Janeway’s Immunobiology, 9th Edition

Icons used throughout the book......Page 2
Title Page......Page 5
Copyright......Page 6
Preface......Page 7
Student Resources......Page 8
Acknowledgments......Page 9
Contents......Page 11
Detailed Contents......Page 12
Chapter 1 Basic Concepts in Immunology......Page 23
The origins of vertebrate immune cells.......Page 24
1-1 Commensal organisms cause little host damage while pathogens damage host tissues by a variety of mechanisms.......Page 25
1-2 Anatomic and chemical barriers are the first defense against pathogens.......Page 27
1-3 The immune system is activated by inflammatory inducers thatindicate the presence of pathogens or tissue damage.......Page 28
1-4 The myeloid lineage comprises most of the cells of the innate immune system.......Page 29
1-5 Sensor cells express pattern recognition receptors that provide an initial discrimination between self and nonself.......Page 30
1-6 Sensor cells induce an inflammatory response by producing mediators such as chemokines and cytokines.......Page 31
Principles of adaptive immunity.......Page 33
1-8 The interaction of antigens with antigen receptors induces lymphocytes to acquire effector and memory activity.......Page 34
1-9 Antibodies and T-cell receptors are composed of constant and variable regions that provide distinct functions.......Page 35
1-10 Antibodies and T-cell receptors recognize antigens by fundamentally different mechanisms.......Page 36
1-12 Lymphocytes activated by antigen give rise to clones of antigen-specific effector cells that mediate adaptive immunity.......Page 37
1-13 Lymphocytes with self-reactive receptors are normally eliminated during development or are functionally inactivated.......Page 38
1-14 Lymphocytes mature in the bone marrow or the thymus and then congregate in lymphoid tissues throughout the body.......Page 39
1-15 Adaptive immune responses are initiated by antigen and antigen-presenting cells in secondary lymphoid tissues.......Page 40
1-16 Lymphocytes encounter and respond to antigen in the peripheral lymphoid organs.......Page 41
1-17 Mucosal surfaces have specialized immune structures that orchestrate responses to environmental microbial encounters.......Page 44
1-18 Lymphocytes activated by antigen proliferate in the peripheral lymphoid organs, generating effector cells and immunological memory.......Page 45
Summary.......Page 46
The effector mechanisms of immunity.......Page 47
1-19 Innate immune responses can select from several effector modules to protect against different types of pathogens.......Page 48
1-20 Antibodies protect against extracellular pathogens and their toxic products.......Page 49
1-21 T cells orchestrate cell-mediated immunity and regulate B-cell responses to most antigens.......Page 51
1-22 Inherited and acquired defects in the immune system result in increased susceptibility to infection.......Page 53
1-23 Understanding adaptive immune responses is important for the control of allergies, autoimmune disease, and the rejection of transplanted organs.......Page 54
1-24 Vaccination is the most effective means of controlling infectious diseases.......Page 55
Summary to Chapter 1.......Page 56
Questions.......Page 57
References.......Page 58
Chapter 2 Innate Immunity: The First Lines
of Defense......Page 59
2-1 Infectious diseases are caused by diverse living agents that replicate in their hosts.......Page 60
2-2 Epithelial surfaces of the body provide the first barrier against infection.......Page 64
2-3 Infectious agents must overcome innate host defenses to establish a focus of infection.......Page 66
2-4 Epithelial cells and phagocytes produce several kinds of antimicrobial proteins.......Page 67
Summary.......Page 70
The complement system and innate immunity.......Page 71
2-5 The complement system recognizes features of microbial surfaces and marks them for destruction by coating them with C3b.......Page 72
2-6 The lectin pathway uses soluble receptors that recognize microbial surfaces to activate the complement cascade.......Page 75
2-7 The classical pathway is initiated by activation of the C1 complex and is homologous to the lectin pathway.......Page 78
2-8 Complement activation is largely confined to the surface on which it is initiated.......Page 79
2-9 The alternative pathway is an amplification loop for C3b formation that is accelerated by properdin in the presence of pathogens.......Page 80
2-10 Membrane and plasma proteins that regulate the formation and stability of C3 convertases determine the extent of complement activation.......Page 82
2-11 Complement developed early in the evolution of multicellular organisms.......Page 83
2-12 Surface-bound C3 convertase deposits large numbers of C3b fragments on pathogen surfaces and generates C5 convertase activity.......Page 84
2-13 Ingestion of complement-tagged pathogens by phagocytes is mediated by receptors for the bound complement proteins.......Page 85
2-14 The small fragments of some complement proteins initiate a local inflammatory response.......Page 87
2-15 The terminal complement proteins polymerize to form pores in membranes that can kill certain pathogens.......Page 88
2-16 Complement control proteins regulate all three pathways of complement activation and protect the host from their destructive effects.......Page 89
2-17 Pathogens produce several types of proteins that can inhibit complement activation.......Page 93
Summary.......Page 94
Summary to Chapter 2.......Page 95
Questions.......Page 96
References.......Page 97
Pattern recognition by cells of the innateimmune system.......Page 99
3-1 After entering tissues, many microbes are recognized, ingested, and killed by phagocytes.......Page 100
3-2 G-protein-coupled receptors on phagocytes link microbe recognition with increased efficiency of intracellular killing.......Page 103
3-3 Microbial recognition and tissue damage initiate an inflammatory response.......Page 107
