognize MHC-I Molecules	254
Killer Cell Immunoglobulin-Like Receptors in Humans	254
The Ly49 Family in Rodents	255
CD94 and NKG2 Family	255
NKG2D	255
NK Cell Receptors That Recognize Non-MHC I Molecules	255
NK-Cell Licensing and Self-Tolerance	255
Specific NK-Cell Functions	256
Control of Viral Infections	256
Control of Malignant Cells	256
Role of NK Cells in Hematopoietic Stem Cell Transplantation	256
NK-Cell Memory	257
Interactions of CTL and NK Cells in the Immune Response	257
Evasion of the Cytotoxic Response	257
Viruses	257
Tumor Cells	258
Multiple-Choice Questions	259.e1
References	258
18 Regulatory Immune Cells	261
CD4 Regulatory T Cells	262
Thymus-Derived Regulatory T Cells	262
Thymus-Derived Tregs Express the Transcription Factor Foxp3	263
Maintenance of Foxp3+ Tregs	265
Suppressive Function of Foxp3+ Tregs	266
Tr1 Cells	267
Other Subsets of Foxp3− Regulatory T Cells	267
Suppressive Non–T Cells	268
Clinical Relevance of Regulatory T Cells	268
Autoimmunity	269
Allergic Disease	269
Transplantation	269
Tumor Immunity	269
Infectious Disease	270
Translational Research	270
Multiple-Choice Questions	271.e1
References	271
19 Host Defenses in Skin	273
Innate Immunity and Skin	275
Pattern Recognition Receptors	275
Cutaneous Production of Cytokines and Chemokines	276
Types of Cytokines and Chemokines	276
Phases of Active Cutaneous Cytokine Secretion	276
Initiation.	276
Amplification.	276
Resolution.	277
Antimicrobial Peptides	277
Adaptive Immunity and Skin	277
Dendritic Cells	277
Epidermal Langerhans Cells	278
Dermal Dendritic Cells	279
T Cells and Immune Responses in Skin	279
Phases of the Cell-Mediated Immune Response in Skin	279
Sensitization/immunization phase.	280
Elicitation/effector phase.	280
Skin Resident T-Cell Subpopulations	280
Th1 responses.	281
Th2 responses.	281
Th17 responses.	281
Regulatory T cells.	281
CD8 T-cell immunity.	281
γδ T cells.	281
Cytokines and Chemokines and the Adaptive Immune Response in Skin	281
Mast Cells and Skin	282
Antibodies and Skin	282
Ultraviolet Radiation and Cutaneous Immunity	282
Multiple-Choice Questions	283.e1
References	283
20 Host Defenses at Mucosal Surfaces	285
The Innate Mucosal Defense System	285
Epithelial Cells and Other Effectors of the Mucosal Physical Barrier	285
Defensins and Other Mucosal Antimicrobial Peptides	285
Mucosal Innate Lymphoid Cells	287
A Common Mucosal Adaptive Immune System	287
MALT as an Inductive Site	287
Gut-Associated Lymphoreticular Tissues	287
Nasal-Associated Lymphoid Tissues	288
Other Sites for Mucosal Induction of an Immune Response	288
Lymphocyte Homing Into Mucosal Compartments	288
Lymphocyte Homing in the GI Tract	290
Lymphocyte Homing in NALTs and Lung-Associated Tissues	291
The Common Mucosal Immune System Revisited	291
Induction of Mucosal Immunity	291
Mucosal Antigen-Presenting Cells	291
CD4 T-Helper Cell Subsets in Mucosal Immunity	291
B-Cell Isotype Switching and IgA Plasma Cell Differentiation	293
Vaccine Development and Mucosal Immune Responses	293
Lessons From Studies of Bacterial Enterotoxins	293
Cellular Targets of Vaccine Adjuvants Can Shape the Immune Response	293
Central Nervous System Targeting Is a Safety Concern With Nasal Vaccines	293
New Mucosal Adjuvants and Delivery Systems	294
Nontoxic Derivatives of Bacterial Enterotoxins	294
Nucleic Acid Toll-Like Receptor Ligands	294
Mucosal Cytokines and Innate Factors as Adjuvants	294
Transgenic Plants	294
Synthesis and Functions of Secretory Antibodies	295
Polymeric Immunoglobulin Receptor and plgA Transport	295
IgA-Mediated Inhibition of Microbial Adherence	295
Neutralization by sIgA of Viruses, Enzymes, and Toxins	295
Antiinflammatory Actions Mediated by SIgA Antibodies	295
IgA Deficiency	295
Mucosal CTLs	296
Enteric Viruses and Mucosal CTLs	296
Respiratory Viruses and Mucosal CTLs	296
Mucosal AIDS Models for CTL Responses	296
Other Mucosal CTL Systems	296
Mucosal Immune Responses in Early Life and Aging	296
Multiple-Choice Questions	298.e1
Correct Order:	298.e1
References	297
21 The Human Complement System:	299
Overview: an Evolutionary and Historical Perspective	299
Complement Pathways	301
Classical Pathway	302
Lectin Pathway	302
Alternative Pathway	303
Membrane Attack Complex	303
Regulation of Complement Activation	303
C1 Esterase Inhibitor	303
Regulators of the C3 and C5 Convertases	303
Factor I	304
Soluble Regulatory Proteins, C4b-Binding Protein, and FH	304
Membrane Regulatory Proteins	304
Properdin	304
Regulators of the Membrane Attack Complex	304
Soluble MAC Inhibitors: Vitronectin and Clusterin	304
Membrane MAC Inhibitor CD59	304
Complement Receptors	304
C1q Receptors	305
Complement Receptor 1 (CR1, CD35)	305
Complement Receptor 2 (CR2, CD21)	305
Complement Receptors 3 and 4	306
Complement Receptor of the Immunoglobulin Superfamily (CRIg)	306
C5a and C3a Receptors	306
Complement in Host Defense and Immunity	306
Complement in Host Defense	306
Complement in Inflammation	307
Pathogen Evasion of Complement	307
Role of Complement in Adaptive Immunity	307
Effects of Complement on the Humoral Immune Response	307
Complement and T-Cell Activation	308
Role of Complement in Clearance of Apoptotic Cells	308
Targeted Activation of Complement for Opsonization	309
Complement Deficiencies	309
Genetics and Incidence	309
CP Deficiencies	309
C1 Deficiency	309
C4 Deficiency	310
C2 Deficiency	310
LP Deficiencies	311
AP Deficiencies	311
C3 Deficiencies	311
Acquired C3 Deficiency: Genetic Deficiencies of FH and FI and C3 and C4 Nephritic Factors	311
Deficiencies of Complement Receptors	311
Deficiencies of CR1 (CD35) and CR2 (CD21)	311
Leukocyte Adhesion Deficiency: CR3 and CR4 Deficiency	311
Deficiencies of Regulatory Proteins	311
Hereditary Angioedema: C1-INH Deficiency	311
Paroxysmal Nocturnal Hemoglobinuria: DAF and CD59 Deficiency	312
Control of Localized Complement Activation: Atypical Hemolytic–Uremic Syndrome, Age-Related Macular Degeneration	312
Complement in Disease	312
Measurement of Complement in a Clinical Setting	312
Role of Complement in Specific Immunological Diseases	313
Systemic Lupus Erythematosus (Chapter 51)	313
Antiphospholipid Syndrome (Chapter 61)	313
Rheumatoid Arthritis (Chapter 52)	314
Vasculitis (Chapters 58, 59)	314
Immunological Renal Diseases (Chapter 68)	314
Asthma (Chapter 41)	314
Neurological Disease	314
Ischemia/Reperfusion Injury	315
Complement-Based Therapeutics	315
Multiple-Choice Questions	317.e1
References/Bibliography	315
22 Phagocyte Deficiencies	319
Neutrophils	319
Production of Macrophages and Granulocytes	319
Evolution of Neutrophil Granules	319
Disorders of Neutrophil Production	319
Severe Congenital Neutropenia and Cyclic Neutropenia	319
Shwachman-Bodian-Diamond Syndrome	321
Autoimmune Neutropenia	321
Primary Autoimmune Neutropenia	321
Secondary Autoimmune Neutropenia	321
Alloimmune Neonatal Neutropenia	321
Defects of Leukocyte Adhesion	321
Leukocyte Adhesion Defect-1	322
Leukocyte Adhesion Defect-2	323
Leukocyte Adhesion Defect-3	323
Chronic Granulomatous Disease	323
The NADPH Oxidase and Its Activity	324
Mutations Leading to CGD	324
X-Linked CGD	324
Autosomal Recessive CGD	325
Clinical Manifestations of CGD	325
Diagnosis of CGD	326
Treatment of CGD	326
Myeloperoxidase Deficiency	327
Primary MPO Deficiency	327
Secondary or Acquired MPO Deficiency	328
Specific Granule Deficiency	328
Chediak-Higashi Syndrome	328
Hyper-IgE Recurrent Infection, or Job’s Syndrome	329
Facial, Skeletal, and Dental Abnormalities	329
Infections and Immunological Characteristics	329
DOCK8 Deficiency (Autosomal Recessive Hyper-IgE Syndrome)	330
GATA2 Deficiency (Monomac Syndrome)	330
Assessment of Neutrophil Function	330
Isolation of Neutrophils	330
Neutrophil Adherence	330
Neutrophil Chemotaxis	331
Expression of Surface Antigens	331
Neutrophil Degranulation	331
Generation of Reactive Oxygen Species	331
Western Blot for Determination of NADPH Oxidase Defect	332
Translational Research	332
Acknowledgment	332
Multiple-Choice Questions	333.e1
References	332
23 Mast Cells, Basophils, and Mastocytosis	335
Development and Distribution of Mast Cells	335
Mast Cell Development and Survival	335
Homing, Distribution, and Heterogeneity of Mast Cells	336
Development and Distribution of Basophils	337
Biological Mediators Produced by Mast Cells and Basophils	338
Preformed Mediators	338
Newly Synthesized Mediators	338
Cytokines, Chemokines, and Growth Factors	339
Mechanisms of Activation of Mast Cells and Basophils	339
FcεRI-Mediated Activation (and Inhibition of IgE-Dependent Activation)	339
Non–IgE-Mediated Activation	339
Mast Cells and Basophils in Disease and Host Defense	340
Allergic Disease	340
Anaphylaxis	340
Asthma	341
Allergic Rhinitis	342
Atopic Dermatitis	342
Mast Cells and Basophils in Immunity	342
Mast Cells in Other Diseases	342
Mast Cell Roles in Normal Physiology	342
Mastocytosis and Other Mast Cell Disorders	342
Epidemiology	343
Pathogenesis	343
Clinical Features	343
Classification	343
Diagnosis	345
Treatment	345
Prognosis	346
Summary and Future Research Directions	346
Multiple-Choice Questions	347.e1
References	346
24 Eosinophils and Eosinophilia	349
Production and Distribution of Eosinophils	349
Eosinophilopoiesis	349
Eosinophil Adherence Mechanisms	349
Eosinophil Chemoattractants	350
Structure of Eosinophils	350
Cell-Surface Receptors and Proteins	351
Constituents of Eosinophils	351
Cationic Granule Proteins	351
Cytokines and Chemokines	352
Activated Eosinophils	352
Mechanisms of Eosinophil Degranulation	352
Functions of Eosinophils	352
Roles in Host Defense	353
Roles in Disease Pathogenesis	353
Other Eosinophil Functions	353
Eosinophilia and Eosinophilic Disorders	353
Infectious Diseases Associated With Eosinophilia	354
Helminth Parasites	354
Other Infections: Protozoa and Fungi	355
Human Immunodeficiency Virus and Retroviral Infections	355
Allergic Diseases Associated With Eosinophilia	355
Myeloproliferative and Neoplastic Disease	355
Hypereosinophilic Syndromes	355
Eosinophilia With Tumors or Leukemias	358
Organ System Involvement and Eosinophilia	358
Pulmonary Eosinophilias	358
Skin and Subcutaneous Diseases	359
Gastrointestinal Diseases	359
Rheumatological Disorders	359
Immunological Disorders	359
Endocrine Diseases	360
Other Causes of Eosinophilia	360
Evaluation of Eosinophilia	360
Multiple-Choice Questions	361.e1
References	360
Three Host Defenses to Infectious Agents	363
25 Host Defenses to Viruses	365
Viral Entry and Infection	365
Innate Immunity to Viruses	365
Adaptive Immunity to Viruses	367
Immunological Memory	369
Immune Evasion and Immunity to Chronic Viral Infections	370
Outcomes of Virus Infection: Immunity or Immunopathology	371
Immunopathology and Autoimmunity	371
Translational Research Opportunities	373
Conclusions	373
Acknowledgments	373
Multiple-Choice Questions	374.e1
References	373
26 Host Defenses to Intracellular Bacteria	375
Balance of Protection and Pathology Defines the Chronic Nature of Intracellular Bacterial Infection	375
Intracellular Bacterial Infections of Clinical Relevance (Table 26.1)	376
Granulomatous Infections	376
Tuberculosis	376
Leprosy	377
Atypical Mycobacterial Infections	377
Typhoid or Enteric Fever	377
Gastroenteritis	377
Listeriosis	377
Brucellosis	377
Lymphogranuloma Venereum	377
Melioidosis	377
Tularemia	377
Nongranulomatous Infections	378
Legionnaires’ Disease or Legionellosis	378
Chlamydial Urethritis, Cervicitis, and Conjunctivitis	378
Trachoma	378
Chlamydia Pneumoniae	378
Typhus	378
Rocky Mountain Spotted Fever, Ehrlichiosis	378
Bartonella	378
Granuloma Pathology as Hallmark of Intracellular Bacterial Infection	378
The Interdependence of Innate and Adaptive Immunity in Protection Against Intracellular Bacteria	379
Innate Immune Mechanisms as First-Line Defense	379
Macrophage Training by Epigenetic Mechanisms	381
Cytokines as Mediators of Defense Against Intracellular Bacteria	381
IFN-γ, TNF-α, IL-12, and IL-18	381
Proinflammatory Cytokines and Phagocyte Attraction	382
Cytokine-Induced Host-Protective Mechanisms	382
Effector Molecules	382
Apoptosis and Autophagy	383
Nutrient Deprivation	383
Evasion From, Interference With, and Resistance to Microbial Killing	383
Strategies Against Toxic Effector Molecules	383
Intraphagosomal Survival	384
Phenotypic Plasticity of the Infected Cell	384
Escape Into Cytoplasm	385
T Lymphocytes as Specific Mediators of Acquired Resistance	385
CD4 T Cells	385
CD8 T Cells	387
Unconventional T Cells	387
T-Cell Memory and Regulation of Immune Responses	387
B Cells	387
Regulatory T Cells	388
Concluding Remarks	388
Acknowledgments	388
Multiple-Choice Questions	389.e1
References	388
27 Host Defenses to Extracellular Bacteria	391
Clearance and Nonspecific Host Defenses at Mucosal Epithelial Surfaces	391
Normal Microbiota as Host Defense	393
Antimicrobial Peptides and Antimicrobial Proteins	393
Recognition of Extracellular Bacteria and Activation of the Immune System	394
Pattern Recognition Receptors	394
Complement	395
Dendritic Cells	395
Macrophages	395
Polymorphonuclear Leukocytes	395
Innate Lymphoid Cells	396
Lymphocytes	396
Immunoglobulins	397
Mechanism of Immune Evasion and Disease by Extracellular Bacteria	397
Host Risk Factors for Local and Systemic Invasion by Extracellular Pathogens	398
Deleterious Host Responses	399
Inflammation and Autoimmunity	399
Sepsis	399
Enhancement of Immune Responses to Extracellular Bacteria (Vaccines and Immunomodulation)	400
Translational Research Opportunities	401
Multiple-Choice Questions	402.e1
References	401
28 Host Defenses to Spirochetes	403
Clinical Manifestations	403
Lyme Disease	403
Four Immunological Deficiencies	449
32 Approach to the Evaluation of the Patient With Suspected Immunodeficiency	451
Epidemiology—Primary Immunodeficiencies Are Not Uncommon	451
Primary Versus Secondary Immunodeficiency	451
Evaluating Patients for Immunodeficiency	451
Exploring the Medical History	452
Age and Environment	452
Immunization and Previous Infections	452
Comorbid Conditions	453
Use of Medications	453
Family and Social Histories	453
Physical Examination Findings	454
Laboratory Testing for Immune Function	454
Immunology Testing	454
Serum Immunoglobulin Levels	454
B-Cell Function: Specific Antibody Production	455
Evaluation of Cellular Immunity	455
Lymphocyte subset enumeration.	456
B-cell panels and NK-cell panels.	456
Lymphocyte functional analysis.	456
Phagocytes	457
Complement	457
Innate Immunity: Interferon-γ Levels, Toll-Like Receptor Assay	457
Molecular Testing for Primary Immune Defects	458
Conclusions	458
Illustrative Cases	458
Case 1	458
Case 2	459
Case 3	459
Case 4	460
Multiple-Choice Questions	461.e1
References	461
33 Human Genomics in Immunology	463
Genome Annotation	463
Human Variation	463
Clinical Impact of Human Variation	465
Comparative Genomics	465
Functional Genomics	466
Applying Human Genomics to Understanding Disorders of the Human Immune System	467
Multiple-Choice Questions	470.e1
References	470
34 Primary Antibody Deficiencies	471
Clinical Manifestations	471
Principles of Diagnosis and Treatment	472
Diagnostic Tests and Their Interpretation	472
Replacement Therapy With Human Immunoglobulin	475
X-Linked Agammaglobulinemia	476
Diagnosis	476
Clinical Manifestations	476
Origin and Pathogenesis	476
Treatment and Prognosis	477
Autosomal Agammaglobulinemia	477
Origin and Pathogenesis	477
The Pre–B-Cell Receptor and Signal Transduction Axis	477
TCF3	477
LRRC8	477
PIK3R1	477
Diagnosis and Treatment	477
Hyper-IgM Syndrome	477
Diagnosis	477
HIGM Syndrome Type 1: CD40L (CD154) Deficiency	477
HIGM Syndrome Type 2: AID Dysfunction	477
HIGM Syndrome Type 3: CD40 Deficiency	477
HIGM Syndrome Type 4: As yet Unknown Causes	478
HIGM Syndrome Type 5: UNG Deficiency	478
NEMO	478
Clinical Manifestations	478
CD40-CD154 Axis (HIGM1, HIGM3, NEMO)	478
AID–UNG Axis (HIGM2 and HIGM5)	478
Origin and Pathogenesis	478
CD40–CD154 Axis (HIGM1, HIGM3, and NEMO)	478
Treatment and Prognosis	479
Selective IgA Deficiency	479
Diagnosis	479
Clinical Manifestations	479
Origin and Pathogenesis	480
Treatment and Prognosis	480
Common Variable Immunodeficiency and CVID-Like Disorders	480
Diagnosis	480
Clinical Manifestations	481
Origin and Pathogenesis	481
The Major Histocompatibility Complex	482
The CD19 (CVID3), CD81 (CVID6), CD21 (CVID7) B-Cell Coreceptor Complex	482
The BAFF–BAFFR (CVID4)–TACI (CVID2) Axis	482
CD20 (CVID5)	482
ICOS (CVID1)	482
The LRBA (Cvid8)–CTLA-4 Axis	482
PKCδ Deficiency	482
TWEAK Deficiency	483
NF-κB1 (CVID12) and NF-κB2 (CVID10) Deficiency	483
PI3K Mutations	483
Other Genes: BLK, IRF2BP2, IKAROS	483
Kabuki Syndrome	483
Treatment and Prognosis	483
Selective IgG Subclass Deficiencies	484
Diagnosis	484
Clinical Manifestations	484
Origin and Pathogenesis	485
Treatment and Prognosis	485
Antibody Deficiency With Normal Serum Immunoglobulin Levels	485
Selective Light-Chain Deficiency	485
Transient Hypogammaglobulinemia of Infancy	485
Diagnosis	485
Clinical Manifestations	485
Treatment and Prognosis	486
Frontiers in Research	486
Multiple-Choice Questions	487.e1
References	486
35 Primary T-Cell Immunodeficiencies	489