3-4 Toll-like receptors represent an ancient pathogen recognition system.......Page 109
3-5 Mammalian Toll-like receptors are activated by many different pathogen-associated molecular patterns.......Page 110
3-7 TLRs activate NFκB, AP-1, and IRF transcription factors to induce the expression of inflammatory cytokines and type I interferons.......Page 114
3-8 The NOD-like receptors are intracellular sensors of bacterial infection and cellular damage.......Page 118
3-9 NLRP proteins react to infection or cellular damage through an inflammasome to induce cell death and inflammation.......Page 120
3-10 The RIG-I-like receptors detect cytoplasmic viral RNAs and activate MAVS to induce type I interferon production and pro‑inflammatory cytokines.......Page 123
3-11 Cytosolic DNA sensors signal through STING to induce production of type I interferons.......Page 125
3-12 Activation of innate sensors in macrophages and dendritic cells triggers changes in gene expression that have far‑reaching effects on the immune response.......Page 126
3-13 Toll signaling in Drosophila is downstream of a distinct set of pathogen-recognition molecules.......Page 127
Summary.......Page 128
3-15 Cytokines and their receptors fall into distinct families of structurally related proteins.......Page 129
3-16 Cytokine receptors of the hematopoietin family are associated with the JAK family of tyrosine kinases, which activate STAT transcription factors.......Page 131
3-17 Chemokines released by macrophages and dendritic cells recruit effector cells to sites of infection.......Page 133
3-18 Cell-adhesion molecules control interactions between leukocytes and endothelial cells during an inflammatory response.......Page 135
3-19 Neutrophils make up the first wave of cells that cross the blood vessel wall to enter an inflamed tissue.......Page 138
3-21 Cytokines made by macrophages and dendritic cells induce a systemic reaction known as the acute-phase response.......Page 140
3-22 Interferons induced by viral infection make several contributions to host defense.......Page 143
3-23 Several types of innate lymphoid cells provide protection in early infection.......Page 146
3-24 NK cells are activated by type I interferon and macrophage-derived cytokines.......Page 147
3-25 NK cells express activating and inhibitory receptors to distinguish between healthy and infected cells.......Page 148
3-26 NK-cell receptors belong to several structural families, the KIRs, KLRs, and NCRs.......Page 150
3-27 NK cells express activating receptors that recognize ligands induced on infected cells or tumor cells.......Page 152
Summary to Chapter 3.......Page 153
Questions.......Page 154
References.......Page 155
Chapter 4 Antigen Recognition by B-cell and
T-cell Receptors......Page 161
The structure of a typical antibody molecule.......Page 162
4-1 IgG antibodies consist of four polypeptide chains.......Page 163
4-3 The domains of an immunoglobulin molecule have similar structures.......Page 164
4-4 The antibody molecule can readily be cleaved into functionally distinct fragments.......Page 166
Summary.......Page 167
4-6 Localized regions of hypervariable sequence form the antigen-binding site.......Page 168
4-7 Antibodies bind antigens via contacts in CDRs that are complementary to the size and shape of the antigen.......Page 169
4-8 Antibodies bind to conformational shapes on the surfaces of antigens using a variety of noncovalent forces.......Page 170
4-9 Antibody interaction with intact antigens is influenced by steric constraints.......Page 172
4-10 Some species generate antibodies with alternative structures.......Page 173
Antigen recognition by T cells.......Page 174
4-11 The TCRα:β heterodimer is very similar to a Fab fragment of immunoglobulin.......Page 175
4-13 There are two classes of MHC molecules with distinct subunit compositions but similar three-dimensional structures.......Page 177
4-15 MHC class I molecules bind short peptides of 8–10 amino acids by both ends.......Page 180
4-16 The length of the peptides bound by MHC class II molecules is not constrained.......Page 182
4-17 The crystal structures of several peptide:MHC:T-cell receptor complexes show a similar orientation of the T-cell receptor over the peptide:MHC complex.......Page 183
4-18 The CD4 and CD8 cell-surface proteins of T cells directly contact MHC molecules and are required to make an effective response to antigen.......Page 185
4-20 A distinct subset of T cells bears an alternative receptor made up of γ and δ chains.......Page 188
Summary.......Page 189
Summary to Chapter 4.......Page 190
Questions.......Page 191
References.......Page 192
Chapter 5 The Generation of Lymphocyte
Antigen Receptors......Page 195
5-1 Immunoglobulin genes are rearranged in the
progenitors of antibody-producing cells.......Page 196
5-2 Complete genes that encode a variable region
are generated by the somatic recombination of
separate gene segments.......Page 197
5-3 Multiple contiguous V gene segments are present
at each immunoglobulin locus.......Page 198
5-4 Rearrangement of V, D, and J gene segments is
guided by flanking DNA sequences.......Page 200
5-5 The reaction that recombines V, D, and J gene
segments involves both lymphocyte-specific and
ubiquitous DNA-modifying enzymes.......Page 201
5-7 The multiple inherited gene segments are used in
different combinations.......Page 206
5-8 Variable addition and subtraction of nucleotides at
the junctions between gene segments contributes
to the diversity of the third hypervariable region.......Page 207
Summary.......Page 208
5-9 The T-cell receptor gene segments are arranged in
a similar pattern to immunoglobulin gene segments
and are rearranged by the same enzymes.......Page 209
5-10 T-cell receptors concentrate diversity in the third
hypervariable region.......Page 211
5-11 γ:δ T-cell receptors are also generated by gene
rearrangement.......Page 212
Structural variation in immunoglobulinconstant regions.......Page 213
5-12 Different classes of immunoglobulins are
distinguished by the structure of their heavychain
constant regions.......Page 214
5-13 The constant region confers functional
specialization on the antibody.......Page 215
5-14 IgM and IgD are derived from the same pre-mRNA
transcript and are both expressed on the surface of
mature B cells.......Page 216
5-15 Transmembrane and secreted forms of immunoglobulin
are generated from alternative heavy-chain
mRNA transcripts.......Page 217
5-16 IgM and IgA can form polymers by interacting with
the J chain.......Page 219
5-17 Some invertebrates generate extensive diversity
in a repertoire of immunoglobulin-like genes.......Page 220
5-18 Agnathans possess an adaptive immune system
that uses somatic gene rearrangement to diversify
receptors built from LRR domains.......Page 222
5-19 RAG-dependent adaptive immunity based on a
diversified repertoire of immunoglobulin-like genes
appeared abruptly in the cartilaginous fishes.......Page 224
5-20 Different species generate immunoglobulin
diversity in different ways.......Page 225
5-22 MHC class I and class II molecules are also first
found in the cartilaginous fishes.......Page 228
Summary to Chapter 5.......Page 229
Questions.......Page 230
References.......Page 231
Chapter 6 Antigen Presentation to
T Lymphocytes......Page 235
6-1 Antigen presentation functions both in arming
effector T cells and in triggering their effector
functions to attack pathogen-infected cells.......Page 236
6-2 Peptides are generated from ubiquitinated
proteins in the cytosol by the proteasome.......Page 238
6-3 Peptides from the cytosol are transported by TAP
into the endoplasmic reticulum and further processed
before binding to MHC class I molecules.......Page 240
6-4 Newly synthesized MHC class I molecules are
retained in the endoplasmic reticulum until they
bind a peptide.......Page 241
6-5 Dendritic cells use cross-presentation to present
exogenous proteins on MHC class I molecules to
prime CD8 T cells.......Page 244
6-6 Peptide:MHC class II complexes are generated in
acidified endocytic vesicles from proteins obtained
through endocytosis, phagocytosis, and autophagy.......Page 245
6-7 The invariant chain directs newly synthesized MHC
class II molecules to acidified intracellular vesicles.......Page 247
6-8 The MHC class II-like molecules HLA-DM and
HLA-DO regulate exchange of CLIP for other
peptides.......Page 248
6-9 Cessation of antigen processing occurs in dendritic
cells after their activation through reduced
expression of the MARCH-1 E3 ligase.......Page 251
Summary.......Page 252
6-10 Many proteins involved in antigen processing and
presentation are encoded by genes within the MHC.......Page 253
6-11 The protein products of MHC class I and class II genes are highly polymorphic.......Page 256
6-12 MHC polymorphism affects antigen recognition by
T cells by influencing both peptide binding and the
contacts between T-cell receptor and MHC molecule.......Page 257
6-13 Alloreactive T cells recognizing nonself MHC
molecules are very abundant.......Page 261
6-14 Many T cells respond to superantigens.......Page 262
6-15 MHC polymorphism extends the range of antigens
to which the immune system can respond.......Page 263
Generation of ligands for unconventional
T-cell subsets.......Page 264
6-16 A variety of genes with specialized functions in
immunity are also encoded in the MHC.......Page 265
6-17 Specialized MHC class I molecules act as ligands for theactivation and inhibition of NK cells and unconventionalT-cell subsets.......Page 267
6-18 Members of the CD1 family of MHC class I-like
molecules present microbial lipids to invariant
NKT cells.......Page 268
6-19 The nonclassical MHC class I molecule MR1
presents microbial folate metabolites to MAIT cells.......Page 270
6-20 γ:δ T cells can recognize a variety of diverse ligands.......Page 271
Summary to Chapter 6.......Page 272
Questions.......Page 273
References.......Page 274
General principles of signal transduction and
propagation.......Page 279
7-1 Transmembrane receptors convert extracellular
signals into intracellular biochemical events.......Page 280
7-2 Intracellular signal propagation is mediated by large
multiprotein signaling complexes.......Page 282
7-4 Signaling proteins are recruited to the membrane by
a variety of mechanisms.......Page 284
7-5 Post-translational modifications of proteins can both
activate and inhibit signaling responses.......Page 285
7-6 The activation of some receptors generates smallmolecule
second messengers.......Page 286
Antigen receptor signaling and lymphocyte activation.......Page 287
7-7 Antigen receptors consist of variable antigen-binding
chains associated with invariant chains that carry
out the signaling function of the receptor.......Page 288
7-8 Antigen recognition by the T-cell receptor and its
co-receptors transduces a signal across the plasma
membrane to initiate signaling.......Page 289
7-9 Antigen recognition by the T-cell receptor and its
co-receptors leads to phosphorylation of ITAMs by
Src-family kinases, generating the first intracellular
signal in a signaling cascade.......Page 290
7-11 ITAMs are also found in other receptors on
leukocytes that signal for cell activation.......Page 292
7-12 Activated ZAP-70 phosphorylates scaffold proteins
and promotes PI 3-kinase activation.......Page 293
7-13 Activated PLC-γ generates the second messengers
diacylglycerol and inositol trisphosphate that lead to
transcription factor activation.......Page 294
7-14 Ca2+ entry activates the transcription factor NFAT.......Page 295
7-15 Ras activation stimulates the mitogen-activated
protein kinase (MAPK) relay and induces expression
of the transcription factor AP-1.......Page 296
7-16 Protein kinase C activates the transcription factors
NFκB and AP-1.......Page 298
7-17 PI 3-kinase activation upregulates cellular metabolic
pathways via the serine/threonine kinase Akt.......Page 299