T-Cell Immunodeficiencies	489
Severe Combined Immunodeficiency	489
Combined Immunodeficiency	489
Omenn Syndrome	489
Severe Combined Immune Deficiency	490
SCID With T-Cell Lymphopenia (T−B+)	490
γc (IL-2Rγ) Deficiency	490
JAK3 Deficiency	490
IL-7Rα Deficiency	491
CD45 Deficiency	491
CD3–TCR Complex Defects	493
SCID With T-Cell Lymphopenia and Syndromic Features	493
Coronin-1A Deficiency	493
FOXN1 Deficiency (Combined Immunodeficiency With Alopecia Totalis)	493
SCID With T-Cell and B-Cell Lymphopenia (T−B−)	493
RAG1/2 Deficiency	493
Artemis Deficiency	494
SCID With T-Cell and B-Cell Lymphopenia (T−B−) and Syndromic Features	494
DNA-PKcs Deficiency	494
DNA Ligase IV Deficiency	495
Cernunnos Deficiency	495
AK2 Deficiency (Reticular Dysgenesis)	495
Adenosine Deaminase Deficiency	495
Combined Immunodeficiency (SCID Phenotype)	495
ZAP-70 Deficiency	495
MHC Class II Deficiency (Bare Lymphocyte Syndrome)	496
MHC Class I Deficiency	496
DOCK2 Deficiency	496
CD3γ Deficiency	496
CARD11/BCL10/MALT1 (CBM) Complex Deficiencies	497
Combined Immunodeficiency (SCID Phenotype) and Syndromic Features	497
TTC7A Deficiency (MIA Syndrome)	497
Calcium Channel Defects (ORAI-1, STIM-1 Deficiencies)	497
Combined Immunodeficiencies With Variable Severity (Non-SCID)	497
Combined Immunodeficiency With Immune Dysregulation	497
IL-2Rα (CD25) Deficiency	497
FOXP3 Deficiency	498
IL-10 and IL-10Rα and IL-10Rβ Deficiencies	498
IKK2 Deficiency	498
DOCK8 Deficiency	499
RHOH Deficiency	499
Combined Immunodeficiency With EBV-Induced Lymphoproliferation	499
Combined Immunodeficiency With Immune Dysregulation and Syndromic Features	499
PNP Deficiency	499
DiGeorge Syndrome	499
Wiskott-Aldrich Syndrome	500
Ataxia Telangiectasia (Louis-Bar Syndrome)	500
Combined Immunodeficiency With Immunoosseous Dysplasia	500
Cartilage Hair Hypoplasia	500
Schimke Immunoosseous Dysplasia	501
Roifman Syndrome	501
SPENCDI–Roifman Immunoskeletal Syndrome	501
Combined Immunodeficiency With Bone Marrow Failure	501
IKAROS Deficiency	501
Dyskeratosis Congenita	502
Moesin Deficiency (MSN Deficiency)	502
Progressive T-Cell or Combined Immunodeficiency	502
STAT1 Dysfunction	502
RelB Deficiency	503
STK4 (Mst1) Deficiency	503
Diagnosis, Management, and Treatment of T-Cell and Combined Immunodeficiency	503
Newborn Screening	503
Isolation	503
Hematopoietic Stem Cell Transplantation	504
Donor Source	504
Conditioning	504
Prophylaxis and Treatment of Graft versus Host Disease	504
Gene Therapy	504
Gene Editing	505
Conclusions	505
References	505
Multiple-Choice Questions	508.e1
36 Immunodeficiencies at the Interface of Innate and Adaptive Immunity	509
Mendelian Susceptibility to Mycobacterial Disease: Genetic Disorders of the IFN-γ Circuit	509
Complete IFN-γR1 and IFN-γR2 Deficiencies	509
Autosomal Recessive Partial IFN-γR1 and IFN-γR2 Deficiencies	510
Autosomal Dominant Partial IFN-γR1 and IFN-γR2 Deficiencies	511
Complete IL-12Rβ1 and IL-12P40 Deficiencies	511
Autosomal Dominant Partial STAT1 Deficiency	512
Complete and Partial IRF8 Deficiency	513
AR Complete ISG15 Deficiency	513
AR Complete TYK2 Deficiency	513
NEMO and CYBB Deficiencies	514
Inherited Disorders of IFN-γ– and IFN-α/β–Mediated Immunity	514
AR Complete and Partial STAT1 Deficiency	514
Genetic Disorders of the TLR3–IFN-α, IFN-β, and IFN-λ Pathway	514
TLR3 Deficiency	514
UNC-93B Deficiency	515
TRIF Deficiency	515
TRAF3 Deficiency	516
TBK1 Deficiency	516
IRF3 Deficiency	516
IRF7 Deficiency	516
Genetic Disorders of NF-κB–Mediated Immunity	517
NEMO Deficiency	517
IκBα Deficiency	517
IL-1 Receptor–Associated Kinase-4 Deficiency	518
MYD88 Deficiency	518
HOIL1 Deficiency	519
HOIP Deficiency	519
Genetic Disorders of Th17-Mediated Immunity	519
Conclusions	521
Acknowledgments	521
Multiple-Choice Questions	522.e1
References	521
37 Infections in the Immunocompromised Host	523
Primary Immunodeficiencies	523
Phagocyte Defects (Chapter 22)	523
Chronic Granulomatous Disease	523
Leukocyte Adhesion Deficiencies	523
Quantitative Phagocyte Defects	524
Humoral Immunodeficiencies (Chapter 34)	525
Primary Cellular and Combined Immunodeficiencies (Chapter 35)	525
Severe Combined Immunodeficiency	525
DiGeorge Syndrome	525
Autosomal Dominant Hyper-IgE Syndrome (Job’s Syndrome)	525
DOCK8 Deficiency	526
Defects of the IL-12/IFN-γ Axis	526
Complement Deficiencies (Chapter 21)	526
Asplenia	526
Secondary Non–Medication-Associated Immunodeficiency	527
Cytokine Autoantibodies	527
Infections in Patients Receiving Immunosuppressive Medications	527
Cytotoxic Agents (e.g., Cyclophosphamide, Methotrexate, Azathioprine)	527
Glucocorticoids	527
Calcineurin Inhibitors and Mammalian Target of Rapamycin Inhibitors	527
Mycophenolate Mofetil	528
Antithymocyte Globulin	528
Monoclonal Antibodies and Small Molecules	528
Tumor Necrosis Factor-α Inhibitors	528
Rituximab	529
Alemtuzumab	529
Daclizumab and Basiliximab	529
Natalizumab	529
Bortezomib	529
Infections in Solid Organ Transplantation	530
Infections in the First Month After Transplantation	530
Infections 1–6 Months After Transplantation	530
Infections 6 Months After Transplantation	530
Infections in Hematopoietic Stem Cell Transplantation	530
Preengraftment Period	531
Early Postengraftment Period	531
Late Postengraftment Period	532
Infections of Particular Importance in Transplant Recipients	532
Cytomegalovirus Infection	532
Other Herpes Viruses	532
Invasive Filamentous Fungal Infections	532
Invasive Candidiasis	533
Translational Research	533
Conclusions	533
Multiple Choice Questions	534.e1
References	533
38 Immune Deficiencies at the Extremes of Age	535
Infancy and the Generation of an Immune System	535
Innate Immune Development	535
Dysfunction of Innate Immune Cells	535
Adaptive Immune Development	536
Infancy and Functional Differentiation of Adaptive Immune Cells	537
Infant Immune Development and the Microbiome	538
Clinical Consequences for Childhood Vaccination	538
Older Age and Immune Cell Generation	538
T-Cell Population Homeostasis	539
Inflammation, Aging, and the Aging Host Environment	539
Cellular Defects and Senescence	540
Clinical Consequences of Immune Aging—Immunodeficiency, Autoimmunity, and Accelerated Degenerative Diseases	541
Strategies and Interventions on the Horizon	542
Multiple-Choice Questions	543.e1
References	542
39 Human Immunodeficiency Virus Infection and Acquired Immunodeficiency Syndrome	545
US Perspective	545
HIV Pathogenesis	545
HIV Lifecycle	545
HIV Entry Through Mucosal Surfaces	548
T-cell Depletion	548
HIV Latency and HIV Reservoirs	548
Anti-HIV Immunity	548
HIV Vaccines: Basic Concepts	548
Routes of Infection	548
Immunopathogenesis	549
Mucosal Dendritic Cells: Myeloid Versus Plasmacytoid	549
Gastrointestinal System: Early Target	549
Chronic Immune Activation and Progression to AIDS	549
Anti-HIV Cellular Immunity	550
Mechanisms of T-Cell Depletion	550
Apoptosis	550
Autophagy	550
Anti-HIV Humoral Immunity	550
Innate Immunity	550
NK Cells in HIV Infection	550
Cytokines in HIV Infection	550
Clinical Features	551
Acute HIV Infection	551
Asymptomatic HIV Infection	551
Symptomatic HIV Infection (pre-AIDS)	551
End-Stage HIV Infection: AIDS	551
Long-Term Nonprogressors/Elite Controllers	552
Diagnosis and Monitoring of HIV Infection	553
Diagnostic Tests	553
Enzyme Immunoassays	553
Rapid HIV EIA Tests	553
Nucleic Acid Amplification Tests	553
Monitoring Tests	554
HIV Viral Load	554
Drug Resistance: HIV Genotype Versus Phenotype	554
Testing for Viral Tropism and Abacavir Hypersensitivity	555
Treatment	555
Antiretroviral Therapy: Attacking HIV’s Lifecycle	555
When to Start Therapy	555
Antiretroviral Agents	556
Reverse Transcriptase Inhibitors, Protease Inhibitors, and Integrase Inhibitors	556
Fusion Inhibitors, CCR5 Blockers, and Low-Molecular-Weight Inhibitors	556
Immunoreconstitution After Therapy	556
Return of T Cells: Memory T Cells, Then Naïve T Cells	556
Immune Reconstitution Inflammatory Syndrome	557
Hyperallergenic State Associated With Immunoreconstitution	557
Prevention	557
Prevention of Mother-to-Child Transmission	557
Prevention of Sexual Transmission	557
Male Medical Circumcision	557
Preexposure Prophylaxis	557
Prophylactic Antiretroviral Therapy	557
Expanded Treatment With Antiretroviral Therapy	557
HIV Vaccines: Clinical Trials	558
Preventive Vaccines	558
Therapeutic Vaccines	558
Future for HIV Vaccines	558
Translational Research Needs and Conclusions	559
Acknowledgments	559
Multiple-Choice Questions	560.e1
References	560
40 Autoantibody-Mediated Phenocopies of Primary Immunodeficiency Diseases	561