7-18 T-cell receptor signaling leads to enhanced integrinmediated
cell adhesion.......Page 300
7-20 The logic of B-cell receptor signaling is similar to that
of T-cell receptor signaling, but some of the signaling
components are specific to B cells.......Page 301
Co-stimulatory and inhibitory receptors modulate
antigen receptor signaling in T and B lymphocytes.......Page 304
7-21 The cell-surface protein CD28 is a required
co-stimulatory signaling receptor for naive T-cell
activation.......Page 305
7-23 TNF receptor superfamily members augment T-cell
and B-cell activation.......Page 306
7-24 Inhibitory receptors on lymphocytes downregulate
immune responses by interfering with co-stimulatory
signaling pathways.......Page 308
7-25 Inhibitory receptors on lymphocytes downregulate
immune responses by recruiting protein or lipid
phosphatases.......Page 309
Summary.......Page 310
Summary to Chapter 7.......Page 311
Questions.......Page 312
References.......Page 313
Chapter 8 The Development of B and
T Lymphocytes......Page 317
Development of B lymphocytes.......Page 318
8-1 Lymphocytes derive from hematopoietic stem cells
in the bone marrow.......Page 319
8-2 B-cell development begins by rearrangement of the
heavy-chain locus.......Page 321
8-3 The pre-B-cell receptor tests for successful
production of a complete heavy chain and signals
for the transition from the pro-B cell to the pre-B
cell stage.......Page 324
8-4 Pre-B-cell receptor signaling inhibits further
heavy-chain locus rearrangement and enforces
allelic exclusion.......Page 325
8-5 Pre-B cells rearrange the light-chain locus and
express cell-surface immunoglobulin.......Page 326
8-6 Immature B cells are tested for autoreactivity
before they leave the bone marrow.......Page 327
8-7 Lymphocytes that encounter sufficient quantities
of self antigens for the first time in the periphery
are eliminated or inactivated.......Page 330
8-8 Immature B cells arriving in the spleen turn over
rapidly and require cytokines and positive signals
through the B-cell receptor for maturation and
long-term survival.......Page 331
8-9 B-1 B cells are an innate lymphocyte subset that
arises early in development.......Page 334
Summary.......Page 335
8-10 T-cell progenitors originate in the bone marrow,
but all the important events in their development
occur in the thymus.......Page 337
8-12 T-cell precursors proliferate extensively in the
thymus, but most die there.......Page 339
8-13 Successive stages in the development of
thymocytes are marked by changes in cell-surface
molecules.......Page 341
8-14 Thymocytes at different developmental stages are
found in distinct parts of the thymus.......Page 343
8-16 T cells expressing γ:δ T-cell receptors arise in two
distinct phases during development.......Page 344
8-17 Successful synthesis of a rearranged β chain allows
the production of a pre-T-cell receptor that triggers
cell proliferation and blocks further β-chain gene
rearrangement.......Page 346
8-18 T-cell α-chain genes undergo successive rearrangements
until positive selection or cell death intervenes.......Page 348
8-19 Only thymocytes whose receptors interact with self
peptide:self MHC complexes can survive and mature.......Page 350
8-20 Positive selection acts on a repertoire of T-cell
receptors with inherent specificity for MHC molecules.......Page 351
8-21 Positive selection coordinates the expression of
CD4 or CD8 with the specificity of the T-cell receptor
and the potential effector functions of the T cell.......Page 352
8-22 Thymic cortical epithelial cells mediate positive
selection of developing thymocytes.......Page 353
8-23 T cells that react strongly with ubiquitous self
antigens are deleted in the thymus.......Page 354
8-25 The specificity and/or the strength of signals for
negative and positive selection must differ.......Page 356
8-26 Self-recognizing regulatory T cells and innate T cells
develop in the thymus.......Page 357
8-28 T cells that encounter sufficient quantities of self
antigens for the first time in the periphery are
eliminated or inactivated.......Page 358
Summary to Chapter 8.......Page 359
Questions.......Page 361
References.......Page 362
Chapter 9 T-cell-Mediated Immunity......Page 367
9-1 T and B lymphocytes are found in distinct locations
in secondary lymphoid tissues.......Page 369
9-2 The development of secondary lymphoid tissues is
controlled by lymphoid tissue inducer cells and
proteins of the tumor necrosis factor family.......Page 371
9-3 T and B cells are partitioned into distinct regions of
secondary lymphoid tissues by the actions of
chemokines.......Page 372
9-4 Naive T cells migrate through secondary lymphoid
tissues, sampling peptide:MHC complexes on
dendritic cells.......Page 373
9-5 Lymphocyte entry into lymphoid tissues depends
on chemokines and adhesion molecules.......Page 374
9-6 Activation of integrins by chemokines is responsible
for the entry of naive T cells into lymph nodes.......Page 375
9-7 The exit of T cells from lymph nodes is controlled
by a chemotactic lipid.......Page 377
9-8 T-cell responses are initiated in secondary
lymphoid organs by activated dendritic cells.......Page 378
9-9 Dendritic cells process antigens from a wide array
of pathogens.......Page 380
9-10 Microbe-induced TLR signaling in tissue-resident
dendritic cells induces their migration to lymphoid
organs and enhances antigen processing.......Page 383
9-12 Macrophages are scavenger cells that can be induced
by pathogens to present foreign antigens to naive
T cells.......Page 385
9-13 B cells are highly efficient at presenting antigens
that bind to their surface immunoglobulin.......Page 386
Priming of naive T cells by pathogen-activated
dendritic cells.......Page 388
9-14 Cell-adhesion molecules mediate the initial
interaction of naive T cells with antigenpresenting
cells.......Page 389
9-16 CD28-dependent co-stimulation of activated T cells
induces expression of interleukin-2 and the