Overview of Pathophysiology	563
Anti–GM-CSF Autoantibodies and Pulmonary Alveolar Proteinosis	563
Anti–IFN-γ Autoantibodies and Susceptibility to Intracellular Pathogens	564
Anti–IL-17 and Anti–IL-22 Autoantibodies and Chronic Mucocutaneous Candidiasis	565
Anti–IL-6 Autoantibodies and Recurrent Staphylococcal Skin Infection	566
Management	566
Conclusions	566
Acknowledgements	567
Multiple-Choice Questions	567.e1
References	567
Five Allergic Diseases	569
41 Immunological Mechanisms of Airway Diseases and Pathways to Therapy	571
Clinical Presentation of Allergic Airway Disease	571
Chronic Rhinitis and Rhinosinusitis	571
Epidemiology and Clinical Presentation	571
Diagnosis	572
Therapy	573
Asthma	573
Epidemiology and Clinical Presentation	573
Diagnosis	574
Therapy	574
Other Airway Allergic Disease Syndromes	574
Extrinsic Eosinophilic Syndromes	575
Tropical Eosinophilic Pneumonias	575
DRESS Syndrome	575
Allergic Bronchopulmonary Aspergillosis	575
Acute Eosinophilic Pneumonia	576
Intrinsic Eosinophilic Syndromes	576
Chronic Eosinophilic Pneumonia	576
Idiopathic Hypereosinophilic Syndrome	576
Churg-Strauss Syndrome	576
Immunological Mechanisms of Allergic Airway Disease	576
Type I (Immediate) Hypersensitivity	577
Cell-Mediated Features of Immediate Hypersensitivity	578
Contributing Immune Mechanisms in Allergic Airway Disease	578
Environmental Factors and Allergic Disease Initiation	579
Nonallergic Respiratory Tract Inflammatory Syndromes	579
Hypersensitivity Pneumonitis	580
Chronic Obstructive Pulmonary Disease	581
Novel Pathways to Therapy in Inflammatory Airway Disease	583
Multiple-Choice Questions	584.e1
References	583
42 Urticaria, Angioedema, and Anaphylaxis	585
Definition	585
Epidemiology	585
Genetics	585
Clinical Patterns	585
Etiopathogenesis and Etiological Classification	585
Mast Cell–Dependent Mechanisms	585
Allergic Urticaria	586
Autoimmune Urticaria	586
Immune Complex–Mediated Urticarial Rash	587
Nonimmunological Mast-Cell Activation	587
Mast-Cell and Basophil Releasability in Urticaria	587
Skin Response to Mast-Cell Activation in Chronic Urticaria	587
Mast Cell–Independent Mechanisms of Urticaria	588
Pseudoallergy (Intolerance)	588
NSAIDs	588
Food-Induced Pseudoallergic Reactions in CSU	588
Kinin-Mediated Angioedema	588
Clinical Classification	588
Spontaneous Urticaria	588
Acute Spontaneous Urticaria	588
Chronic Spontaneous Urticaria	589
Episodic Spontaneous Urticaria	589
Inducible Urticarias	589
Mechanical Urticaria	589
Symptomatic Dermographism	589
Delayed Pressure Urticaria	589
Vibratory Angioedema	590
Thermal or Ultraviolet-Induced Urticaria	590
Cold Urticaria	590
Heat Urticaria	590
Solar Urticaria	590
Other Patterns of Inducible Urticaria	590
Cholinergic Urticaria	590
Aquagenic Urticaria	590
Contact Urticaria	591
Differential Diagnosis of Urticaria	591
Urticarial Vasculitis	591
Angioedema Without Wheals	591
Angioedema Caused by C1 Inhibitor Deficiency	591
Angioedema With Normal C1 Inhibitor	591
Histaminergic angioedema (without wheals)	591
Idiopathic.	591
Drug-induced.	591
Bradykininergic angioedema	591
Hereditary.	591
Drug-induced.	592
Autoinflammatory Syndromes Presenting With Urticarial Rash	592
Acquired	592
Schnitzler syndrome.	592
Hereditary (Cryopyrin-Associated) Periodic Syndromes	592
Differential Diagnosis	592
Workup in Patients With Urticaria	592
Workup in Acute Urticaria	593
Workup in Physical Urticarias	593
Workup in Chronic and Episodic Spontaneous Urticarias	593
The Diagnosis of Autoimmune Chronic Urticaria	593
Management of Urticaria	593
General Measures	593
First-Line Therapy	593
Second-Line Therapy	594
Third-Line Therapy	594
Management of Hereditary Angioedema	594
Treatment of the Acute Attack	594
Short-Term Prophylaxis	594
Long-Term Prophylaxis	595
Anaphylaxis	595
Epidemiology of Anaphylaxis	595
Pathophysiology of Anaphylaxis	595
Etiology of Anaphylaxis	595
Food-Induced Anaphylaxis	595
Drug-Induced Anaphylaxis	595
Perioperative Anaphylaxis	596
Insect Sting–Induced Anaphylaxis	596
Latex-Induced Anaphylaxis	596
Other Rare Causes of Anaphylaxis	596
Anaphylaxis in Clonal Mast-Cell Disorders	596
Clinical Diversity of Anaphylaxis	596
Diagnosis of Anaphylaxis	597
Management of Anaphylaxis	597
Prevention of Anaphylaxis	598
Translational Research Opportunities	598
Multiple-Choice Questions	600.e1
References	599
43 Allergic Reactions to Stinging and Biting Insects	601
Entomological Aspects	601
Apidae	601
Vespidae	601
Ants (Myrmicinae, Formicinae)	601
Allergens in Hymenoptera venoms	602
Clinical Picture	602
Normal Local Reactions	602
Large Local Reactions	605
Systemic Reactions	605
Systemic Toxic Reactions	605
Unusual Reactions	605
Epidemiological Aspects	605
Prevalence of Allergy to Stings by Flying Hymenoptera	605
Risk Factors for Hymenoptera Allergy	605
Mortality Caused by Hymenoptera Stings	606
Natural History of Hymenoptera Sting Allergy (Table 43.3)	606
Epidemiological Aspects of Allergic Reactions to Ant Stings	606
Diagnosis	606
History	606
Skin Tests	606
Venom-Specific Serum IgE Antibodies	606
Sensitivity and Specificity of Skin Tests and sIgE	606
Cross-Reactivity	607
Cellular Tests	607
Allergen-Specific IgG	607
Baseline Serum Tryptase	607
Sting Challenge Tests	607
Prevention and Treatment	607
Prevention	607
Treatment of Large Local Reactions	607
Systemic Allergic Reactions	607
Emergency Medication Kit	608
Venom Immunotherapy	608
Indications	608
Dosage and Treatment Regimens	608
Adverse Reactions to VIT	608
Efficacy of VIT	608
Duration of VIT	608
Risk Factors for Recurrence of SRs After Stopping VIT	608
Allergic Reactions to Biting Insects	608
Clinical Symptoms	609
Allergens	609
Prevention and Treatment	609
Multiple-Choice Questions	610.e1
References	609
44 Atopic and Contact Dermatitis	611
Clinical Aspects of Atopic Dermatitis	611
Epidemiology	611
Natural History	611
Clinical Features	611
Complicating Features	611
Ocular Problems	611
Hand Dermatitis	611
Infections	611
Systemic Complications	612
Psychosocial Implications	612
Differential Diagnosis	612
Pathogenesis of Atopic Dermatitis	613
Genetics	613
Immune Abnormalities in Atopic Dermatitis	613
Immunohistology	613
Immune Pathways in Atopic Dermatitis	613
Epidermal Barrier Dysfunction	615
Management of Atopic Dermatitis	615
Identification and Elimination of Exacerbating Factors	615
Irritants	615
Allergens	615
Psychosocial Factors	616
Patient Education	616
Hydration	616
Moisturizers and Occlusives	616
Corticosteroids	616
Topical Calcineurin Inhibitors	616
Antiinfective Therapy	616
Antipruritic Agents	617
Recalcitrant Disease	617
Hospitalization	617
Wet Wrap Therapy	617
Systemic Immunosuppressive Agents	617
Phototherapy and Photochemotherapy	617
Allergen-Specific Immunotherapy	617
Biologics and Investigational Therapies	617
Intravenous Gammaglobulin	617
Omalizumab	617
Rituximab	618
Dupilumab	618
Anti–IL-12/IL-23	618
Other Biologics	618
Recombinant Human Interferon-γ	618
Phosphodiesterase-4 Inhibitors	618
Probiotics	618
Prevention	618
Contact Dermatitis	618
Pathogenesis of Allergic Contact Dermatitis	619
The Genes	619
The Allergens	619
The Immune Response	619
Pathogenesis of Irritant Contact Dermatitis	620
Clinical Manifestations of Contact Dermatitis	620
Management of Allergic Contact Dermatitis	621
Identification of the Allergen	622
Allergen Avoidance	622
Symptomatic Therapy	622
Perspectives in Atopic Dermatitis and Allergic Contact Dermatitis	622
Multiple-Choice Questions	624.e1
References	623
45 Food Allergy	625
Prevalence	625
Spectrum of Disease	625
IgE-Mediated Food Allergies	625
Mixed IgE/Non-IgE– and Non–IgE-Mediated Food Allergies	626
Pathophysiology	627
Properties of Food Allergens	627
The Allergic Response	627
Natural History	628
Diagnosis	628
Management	629
Treatment of a Reaction	629
Prevention of Food Allergy	629
Experimental Interventional Therapies	629
Oral Immunotherapy	630
Sublingual Immunotherapy	630
Epicutaneous Immunotherapy	630
Conclusions	630
Multiple-Choice Questions	631.e1
References	631
46 Eosinophil-Associated Gastrointestinal Disorders	633
Eosinophilic Esophagitis	633
Definition	633
Epidemiology	633
Demographic Cornerstones	633
Incidence and Prevalence of Eosinophilic Esophagitis	634
Pathophysiology	634
Eosinophils’ Natural Lifecycle	634
The Role of IgE in Eosinophilic Esophagitis	635
Th2-Mediated Immune Response	635
Esophageal Remodeling	635
Clinical Manifestation of Eosinophilic Esophagitis	635
Endoscopy and Histology	636
Treatment	637
Drugs	637
Diet	637
Dilatation	637
Idiopathic Eosinophilic Gastroenteritis	638
Six Systemic Immune Diseases	675