high-affinity IL-2 receptor.......Page 390
9-17 Additional co-stimulatory pathways are involved in
T-cell activation.......Page 391
9-18 Proliferating T cells differentiate into effector T cells
that do not require co-stimulation to act.......Page 392
9-20 CD4 T cells differentiate into several subsets of
functionally different effector cells.......Page 394
9-21 Cytokines induce the differentiation of naive CD4
T cells down distinct effector pathways.......Page 397
9-22 CD4 T-cell subsets can cross-regulate each other’s
differentiation through the cytokines they produce.......Page 399
9-23 Regulatory CD4 T cells are involved in controlling
adaptive immune responses.......Page 401
General properties of effector T cells and
their cytokines.......Page 402
9-25 An immunological synapse forms between effector
T cells and their targets to regulate signaling and to
direct the release of effector molecules.......Page 403
9-27 Cytokines can act locally or at a distance.......Page 405
Summary.......Page 408
9-29 Cytotoxic T cells induce target cells to undergo
programmed cell death via extrinsic and intrinsic
pathways of apoptosis.......Page 409
9-30 The intrinsic pathway of apoptosis is mediated by
the release of cytochrome c from mitochondria.......Page 411
9-31 Cytotoxic effector proteins that trigger apoptosis are
contained in the granules of CD8 cytotoxic T cells.......Page 412
9-32 Cytotoxic T cells are selective serial killers of targets
expressing a specific antigen.......Page 413
Summary to Chapter 9.......Page 414
Questions.......Page 415
References.......Page 417
Chapter 10 The Humoral Immune Response......Page 421
10-1 Activation of B cells by antigen involves signals from
the B-cell receptor and either TFH cells or microbial
antigens.......Page 422
10-2 Linked recognition of antigen by T cells and B cells
promotes robust antibody responses.......Page 424
10-3 B cells that encounter their antigens migrate toward
the boundaries between B-cell and T-cell areas in
secondary lymphoid tissues.......Page 425
10-5 Activated B cells differentiate into antibody-secreting
plasmablasts and plasma cells.......Page 428
10-6 The second phase of a primary B-cell immune
response occurs when activated B cells migrate into
follicles and proliferate to form germinal centers.......Page 430
10-7 Germinal center B cells undergo V-region somatic
hypermutation, and cells with mutations that improve
affinity for antigen are selected.......Page 432
10-8 Positive selection of germinal center B cells involves
contact with TFH cells and CD40 signaling.......Page 434
10-9 Activation-induced cytidine deaminase (AID)
introduces mutations into genes transcribed
in B cells.......Page 435
10-10 Mismatch and base-excision repair pathways
contribute to somatic hypermutation following
initiation by AID.......Page 436
10-11 AID initiates class switching to allow the same
assembled VH exon to be associated with different
CH genes in the course of an immune response.......Page 437
10-12 Cytokines made by TFH cells direct the choice of
isotype for class switching in T-dependent antibody
responses.......Page 440
10-14 Some antigens do not require T-cell help to induce
B-cell responses.......Page 441
Summary.......Page 443
The distributions and functions of immunoglobulin
classes.......Page 444
10-15 Antibodies of different classes operate in distinct
places and have distinct effector functions.......Page 445
10-16 Polymeric immunoglobulin receptor binds to the
Fc regions of IgA and IgM and transports them
across epithelial barriers.......Page 447
10-18 High-affinity IgG and IgA antibodies can neutralize
toxins and block the infectivity of viruses and
bacteria.......Page 448
10-19 Antibody:antigen complexes activate the classical
pathway of complement by binding to C1q.......Page 451
10-20 Complement receptors and Fc receptors both
contribute to removal of immune complexes from
the circulation.......Page 452
Summary.......Page 453
10-21 The Fc receptors of accessory cells are signaling
receptors specific for immunoglobulins of different
classes.......Page 454
10-22 Fc receptors on phagocytes are activated by
antibodies bound to the surface of pathogens
and enable the phagocytes to ingest and
destroy pathogens.......Page 455
10-23 Fc receptors activate NK cells to destroy
antibody-coated targets.......Page 457
10-24 Mast cells and basophils bind IgE antibody via
the high‑affinity Fcε receptor.......Page 458
10-25 IgE-mediated activation of accessory cells has
an important role in resistance to parasite infection.......Page 459
Summary.......Page 460
Summary to Chapter 10.......Page 461
Questions.......Page 462
References.......Page 463
Chapter 11 Integrated Dynamics of
Innate and Adaptive Immunity......Page 467
11-1 The course of an infection can be divided into
several distinct phases.......Page 468
11-2 The effector mechanisms that are recruited to
clear an infection depend on the infectious agent.......Page 471
Effector T cells augment the effector functions of
innate immune cells.......Page 474
11-3 Effector T cells are guided to specific tissues and
sites of infection by changes in their expression of
adhesion molecules and chemokine receptors.......Page 475
11-4 Pathogen-specific effector T cells are enriched at
sites of infection as adaptive immunity progresses.......Page 479
11-5 TH1 cells coordinate and amplify the host response
to intracellular pathogens through classical
activation of macrophages.......Page 480
11-6 Activation of macrophages by TH1 cells must be
tightly regulated to avoid tissue damage.......Page 482
11-8 Defects in type 1 immunity reveal its important
role in the elimination of intracellular pathogens.......Page 483
11-9 TH2 cells coordinate type 2 responses to expel
intestinal helminths and repair tissue injury.......Page 484
11-10 TH17 cells coordinate type 3 responses to enhance
the clearance of extracellular bacteria and fungi.......Page 487