50 Mechanisms of Autoimmunity	677
The Distinct Phases in the Development of Autoimmunity	677
Phase I: Susceptibility	678
Incomplete Thymic Tolerance Induction Predisposes to Autoimmunity	678
Impaired Clearance and Tolerance Induction by Apoptotic Cells: Susceptibility Defect in Systemic Autoimmunity	679
Defective Production of Regulatory T Cells	679
Signaling Thresholds and Susceptibility to Autoimmunity	679
Phase 2: Initiation	680
Dominance and Crypticity	680
High-Affinity Binding of Antigen to Ligands or Antibodies	680
Tissue-Specific Protease Expression	680
Posttranslational Modification of Autoantigen Structure	680
Novel Antigen Cleavage During Cell Damage, Cell Death, or Inflammation	681
Autoantigen Alteration Caused by Mutation, Truncation, or Splicing	681
Antigen Mimicry	682
Phase III: Propagation	682
Principles of Amplification	682
Acquisition of Adjuvant Properties by Disease-Specific Autoantigens	682
Role of Innate Immune Receptors in Amplification	682
Enhanced Autoantigen Expression in the Target Tissue	683
Translational Research	684
Multiple-Choice Questions	684.e1
References	684
51 Systemic Lupus Erythematosus	685
Epidemiology	685
Mortality	685
Damage	685
Immunopathogenesis	686
Autoantibodies	686
The Predisposed Host: Genetic Contributions	686
Genes Associated With Antigen Presentation	688
Genes Associated With Impaired Clearance of Apoptotic Debris	688
Genes Associated With Lymphocyte Activation, Proliferation, and Function	688
Genes Encoding Cytokines and Chemokines	689
Genes Associated With Cell Survival	689
Genes Regulating Target Organ Damage	689
Epigenetic Contributions	689
B Cells	690
B-Cell Selection	690
B-Cell Signaling	690
B-Cell Rescue	690
B-Cell Pathogenicity Unrelated to Antibody Production	691
Neutrophils	691
Dendritic Cells	691
T Cells	691
Hormonal Influences	691
Clinical Manifestations	692
Musculoskeletal Involvement	692
Arthritis and Arthralgia	692
Tendinitis	693
Myositis/Myalgia	693
Avascular Necrosis	693
Mucocutaneous Manifestations	693
Skin	693
Acute Cutaneous SLE	693
Subacute Cutaneous SLE	693
Chronic Cutaneous SLE	694
Hair and Nail	694
Oral Lesions	695
Gastrointestinal Manifestations	695
Esophagus	695
Abdominal Pain/Vasculitis	695
Intestinal Pseudoobstruction	695
Peritonitis	695
Pancreatitis	695
Liver	696
Protein-Losing Enteropathy (PLE)	696
Pulmonary Involvement	696
Pleuritis	696
Lupus Pneumonitis	696
Pulmonary Hemorrhage	696
Chronic Diffuse Interstitial Lung Disease	697
Pulmonary Hypertension	697
Shrinking-Lung Syndrome	697
Cardiac Involvement	697
Myocardium	697
Valvular Heart Disease	697
Pericarditis	697
Coronary Artery Disease	697
Renal Involvement	698
Hematological	698
Anemia	698
Leukopenia	699
Thrombocytopenia	699
Central and Peripheral Nervous System	699
NPSLE Nomenclature	699
NPSLE Pathogenesis	699
NPSLE Assessment and Attribution	700
Drug-Induced Lupus	700
Treatment	700
Translational Research	702
Conclusions	702
Multiple-Choice Questions	704.e1
References	702
52 Rheumatoid Arthritis	705
Epidemiology	705
Etiology and Pathogenesis	706
Environmental and Nongenetic Factors	706
Immunogenetics	707
Synovial Pathology	709
Increased Vascularity and Cell Migration	709
Organization of Lymphoid Tertiary Microstructures	709
Gene Expression Signatures	710
Immunobiology of RA	710
Initiation of the Immune Response	710
Autoantigens in RA	711
The Discovery of Citrulline as a Key Target for Autoimmunity in RA	712
Lymphocyte Biology	714
Molecular Basis of Persistence	714
Immune Regulation	714
Impact of the Immune Response on Cartilage and Bone	715
Clinical Features	715
Disease Onset	715
Diagnosis	715
Classification Criteria	715
Laboratory Findings	716
Insights Into the Preclinical Phase of Disease	717
Treatment	718
Disease-Modifying Antirheumatic Drugs	718
Anticytokine Therapy	718
Anti-T-Cell Therapy	719
Anti-B-Cell Therapy	719
Future Prospects for Therapy	720
Multiple-Choice Questions	721.e1
References	720
53 Juvenile Idiopathic Arthritis	723
Etiology and Pathogenesis	723
Genetic Contribution	723
Polygenic Disorder	723
HLA Associations	724
Non-HLA Associations	724
Environmental Factors	725
Immune Abnormalities	725
Autoantibodies	725
T-Helper Cells	725
Cytokines	725
Macrophage Activation Syndrome	725
JIA Clinical Subtypes	726
Oligoarticular JIA	726
Polyarticular JIA	726
Psoriatic Arthritis	727
Enthesitis-Related Arthritis	727
Systemic JIA	727
Laboratory Evaluation	727
Differential Diagnosis	728
Clinically Silent Complications	728
Treatment	729
Overview	729
Nonsteroidal Antiinflammatory Drugs	730
Glucocorticoids	730
Nonbiological DMARDs	730
Biological DMARDs	731
Treatment of Oligoarthritis (Arthritis of ≤4 Joints)	731
Treatment of Polyarthritis (Arthritis of ≥5 Joints)	731
Treatment of Arthritis Involving Specific Joints	731
Treatment of Erosive Arthritis	731
Treatment of Systemic Features of Systemic Arthritis	732
Treatment of Arthritis of Systemic Arthritis	732
Treatment of Uveitis	732
Duration of Therapy	732
Translational Research	732
Multiple-Choice Questions	733.e1
References	732
54 Sjögren Syndrome	735
Epidemiology	735
Immunopathogenesis	735
Immunogenetic Factors	735
Environmental Factors	735
Epithelial Cell Activation and Chronic Inflammation	736
Autoantibodies	736
Autonomic Nervous System Abnormalities	736
Clinical Manifestations	736
Constitutional Symptoms	736
Ocular Involvement	736
Oral Involvement	737
Musculoskeletal Involvement	738
Neuropsychiatric Manifestations	738
Dermatological Involvement	738
Gastrointestinal Involvement	739
Pulmonary Involvement	739
Cardiac Involvement	739
Genitourinary and Renal Involvement	739
Clinical Manifestations in Children	739
Associated Autoimmune Conditions	739
Lymphoma Associated With SS	739
Diagnosis and Classification Criteria	739
Novel Biomarkers for Diagnosis and Management of Sjӧgren Syndrome	740
Treatment	740
Symptomatic Treatment of Sicca Symptoms	740
Immune-Modulating Medications	741
Treatment for Lymphoma Associated With SS	741
Patient Education	741
Translational Research and Future Directions	741
Multiple-Choice Questions	742.e1
References	742
55 Scleroderma–Systemic Sclerosis	743
Prevalence and Epidemiology	743
Etiology and Pathogenesis	743
Genetic Factors	743
Environmental Factors	743
Pathology	743
Pathogenesis	744
Microangiopathy	744
Cellular and Humoral Immune Responses	745
Fibrosis: Cellular and Molecular Components	746
Clinical Features	746
Overview	746
Symptoms	748
Diffuse SSc	748
Limited Cutaneous SSc	749
Raynaud Phenomenon	749
Gastrointestinal Involvement	750
Pulmonary Involvement	750
Interstitial Lung Disease	751
Pulmonary Arterial Hypertension	751
Cardiac Involvement	751
Renal Involvement	752
Musculoskeletal Complications	752
Emotional Aspects	753
Treatment	753
Other Fibrosing Diseases	753
Multiple-Choice Questions	755.e1
References	754
56 Inflammatory Muscle Diseases	757
Clinical Features	757
Classification	758
Etiology	761
Immunological Clues to Origin	761
Drugs and Toxins	761
Bacterial and Parasitic Diseases	761
Pathogenesis	762
Genetics	763
Natural History	763
Patient Management	763
Corticosteroids	764
Second-Line and Third-Line Immunosuppressive Therapies	764
Monitoring Disease Activity	764
Treatment-Resistant Myositis	764
Nonskeletal Muscle Involvement	764
Diagnostic Tools, Evaluation, and Differential Diagnosis	764
Pitfalls	766
Multiple-Choice Questions	767.e1
References	766
57 Spondyloarthritis	769
Classification of Spondyloarthritis	769
Epidemiology	769
Pathogenesis	769
Genetics of Spondyloarthritis	769
Familial Aggregation	769
HLA-B27 and Spondyloarthritis	770
Other MHC Genes and SpA Susceptibility	773
Non-MHC Genes in Susceptibility to Spondyloarthritis	774
Genes and Severity of SpA	775
Infection	775
The Gut and Spondyloarthritis	775
Pathology of SpA	776
Clinical Features	776
Ankylosing Spondylitis	776
Musculoskeletal Symptoms	776
Extraarticular Manifestations	777
Uveitis.	777
Cardiac manifestations.	777
Pulmonary manifestations.	777
Renal manifestations.	778
Osteoporosis.	778
Spondylodiscitis and spinal fractures.	778
Neurological manifestations.	778
Fatigue and psychosocial manifestations.	778
AS in women.	778
Reactive Arthritis	778
Juvenile Spondyloarthritis	779
Psoriatic Arthritis	779
Enteropathic Arthritis	779
Undifferentiated Spondyloarthritis	780
Laboratory Investigations	780
Diagnosis	780
Measures of SpA Activity and Severity	780
Radiographic Imaging of Spondyloarthritis	781
Axial Spondyloarthritis	781
Psoriatic Arthritis	781
Disease Course and Prognosis	781
Ankylosing Spondylitis	781
Reactive Arthritis	782
Psoriatic Arthritis	782