11-11 Differentiated effector T cells continue to respond
to signals as they carry out their effector functions.......Page 488
11-12 Effector T cells can be activated to release
cytokines independently of antigen recognition.......Page 489
11-13 Effector T cells demonstrate plasticity and
cooperativity that enable adaptation during
anti-pathogen responses.......Page 490
11-14 Integration of cell- and antibody-mediated
immunity is critical for protection against many
types of pathogens.......Page 491
11-15 Primary CD8 T-cell responses to pathogens can
occur in the absence of CD4 T-cell help.......Page 492
11-16 Resolution of an infection is accompanied by the
death of most of the effector cells and the
generation of memory cells.......Page 493
Summary.......Page 494
11-17 Immunological memory is long lived after infection
or vaccination.......Page 495
11-18 Memory B-cell responses are more rapid and have
higher affinity for antigen compared with responses
of naive B cells.......Page 497
11-19 Memory B cells can reenter germinal centers and
undergo additional somatic hypermutation and
affinity maturation during secondary immune
responses.......Page 498
11-20 MHC tetramers identify memory T cells that persist
at an increased frequency relative to their frequency
as naive T cells.......Page 499
11-21 Memory T cells arise from effector T cells that
maintain sensitivity to IL-7 or IL-15.......Page 500
11-22 Memory T cells are heterogeneous and include
central memory, effector memory, and tissueresident
subsets.......Page 502
11-23 CD4 T-cell help is required for CD8 T-cell memory
and involves CD40 and IL-2 signaling.......Page 504
11-24 In immune individuals, secondary and subsequent
responses are mainly attributable to memory
lymphocytes.......Page 506
Summary.......Page 507
Summary to Chapter 11.......Page 508
Questions.......Page 509
References.......Page 510
12-1 The mucosal immune system protects the internal
surfaces of the body.......Page 515
12-2 Cells of the mucosal immune system are located
both in anatomically defined compartments and
scattered throughout mucosal tissues.......Page 518
12-3 The intestine has distinctive routes and
mechanisms of antigen uptake.......Page 521
12-4 The mucosal immune system contains large
numbers of effector lymphocytes even in the
absence of disease.......Page 522
12-5 The circulation of lymphocytes within the mucosal
immune system is controlled by tissue-specific
adhesion molecules and chemokine receptors.......Page 523
12-6 Priming of lymphocytes in one mucosal tissue may
induce protective immunity at other mucosal
surfaces.......Page 524
12-7 Distinct populations of dendritic cells control
mucosal immune responses.......Page 525
12-9 Antigen-presenting cells in the intestinal mucosa
acquire antigen by a variety of routes.......Page 527
12-10 Secretory IgA is the class of antibody associated
with the mucosal immune system.......Page 528
12-12 IgA deficiency is relatively common in humans but
may be compensated for by secretory IgM.......Page 531
12-13 The intestinal lamina propria contains antigenexperienced
T cells and populations of unusual
innate lymphoid cells.......Page 532
12-14 The intestinal epithelium is a unique compartment
of the immune system.......Page 533
The mucosal response to infection and regulation
of mucosal immune responses.......Page 536
12-15 Enteric pathogens cause a local inflammatory response and the development of protective immunity.......Page 537
12-17 Effector T-cell responses in the intestine protect
the function of the epithelium.......Page 540
12-18 The mucosal immune system must maintain
tolerance to harmless foreign antigens.......Page 541
12-19 The normal intestine contains large quantities of
bacteria that are required for health.......Page 542
12-20 Innate and adaptive immune systems control
microbiota while preventing inflammation without
compromising the ability to react to invaders.......Page 543
12-21 The intestinal microbiota plays a major role in
shaping intestinal and systemic immune function.......Page 544
12-22 Full immune responses to commensal bacteria
provoke intestinal disease.......Page 546
Summary to Chapter 12.......Page 547
Questions.......Page 548
References.......Page 549
Immunodeficiency diseases.......Page 555
13-2 Primary immunodeficiency diseases are caused
by inherited gene defects.......Page 556
13-3 Defects in T-cell development can result in severe
combined immunodeficiencies.......Page 557
13-5 Defects in antigen receptor gene rearrangement
can result in SCID.......Page 560
13-7 Genetic defects in thymic function that block T-cell
development result in severe immunodeficiencies.......Page 561
13-8 Defects in B-cell development result in deficiencies
in antibody production that cause an inability to
clear extracellular bacteria and some viruses.......Page 563
13-9 Immune deficiencies can be caused by defects in
B-cell or T-cell activation and function that lead to
abnormal antibody responses.......Page 565
13-10 Normal pathways for host defense against different
infectious agents are pinpointed by genetic deficiencies
of cytokine pathways central to type 1/TH1 and type
3/TH17 responses.......Page 568
13-11 Inherited defects in the cytolytic pathway of
lymphocytes can cause uncontrolled lymphoproliferation
and inflammatory responses to viral
infections.......Page 570
13-12 X-linked lymphoproliferative syndrome is associated
with fatal infection by Epstein–Barr virus and with the
development of lymphomas.......Page 572
13-13 Immunodeficiency is caused by inherited defects
in the development of dendritic cells.......Page 573
13-14 Defects in complement components and complementregulatory
proteins cause defective humoral immune
function and tissue damage.......Page 574
13-15 Defects in phagocytic cells permit widespread
bacterial infections.......Page 575
13-16 Mutations in the molecular regulators of inflammation
can cause uncontrolled inflammatory responses that