Juvenile Spondyloarthritis	782
Treatment	783
Patient Education and Physiotherapy	783
Medical Treatment	784
Nonsteroidal Antiinflammatory Drugs	784
Disease-Modifying Antiinflammatory Drugs	784
Sulfasalazine.	784
Other DMARDs.	784
Corticosteroids.	784
Intraarticular/Intralesional Corticosteroids	784
Antibiotics	785
TNF-α Blockers	785
Interleukin-17 Blockers (Secukinumab)	785
Surgical Treatment of AS Complications	785
Conclusions and Research Opportunities	785
References	786
58 Small- and Medium-Vessel Primary Vasculitis	789
Epidemiology	789
Pathogenesis of AAV	790
The Pathogenic Role of ANCA in GPA and MPA	790
Genetics	791
Epigenetics	792
Environmental and Infectious Triggers	792
Drug Induced AAV	793
Propylthiouracil	793
Hydralazine	793
Levamisole-Contaminated Cocaine	793
Loss of B- and T-Cell Tolerance in ANCA-Associated Vasculitis	795
Role of Neutrophils	795
Role of Complement	795
Pathogenesis of Kawasaki Disease	797
Pathogenesis of Polyarteritis Nodosa	797
Pathogenesis of Cryoglobulinemic Vasculitis	797
Pathogenesis of EGPA	798
Classification	798
Diagnosis	798
Individual Diseases	798
Laboratory Investigations	799
Assessment	799
Damage Assessment in Vasculitis	800
Treatment	800
No Treatment/Symptom Relief	802
Target-Directed Therapies	802
Specific Therapies	802
Glucocorticoids	802
Other Immunosuppressive Therapies	802
Specific Immunotherapy	803
Other Therapies	803
Outcomes	804
Acknowledgements	805
Multiple-Choice Questions	807.e1
References	805
59 Large-Vessel Vasculitides	809
Epidemiology	809
Etiology and Pathogenesis	810
Innate Immune System Defects	810
Adaptive Immune System Defects	812
Defective T Regulatory Cells and Insufficient Immune Checkpoints in Giant Cell Arteritis	813
Clinical Features in Giant Cell Arteritis	813
Clinical Features in Polymyalgia Rheumatica	814
Clinical Features in Takayasu Arteritis	814
Diagnosis	817
Laboratory Tests	817
Tissue Biopsy	817
Diagnostic Imaging	820
Therapeutic Management	821
Induction Therapy	822
Maintenance Therapy	822
Revascularization Procedures	823
Multiple Choice Questions	824.e1
References	823
60 Systemic Autoinflammatory Syndromes	825
Epidemiology	825
Signs and Symptoms	826
Familial Mediterranean Fever	826
Cryopyrin-Associated Periodic Syndrome	826
Tumor Necrosis Factor Receptor–Associated Periodic Syndrome	827
Mevalonate Kinase Deficiency	827
Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Adenitis Syndrome	827
Schnitzler Syndrome	827
Pathogenesis	828
Familial Mediterranean Fever	828
Cryopyrin-Associated Periodic Syndrome	828
Tumor Necrosis Factor Receptor–Associated Periodic Syndrome	829
Mevalonate Kinase Deficiency	829
Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Adenitis Syndrome	829
Schnitzler Syndrome	829
Laboratory Tests	830
Diagnosis	830
Familial Mediterranean Fever	830
Cryopyrin-Associated Periodic Syndrome	830
Tumor Necrosis Factor Receptor–Associated Periodic Syndrome	830
Mevalonate Kinase Deficiency	830
Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Adenitis Syndrome	831
Schnitzler Syndrome	831
Autoinflammation of Unknown Origin	831
Treatment	831
Colchicine	831
Inhibition of Interleukin-1	831
Inhibition of Interleukin-6	832
Inhibition of Tumor Necrosis Factor	832
Corticosteroids	832
Simvastatin	832
Other Immunosuppressive Drugs	832
Other Treatments	832
Amyloidosis	832
Conclusions	833
Multiple-Choice Questions	834.e1
References	833
61 Antiphospholipid Syndrome	835
Epidemiology	835
Etiopathogenesis	835
Diagnosis	837
Clinical Manifestations	837
Laboratory Tests	838
Imaging Studies	839
Pathological Studies	839
Treatment	839
Asymptomatic Individuals	839
Venous and Arterial Thromboembolism	840
Pregnancy Morbidity	840
Other Clinical Manifestations of APS	840
Perioperative Management	840
Additional Therapeutic Considerations	840
Conclusions and Translational Research	841
Multiple-Choice Questions	841.e1
References	841
Seven Organ-Specific Inflammatory Disease	843
62 Immunohematological Disorders	845
Immune-Mediated Hemolytic Anemia	845
Autoimmune Hemolysis Mediated by Warm Antibody	845
Drug-Induced Immune Hemolysis	845
Cold Agglutinin Diseases	845
Paroxysmal Cold Hemoglobinuria	845
Hemolytic Transfusion Reactions	846
Immune Hemolysis Associated With Transplantation	846
Immunopathogenesis	846
Diagnosis	847
Therapy	848
Immune-Mediated Neutropenia	848
Isoimmune Neonatal Neutropenia	848
Primary Autoimmune Neutropenia	848
Neutropenia Associated With Systemic Autoimmune or Lymphoproliferative Diseases	848
Felty Syndrome	848
T-Cell Large Granular Lymphocyte Leukemia	849
Clinical Overlap Between Felty Syndrome and T-LGL Leukemia	849
Drug-Induced Immune Neutropenia	849
Immunopathogenesis	849
Regulation of Antineutrophil Antibody Production	849
Antibody Specificity	850
Patterns of Autoantibody Specificity	850
Impact of Antibodies and Immune Complexes on Neutrophil Survival	850
Myelopoiesis in Immune Neutropenia	851
Diagnosis	851
Clinical Presentation	851
Laboratory Findings	851
Detection of antineutrophil antibodies.	851
Clinical use of antineutrophil antibody studies.	851
Therapy	851
Overview	851
Colony-Stimulating Factors	852
Immunosuppressive Agents	852
Other Therapy	852
Prophylactic Antibiotics	852
Immune-Mediated Thrombocytpenias	852
Immune Thrombocytopenia	852
ITP During Pregnancy and the Neonatal Period	852
Neonatal Alloimmune Thrombocytopenia and Posttransfusion Purpura	852
Drug-Induced Thrombocytopenia	853
Pathogenesis	853
Laboratory Diagnosis	853
Therapy of ITP	854
Therapy of ITP During Pregnancy and the Neonatal Period	854
Multiple-Choice Questions	856.e1
References	855
63 Bullous Diseases of the Skin and Mucous Membranes	857
Pemphigus	857
Pemphigus Vulgaris	857
Pemphigus Foliaceus	857
Paraneoplastic Pemphigus	859
IgA Pemphigus	859
Pathogenesis	859
Therapy	860
Bullous Pemphigoid	860
Clinical Features	860
Pathogenesis	861
Therapy	862
Epidermolysis Bullosa Acquisita	863
Pathogenesis	863
Treatment	864
Pemphigoid Gestationis	864
Pathogenesis	864
Treatment	865
Mucous Membrane Pemphigoid	865
Pathogenesis	865
Therapy	865
Linear IgA Bullous Disease	866
Pathogenesis	866
Therapy	866
Dermatitis Herpetiformis	866
Clinical Features	866
Pathogenesis	867
Therapy	868
Translational Research	868
Multiple-Choice Questions	870.e1
References	868
64 Immunology of Psoriasis	871
Clinical and Histological Features of Psoriasis	871
Immune-Related Genetic Factors Predisposing to Psoriasis	871
Effector Cells and Immune Mechanisms Operating in Psoriasis	872
Plasmacytoid DCs as Inducers of Primary Immune Responses in Psoriasis	875
DC Driving of T-Cell Responses in Psoriatic Skin	875
Activation of T Lymphocytes and Establishment of the Cytokine Milieu Influencing Keratinocyte Proliferation and Immune Functions	876
Intrinsic Defects of Keratinocytes Are Fundamental for the Amplification of Psoriatic Processes	877
Conclusions	877
Multiple-Choice Questions	878.e1
References	877
65 Myasthenia Gravis	879
Classification	879
Diagnosis	879
AChR Structure	880
Neuromuscular Transmission	881
Immunopathogenesis of MG	881
Properties of Anti-AChR Antibodies and Characterization of B-Cell Epitopes	882
Anti-AChR Antibody Levels and Relationship to Disease Activity	882
Pathogenic Effects of Anti-AChR Antibodies	883
Complement-Mediated Damage	883
Acceleration of AChR Degradation	883
Receptor Blockade	883
Role of T Cells	884
Experimental Autoimmune Myasthenia Gravis	884
The Thymus in Myasthenia Gravis	884
Thymic Pathology	885
Intrathymic Factors Possibly Contributing to Local Anti-AChR Antibody Response	885
Etiological Factors	885
Genetic Factors	885
Exogenous Factors	886
Treatment of Myasthenia Gravis	886
Anticholinesterases	886
Thymectomy	886
Corticosteroids	887
Plasmapheresis	887
Intravenous Immunoglobulin	887
Immunosuppressive Agents	887
Possible Future Therapeutic Options	888
Conclusions	888
Acknowledgment	889
Multiple-Choice Questions	890.e1
References	889
66 Multiple Sclerosis	891
Clinical Subsets and Phenomenology	891
Relapsing-Remitting MS (RRMS)	891
Secondary Progressive MS (SPMS)	891
Primary Progressive MS (PPMS)	892
Diagnosis	892
Risk Factors	893
Genetic Risk Factors	893
Environmental Risk Factors	893
Geographic Prevalence Patterns	893
Vitamin D	894
Infection	894
Obesity	894
Modifiable Habits	894
Sex Hormones	895
Pathological Features of MS	895
White Matter Lesions	895
Gray Matter Lesions	895
Meningeal Inflammation	896
Immunopathogenesis	896
Animal Models of MS	896
Immune Dysregulation in Patients With MS	897
Disease-Modifying Therapies	897
Recombinant IFN-β	898
Glatiramer Acetate	898
Teriflunomide	898
Dimethyl Fumarate	898
Fingolimod	898
Natalizumab	899
Alemtuzumab	899
Daclizumab	899
B Cell–Depleting Monoclonal Antibodies	899
Future Directions	900
Multiple-Choice Questions	902.e1
References	900
67 Autoimmune Peripheral Neuropathies	903
Acute Inflammatory Polyneuropathy: Guillain-Barré Syndrome(s)	903
Diagnosis	904
Antecedent Illnesses or Events	904
Immunopathology of Guillain-Barré Syndrome	904
Cellular Factors	904
Humoral Factors and Antiganglioside Antibodies	905
Molecular Mimicry: Relationship Between Campylobacter jejuni and Gangliosides in Acute Motor Axonal Neuropathy	905
Nodal and Paranodal Alterations and Specific Antinodal Antibodies	906
Chronic Inflammatory Demyelinating Polyneuropathy	907
Clinical Features and Disease Variants	907
Diagnosis	907
Immunopathogenesis	908
Multifocal Motor Neuropathy With Conduction Block	908
Polyneuropathies Associated With Monoclonal Gammopathies of Undetermined Significance	909
Antibodies to Myelin-Associated Glycoprotein in Patients With IgM M Monoclonal Gammopathies of Undetermined Significance Polyneuropathy (Anti-MAG Neuropathy)	909
Polyneuropathy, Organomegaly, Endocrinopathy, Myeloma, and Skin Changes	911
Cryoglobulinemic Neuropathy	911
Paraneoplastic Peripheral Neuropathies With Anti-Hu Antibodies	911
Autoimmune Autonomic Neuropathies	911
Mononeuropathy Multiplex and Localized, Isolated Vasculitis of the Peripheral Nerves	912
Neuropathy With Viruses and Human Immunodeficiency Virus	912
Treatment	913
Guillain-Barré Syndrome	913
Supportive Care	913
Eight Immunology of Neoplasia	1031
77 Immunotherapy of Cancer	1033
Activation and Regulation of T-Cell Responses	1034
Immune Checkpoint Therapy	1035
Anti-CTLA-4 Therapy	1035
Anti-PD-1/PD-L1 Therapy	1035
T-Cell Immunoglobulin and Mucin Domain 3	1035
Lymphocyte Activation Gene 3	1036
V-Domain Ig Suppressor of T-Cell Activation	1036
Immune Checkpoint Therapy With Clinical Benefit in Solid Tumors and Hematological Malignancies	1036
Melanoma	1036
Lung Cancer	1037
Renal Cell Carcinoma	1038
Bladder Cancer	1038
Head and Neck Cancer	1038
Hodgkin Lymphoma	1038
Early and Late-Phase Trials With Checkpoint Therapy in Other Tumors	1038
Pancreatic Cancer	1038
Prostate Cancer	1038
Immune Costimulatory Molecules	1039
Inducible T-Cell Costimulator	1039
4-1BB (CD137)	1039
OX40 (CD134)	1040
Adoptive Cell Transfer	1040
Adoptive Transfer of Tumor-Specific Cytotoxic T Cells	1040
Adoptive Immunotherapy With Genetically Modified Lymphocytes	1040
Clinical Development of Chimeric Antigen Receptor T Cells	1040
Adoptive Transfer of Viral-Specific T Cells	1041
Monoclonal Antibodies	1041
Naked mAbs	1041
Conjugated/Tagged/Labeled/Loaded mAbs	1042
Bispecific Monoclonal Antibodies	1042
Cytokine Therapy	1042
Cancer Vaccines	1042
Oncolytic Virus Immunotherapy	1042
Clinical Challenges in Immunotherapy	1042
Resistance Mechanisms	1043
Activation of Oncogenic Pathways	1043
Loss of Interferon γ Signaling	1043
Immunosuppressive Tumor Microenvironment	1043
Gut Microbiome	1043
Immune-Related Adverse Events	1044
irAEs With Immune Checkpoint Immunotherapy	1044
irAEs With Adoptive T-Cell Therapy	1045
Perspectives on Future Developments	1045
Biomarkers	1045
Combination Therapy	1045
Conclusions	1046
Multiple-Choice Questions	1048.e1
References	1046
78 Lymphoid Leukemias	1049
Acute Lymphoblastic Leukemia	1049
Epidemiology and Etiology	1049
Immunological and Molecular Classification of ALL	1050
Immunological Classification	1050
B-Cell Precursor Leukemias	1050
T-Cell ALL	1050
Genetic and Molecular Classification	1051
Numerical Chromosomal Aberrations	1051
Chromosomal Translocations	1051
Amplifications and Deletions	1051
Oncogenic-Activating Mutations	1051
Genes Involved in Leukemogenesis Often Play Key Roles in Normal Development	1051
Major, Clinically Relevant, Molecular Subtypes of ALL	1053
B-Lineage ALL	1053
T-Lineage ALL	1053
Clinical Features	1053
Special Diagnostic Tests	1054
Principles of Therapy	1055
Prognostic Factors	1055
Where Immunology Meets Oncology—Minimal Residual Disease	1055
Course and Prognosis	1056
Treatment Sequelae	1057
Current Controversies and Future Perspectives	1057
Chronic Lymphocytic Leukemia	1057
Epidemiology	1057
Pathogenesis and the Biology of Leukemic Lymphocytes	1058
Clinical Features of CLL	1059
Treatment	1060
Immunological Aspects of CLL	1061
The Pathophysiological Rationale	1061
Immunological Deficiencies	1062
Autoimmune Phenomena	1062
Other Malignancies	1062
Conclusions	1062
Multiple-Choice Questions	1063.e1
References	1063
79 Lymphomas	1065
Mature B-Cell Neoplasms	1067
Lymphoplasmacytic Lymphoma	1067
Mantle-Cell Lymphoma	1067
Follicular Lymphoma	1068
Mucosa-Associated Lymphoid Tissue Lymphomas	1069
Nodal Marginal Zone Lymphoma	1069
Splenic Marginal Zone Lymphomas	1069
Diffuse Large B-Cell Lymphoma, Not Otherwise Specified	1070
Primary Mediastinal Large B-Cell Lymphoma	1071
Burkitt Lymphoma	1071
T-Cell and NK-Cell Neoplasms	1072
Overview of the Classification of T-Cell Neoplasms	1072
Extranodal NK/T-Cell Lymphoma, Nasal Type	1072
Nodal T-Cell Lymphoma With TFH Phenotype: Angioimmunoblastic T-Cell Lymphoma	1072
Peripheral T-Cell Lymphomas, Not Otherwise Specified	1073
Anaplastic Large-Cell Lymphoma	1073
Primary Cutaneous ALCL	1073
Subcutaneous Panniculitis-Like T-Cell Lymphoma	1073
Primary Cutaneous γ/δ T-Cell Lymphomas	1074
Mycosis Fungoides and Sézary Syndrome	1074
Enteropathy-Associated T-Cell Lymphoma	1074
Hepatosplenic T-Cell Lymphoma	1074
Adult T-Cell Leukemia/Lymphoma	1074
Hodgkin Lymphomas	1075
Nodular Lymphocyte-Predominant Hodgkin Lymphoma	1075
Classic Hodgkin Lymphoma, Nodular Sclerosis	1075
Classic Hodgkin Lymphoma, Mixed Cellularity	1075
Classic Hodgkin Lymphoma, Lymphocyte Depletion	1075
Classic Hodgkin Lymphoma, Lymphocyte-Rich	1076
Multiple-Choice Questions	1077.e1
References	1076
80 Monoclonal Gammopathies	1079
Monoclonal Gammopathy of Undetermined Significance	1079
Epidemiology	1079
Clinical Presentation and Laboratory Findings	1079
Diagnosis	1080
Clinical Course	1080
Management and Prognosis	1080
Multiple Myeloma	1080
Epidemiology	1081
Clinical Presentation	1081
Laboratory Findings	1081
Biochemical Tests	1081
Hematology	1081
Bone Marrow Evaluation	1082
Radiography	1083
Diagnosis	1083
Management	1084
Prognosis	1085
Smoldering Multiple Myeloma	1085
Prognosis and Management	1086
Nonsecretory Myeloma	1086
Oligosecretory Myeloma	1086
Plasma Cell Leukemia	1087
Clinical Presentation and Diagnosis	1087
Nine Transplantation	1095
81 Concepts and Challenges in Organ Transplantation	1097
Rejection	1097
Innate Immunity and Ischemia-Reperfusion Injury	1097
Initiation of the Adaptive Immune System	1098
Signal 1: Recognition of Alloantigen	1098
Signal 2: Costimulation	1099
Signal 3: Proliferation and Differentiation of Effector T Cells	1100
Memory T Cells	1100
Cell Migration	1100
The Effector Response and Graft Destruction	1100
Acute Antibody-Mediated Rejection	1101
Acute Cellular Rejection	1101
Delayed Allograft Rejection and Dysfunction	1101
Clinical Implications	1101
Immunosuppression	1103
Immunodepletion	1104
Antithymocyte Globulin	1105
Anti-CD52 Monoclonal Antibody (Alemtuzumab)	1105
Signal 1: Blockade of Antigen Recognition	1106
Anti-CD3 Monoclonal Antibody	1106
Anti-CD20 Monoclonal Antibody (Rituximab)	1106
Signal 2: Blockade of Costimulation	1106
CD28:B7 (CD80/CD86) Blockade	1107
Signal 3: Blockade of Proliferation/Differentiation	1107
Anti-IL-2R Monoclonal Antibody (Basiliximab and Daclizumab)	1107
Glucocorticoids	1108
Antiproliferative Agents	1108
Calcineurin Inhibitors	1108
Mechanistic Target of Rapamycin Inhibitors	1108
Tolerance	1108
Molecule-Based Tolerogenic Protocols	1109
Full Chimerism	1110
Mixed Chimerism	1111
Regulatory T Cells	1111
Biomarkers of Rejection or Tolerance	1112
Multiple-Choice Questions	1114.e1
References	1112
82 Immune Reconstitution Therapy for Immunodeficiency	1115
Hematopoietic Stem Cell Transplantation: General Considerations	1115
Sources of Hematopoietic Stem Cells for Transplantation	1115
Donor Selection and Manipulation of the Graft	1115
HSCT From a Related HLA-Identical Donor	1115
HSCT From a Haploidentical Donor	1116
In Utero Haploidentical HSCT	1116
HSCT From Matched Unrelated Donors	1117
HSCT Using Unmanipulated Cord Blood	1117
Complications of Hematopoietic Stem Cell Transplantation	1117
Graft Rejection	1117
Acute Graft-Versus-Host Disease	1118
Chronic Graft-Versus-Host Disease	1118
Prevention of GvHD	1118
Treatment of GvHD	1119
Infections	1119
Toxicity Related to Conditioning Regimen	1119