result in ‘autoinflammatory disease.’......Page 578
13-17 Hematopoietic stem cell transplantation or gene
therapy can be useful to correct genetic defects.......Page 579
13-18 Noninherited, secondary immunodeficiencies are
major predisposing causes of infection and death.......Page 580
Summary.......Page 581
13-19 Extracellular bacterial pathogens have evolved
different strategies to avoid detection by pattern
recognition receptors and destruction by antibody,
complement, and antimicrobial peptides.......Page 582
13-20 Intracellular bacterial pathogens can evade the
immune system by seeking shelter within phagocytes.......Page 585
13-21 Immune evasion is also practiced by protozoan
parasites.......Page 587
13-22 RNA viruses use different mechanisms of antigenic
variation to keep a step ahead of the adaptive
immune system.......Page 588
13-23 DNA viruses use multiple mechanisms to subvert
NK-cell and CTL responses.......Page 590
13-24 Some latent viruses persist in vivo by ceasing to
replicate until immunity wanes.......Page 593
Acquired immune deficiency syndrome.......Page 595
13-25 HIV is a retrovirus that establishes a chronic
infection that slowly progresses to AIDS.......Page 596
13-26 HIV infects and replicates within cells of the
immune system.......Page 598
13-27 Activated CD4 T cells are the major source of
HIV replication.......Page 600
13-28 There are several routes by which HIV is
transmitted and establishes infection.......Page 601
13-29 HIV variants with tropism for different co-receptors
play different roles in transmission and progression
of disease.......Page 602
13-30 A genetic deficiency of the co-receptor CCR5
confers resistance to HIV infection.......Page 604
13-31 An immune response controls but does not
eliminate HIV.......Page 605
13-33 Genetic variation in the host can alter the rate of
disease progression.......Page 607
13-34 The destruction of immune function as a result of
HIV infection leads to increased susceptibility to
opportunistic infection and eventually to death.......Page 609
13-35 Drugs that block HIV replication lead to a rapid
decrease in titer of infectious virus and an
increase in CD4 T cells.......Page 610
13-36 In the course of infection HIV accumulates many
mutations, which can result in the outgrowth of
drug-resistant variants.......Page 612
13-37 Vaccination against HIV is an attractive solution
but poses many difficulties.......Page 613
13-38 Prevention and education are important in
controlling the spread of HIV and AIDS.......Page 614
Summary.......Page 615
Questions.......Page 616
References.......Page 617
Chapter 14 Allergy and Allergic Diseases......Page 623
IgE and IgE-mediated allergic diseases.......Page 624
14-1 Sensitization involves class switching to IgE
production on first contact with an allergen.......Page 625
14-2 Although many types of antigens can cause
allergic sensitization, proteases are common
sensitizing agents.......Page 627
14-3 Genetic factors contribute to the development of
IgE‑mediated allergic disease.......Page 629
14-4 Environmental factors may interact with genetic
susceptibility to cause allergic disease.......Page 631
14-5 Regulatory T cells can control allergic responses.......Page 633
Effector mechanisms in IgE-mediated
allergic reactions.......Page 634
14-7 Mast cells reside in tissues and orchestrate allergic
reactions.......Page 635
14-8 Eosinophils and basophils cause inflammation and
tissue damage in allergic reactions.......Page 638
14-9 IgE-mediated allergic reactions have a rapid onset
but can also lead to chronic responses.......Page 639
14-10 Allergen introduced into the bloodstream can cause
anaphylaxis.......Page 641
14-11 Allergen inhalation is associated with the
development of rhinitis and asthma.......Page 643
14-12 Allergy to particular foods causes systemic
reactions as well as symptoms limited to the gut.......Page 646
14-13 IgE-mediated allergic disease can be treated by
inhibiting the effector pathways that lead to
symptoms or by desensitization techniques
that aim at restoring biological tolerance to
the allergen.......Page 647
Summary.......Page 649
14-15 Systemic disease caused by immune-complex
formation can follow the administration of large
quantities of poorly catabolized antigens.......Page 650
14-16 Hypersensitivity reactions can be mediated by TH1
cells and CD8 cytotoxic T cells.......Page 652
14-17 Celiac disease has features of both an allergic
response and autoimmunity.......Page 656
Summary to Chapter 14.......Page 658
Questions.......Page 659
References.......Page 660
15-1 A critical function of the immune system is to
discriminate self from nonself.......Page 665
15-2 Multiple tolerance mechanisms normally prevent
autoimmunity.......Page 667
15-3 Central deletion or inactivation of newly formed
lymphocytes is the first checkpoint of self-tolerance.......Page 668
15-4 Lymphocytes that bind self antigens with relatively
low affinity usually ignore them but in some
circumstances become activated.......Page 669
15-5 Antigens in immunologically privileged sites do not
induce immune attack but can serve as targets.......Page 670
15-6 Autoreactive T cells that express particular
cytokines may be nonpathogenic or may
suppress pathogenic lymphocytes.......Page 671
15-7 Autoimmune responses can be controlled at
various stages by regulatory T cells.......Page 672
15-8 Specific adaptive immune responses to self
antigens can cause autoimmune disease.......Page 674
15-9 Autoimmunity can be classified into either organspecific
or systemic disease.......Page 675
15-10 Multiple components of the immune system are
typically recruited in autoimmune disease.......Page 676
15-11 Chronic autoimmune disease develops through
positive feedback from inflammation, inability to
clear the self antigen, and a broadening of the
autoimmune response.......Page 679
15-12 Both antibody and effector T cells can cause
tissue damage in autoimmune disease.......Page 681