HSCT for SCID	1120
General Considerations	1120
Survival Following HSCT for SCID	1120
Complications Following HSCT for SCID	1121
Quality and Kinetics of T-Cell Immune Reconstitution	1122
Reconstitution of B- and NK-Cell Immunity	1124
HSCT for Combined Immunodeficiencies Other Than SCID	1124
Wiskott-Aldrich Syndrome	1125
Cytotoxicity Defects	1125
Phagocytic Cell Disorders	1125
Other Primary Immune Deficiencies	1126
Future Translational Research for HCST in the Treatment of PID	1126
Multiple-Choice Questions	1128.e1
References	1127
83 Hematopoietic Stem Cell Transplantation for Malignant Diseases	1129
Immune Mechanisms Related to Allo-HSCT	1130
Histocompatibility	1130
Graft-Versus-Host Disease	1130
Clinical Aspects of aGvHD	1131
Autologous GvHD	1132
Clinical Aspects of cGvHD	1132
GvT Responses	1132
Adjuvant Therapy With HSCT	1134
Clinical HSCT	1134
Sources of HSCs	1134
Purging of Cell Populations	1136
Expansion of HSC Products	1136
Hematological Recovery	1136
Conditioning Regimens	1136
Dose-Intensive and Reduced Intensity Chemotherapy	1136
HSCT for Individual Diseases	1137
Acute Myelogenous Leukemia	1137
Myelodysplastic Syndromes	1137
Chronic Myelogenous Leukemia	1137
Myeloproliferative Diseases	1138
Acute Lymphoblastic Leukemia	1138
Chronic Lymphocytic Leukemia	1138
Multiple Myeloma	1138
Non-Hodgkin Lymphoma	1138
Low-Grade NHL	1138
Aggressive NHL	1138
Hodgkin Lymphoma	1139
Solid Tumors	1139
Future Directions	1139
Multiple-Choice Questions	1140.e1
References	1140
Ten Prevention and Therapy of Immunological Diseases	1141
84 Immunoglobulin Therapy	1143
Replacement Therapy With IVIG	1143
Adverse Events Associated With IVIG Therapy	1146
Rate-Related Adverse Events	1146
Central Nervous System–Related Adverse Events	1146
Renal Adverse Events	1147
Thromboembolic Events	1147
Transfusion Reaction Caused by Antibodies Against IgA	1147
Other Adverse Reactions	1148
Summary: Ig Replacement in Treatment of Immune Deficiency	1148
Mechanisms of Action of Ig Therapy in Autoimmune and Inflammatory Diseases	1148
Blockade of Fc Receptors of the Reticuloendothelial System	1148
Interactions of Idiotype and Antiidiotype as Immune Modulation	1148
The Role of the FcRn Receptor on Immune Modulation	1149
Modulation of Immunoregulatory Function Through the Fc Receptor	1149
Neutralizing Antibody Activity in IVIG Against Bacterial Toxins	1150
Modulation of Adhesion Molecules on Endothelial Cells and Antibodies in IVIG to Cell Surface Receptors	1150
Modulation of Complement Effector Function	1151
Effects of Ig on the Regulatory T-Cell Pathways	1151
Summary: IVIG in Treatment of Autoimmune and Inflammatory Diseases	1151
Multiple-Choice Questions	1153.e1
References	1152
85 Gene Therapy for Primary Immune Deficiency Diseases	1155
Gene Transfer to Hematopoietic Stem Cells	1155
Clinical Trials of Gene Therapy for Primary Immune Deficiencies	1156
Role of Cytoreductive Conditioning to Facilitate Engraftment	1157
Adenosine Deaminase (ADA)-Deficient Severe Combined Immune Deficiency (SCID; Chapter 35)	1157
X-linked SCID (Chapter 35)	1159
Leukocyte Adhesion Defect (LAD; Chapter 22)	1159
Chronic Granulomatous Disease (CGD; Chapter 22)	1159
Wiskott-Aldrich Syndrome (WAS; Chapter 35)	1160
Gene Therapy Considerations for Other PID	1161
Gene Correction (Editing) for Gene Therapy of PID	1161
Use of Pluripotent Stem Cells as a Source of HSC for Gene Therapy of PID	1163
Gene Therapy for PID Involving Serum Protein Deficiencies	1163
Advancing Gene Therapy for PID From Experimental to Standard of Care	1163
Conclusion	1163
Multiple-Choice Questions	1164.e1
References	1164
86 Glucocorticoids	1165
Mechanisms of Action	1165
Genomic Actions of Glucocorticoids	1165
Structure of the Cytosolic Glucocorticoid Receptor	1165
Translocation Into the Nucleus	1166
Interactions With Transcription Factors	1166
The cGCRβ Isoform	1167
Posttranscriptional and Posttranslational Mechanisms	1167
Glucocorticoid Receptor Resistance	1168
Nongenomic Actions of Glucocorticoids	1168
cGCR-Mediated Nongenomic Actions	1168
Nonspecific Nongenomic Actions	1168
Specific Nongenomic Actions	1168
Glucocorticoid Effects on Immune Cells	1168
The Role of Endogenous Glucocorticoids in Inflammatory Arthritis	1169
Therapeutic Use	1169
Terminology	1169
Glucocorticoid Treatment Regimens: General Aspects	1170
Low Dose	1170
Medium Dose	1170
High Dose	1170
Very High Dose	1170
Pulse Therapy	1171
Alternate-Day Regimens	1171
Glucocorticoid Withdrawal Regimens	1171
Glucocorticoids in Rheumatoid Arthritis: an Example	1171
Low-Dose Maintenance Therapy	1171
Glucocorticoid Pulse Therapy	1171
Intraarticular Glucocorticoid Injections	1171
Adverse Effects	1172
Osteoporosis	1172
Osteonecrosis	1172
Myopathy	1172
Cardiovascular Adverse Effects	1172
Dermatological Adverse Effects	1173
Gastrointestinal Adverse Effects	1173
Infectious Diseases	1173
Other Adverse Effects	1173
Importance of Timing of Glucocorticoid Administration	1173
New Glucocorticoid Receptor Ligands on the Horizon	1173
Selective Glucocorticoid Receptor Agonists	1173
Nitrosteroids	1173
Long-Circulating Liposomal Glucocorticoids	1174
Combining Prednisolone and Dipyridamole	1174
Conclusions	1174
Acknowledgments	1174
Multiple-Choice Questions	1175.e1
References	1174
87 Immunomodulating Pharmaceuticals	1177
Methotrexate	1177
Pharmacokinetics of Methotrexate	1177
Mechanisms of Action for Methotrexate	1177
Adverse Effects	1178
Sulfasalazine	1178
Mechanisms of Action for Sulfasalazine	1179
Eleven Diagnostic Immunology	1237
92 Flow Cytometry	1239
Instrumentation	1239
Fluorescence Reagents	1240
Data Analysis	1241
Gating	1241
Data Display	1241
Positive–Negative Discrimination	1242
Compensation	1243
Quality Control	1243
Methods	1243
Practical Applications of Flow Cytometry	1245
Immunophenotyping Studies	1245
Intracellular Evaluation	1246
Cellular Activation	1246
Intracellular Cytokine Detection	1247
Cell Cycle Analysis	1247
Apoptosis Detection	1248
Peptide–MHC Multimers	1249
Conclusions	1250
Multiple-Choice Questions	1251.e1
References	1250
93 Assessment of Functional Immune Responses in Lymphocytes	1253
T-Cell Response	1253
Measurement of T-Cell Function via Activation Markers	1255
Assessment of Cellular Viability in Lymphocytes	1255
Measurement of T-Cell Competence via Proliferation	1256
Measurement of Cell-Mediated Cytotoxicity	1257
NK Cell Activation and Function	1260
NK Cell Cytotoxicity	1261
Evaluation of Regulatory T-Cell (Treg) Function	1265
Assessment of Signaling and DNA Repair Pathways in Lymphocytes via Phosphoflow Cytometry	1266
Assessment of B-Cell Function	1267
Summary	1270
Multiple-Choice Questions	1271.e1
References	1270
94 Assessment of Neutrophil Function	1273
Isolation of Neutrophils	1274
Appendices	1311
Appendix 1 Selected CD Molecules and Their Characteristics	1311
Appendix 2 Laboratory Reference Values	1317
Index	1319
A	1319
B	1325
C	1327
D	1333
E	1335
F	1337
G	1338
H	1340
I	1343
J	1350
K	1350
L	1351
M	1353
N	1357
O	1358
P	1359
Q	1362
R	1362
S	1364
T	1367
U	1371
V	1372
W	1373
X	1373
Y	1373
Z	1373
Answers	e1
Chapter 1	e1
Chapter 2	e1
Chapter 3	e1
Chapter 4	e1
Chapter 5	e2
Chapter 6	e2
Chapter 7	e2
Chapter 8	e3
Chapter 9	e3
Chapter 10	e3
Chapter 11	e4
Chapter 12	e4
Chapter 13	e4
Chapter 14	e4
Chapter 15	e4
Chapter 16	e5
Chapter 17	e5
Chapter 18	e5
Chapter 19	e5
Chapter 20	e5
Chapter 21	e5
Chapter 22	e5
Chapter 23	e6
Chapter 24	e6
Chapter 25	e6
Chapter 26	e6
Chapter 27	e6
Chapter 28	e6
Chapter 29	e6
Chapter 30	e6
Chapter 31	e7
Chapter 32	e7
Chapter 33	e7
Chapter 34	e7
Chapter 35	e7
Chapter 36	e8
Chapter 37	e8
Chapter 38	e8
Chapter 39	e8
Chapter 40	e8
Chapter 41	e8
Chapter 42	e8
Chapter 43	e9
Chapter 44	e9
Chapter 45	e9
Chapter 46	e9
Chapter 47	e10
Chapter 48	e10
Chapter 49	e10
Chapter 50	e10
Chapter 51	e10
Chapter 52	e10
Chapter 53	e10
Chapter 54	e11
Chapter 55	e11
Chapter 56	e11
Chapter 58	e11
Chapter 59	e11
Chapter 60	e11
Chapter 62	e11
Chapter 63	e12
Chapter 64	e12
Chapter 65	e12
Chapter 66	e12
Chapter 67	e12
Chapter 68	e12
Chapter 69	e13
Chapter 70	e13
Chapter 71	e13
Chapter 72	e14
Chapter 73	e14
Chapter 74	e14
Chapter 75	e14
Chapter 76	e15
Chapter 77	e15
Chapter 78	e15
Chapter 79	e15
Chapter 80	e15
Chapter 81	e15
Chapter 82	e16
Chapter 83	e16
Chapter 84	e16
Chapter 85	e17
Chapter 86	e17
Chapter 87	e17
Chapter 88	e17
Chapter 89	e17
Chapter 90	e18
Chapter 91	e18
Chapter 92	e19
Chapter 93	e19
Chapter 94	e19
Chapter 95	e19
Chapter 96	e19
Inside Back Cover	ibc1

Clinical Immunology E-Book

Additional Information

Book Details

Abstract

Table of Contents

Contact Us

Quick Navigation