15-14 The fixation of sublytic doses of complement to
cells in tissues stimulates a powerful inflammatory
response.......Page 683
15-15 Autoantibodies against receptors cause disease by
stimulating or blocking receptor function.......Page 684
15-16 Autoantibodies against extracellular antigens cause
inflammatory injury.......Page 685
15-17 T cells specific for self antigens can cause direct
tissue injury and sustain autoantibody responses.......Page 687
Summary.......Page 690
15-18 Autoimmune diseases have a strong genetic
component.......Page 691
15-19 Genomics-based approaches are providing new
insight into the immunogenetic basis of autoimmunity.......Page 692
15-21 Monogenic defects of immune tolerance.......Page 696
15-22 MHC genes have an important role in controlling
susceptibility to autoimmune disease.......Page 698
15-23 Genetic variants that impair innate immune
responses can predispose to T-cell-mediated
chronic inflammatory disease.......Page 700
15-24 External events can initiate autoimmunity.......Page 701
15-26 Cross-reactivity between foreign molecules on
pathogens and self molecules can lead to antiself
responses and autoimmune disease.......Page 702
Summary.......Page 704
15-29 Graft rejection is an immunological response
mediated primarily by T cells.......Page 705
15-30 Transplant rejection is caused primarily by the strong
immune response to nonself MHC molecules.......Page 706
15-31 In MHC-identical grafts, rejection is caused by
peptides from other alloantigens bound to graft
MHC molecules.......Page 707
15-32 There are two ways of presenting alloantigens on the
transplanted donor organ to the recipient’s
T lymphocytes.......Page 708
15-34 Late failure of transplanted organs is caused by
chronic injury to the graft.......Page 710
15-35 A variety of organs are transplanted routinely in
clinical medicine.......Page 711
15-36 The converse of graft rejection is graft-versushost
disease.......Page 713
15-37 Regulatory T cells are involved in alloreactive
immune responses.......Page 714
15-38 The fetus is an allograft that is tolerated repeatedly.......Page 715
Summary to Chapter 15.......Page 716
Questions.......Page 717
References.......Page 718
Treatment of unwanted immune responses.......Page 723
16-1 Corticosteroids are powerful anti-inflammatory
drugs that alter the transcription of many genes.......Page 724
16-2 Cytotoxic drugs cause immunosuppression by
killing dividing cells and have serious side-effects.......Page 725
16-3 Cyclosporin A, tacrolimus, rapamycin, and JAK
inhibitors are effective immunosuppressive agents
that interfere with various T-cell signaling pathways.......Page 726
16-4 Antibodies against cell-surface molecules can be
used to eliminate lymphocyte subsets or to inhibit
lymphocyte function.......Page 728
16-5 Antibodies can be engineered to reduce their
immunogenicity in humans.......Page 729
16-6 Monoclonal antibodies can be used to prevent
allograft rejection......Page 730
16-7 Depletion of autoreactive lymphocytes can treat
autoimmune disease.......Page 732
16-8 Biologics that block TNF-α, IL-1, or IL-6 can
alleviate autoimmune diseases.......Page 733
16-9 Biologic agents can block cell migration to sites of
inflammation and reduce immune responses.......Page 734
16-11 Some commonly used drugs have
immunomodulatory properties.......Page 735
Summary.......Page 736
16-13 The development of transplantable tumors in mice
led to the discovery of protective immune
responses to tumors.......Page 738
16-14 Tumors are ‘edited’ by the immune system as they
evolve and can escape rejection in many ways.......Page 739
16-15 Tumor rejection antigens can be recognized by
T cells and form the basis of immunotherapies.......Page 742
16-16 T cells expressing chimeric antigen receptors are
an effective treatment in some leukemias.......Page 745
16-17 Monoclonal antibodies against tumor antigens,
alone or linked to toxins, can control tumor growth.......Page 746
16-18 Enhancing the immune response to tumors by
vaccination holds promise for cancer prevention
and therapy.......Page 748
16-19 Checkpoint blockade can augment immune
responses to existing tumors.......Page 749
Summary.......Page 750
Fighting infectious diseases with vaccination.......Page 751
16-20 Vaccines can be based on attenuated pathogens
or material from killed organisms.......Page 752
16-21 Most effective vaccines generate antibodies that
prevent the damage caused by toxins or that
neutralize the pathogen and stop infection.......Page 753
16-23 Live-attenuated viral vaccines are usually more
potent than ‘killed’ vaccines and can be made safer
by the use of recombinant DNA technology.......Page 754
16-24 Live-attenuated vaccines can be developed by
selecting nonpathogenic or disabled bacteria or by
creating genetically attenuated parasites (GAPs).......Page 756
16-25 The route of vaccination is an important
determinant of success.......Page 757
16-26 Bordetella pertussis vaccination illustrates the
importance of the perceived safety of a vaccine.......Page 758
16-27 Conjugate vaccines have been developed as a
result of linked recognition between T and B cells.......Page 759
16-28 Peptide-based vaccines can elicit protective
immunity, but they require adjuvants and must
be targeted to the appropriate cells and cell
compartment to be effective.......Page 760
16-29 Adjuvants are important for enhancing the
immunogenicity of vaccines, but few are approved
for use in humans.......Page 761
16-30 Protective immunity can be induced by DNA-based
vaccination.......Page 762
16-31 Vaccination and checkpoint blockade may be
useful in controlling existing chronic infections.......Page 763
Summary to Chapter 16.......Page 764
Questions.......Page 765
References.......Page 766
A-1. Immunization.......Page 771
A-2 Antibody responses.......Page 774
A-4 Radioimmunoassay (RIA), enzyme-linked
immunosorbent assay (ELISA), and competitive
inhibition assay.......Page 775
A-5 Hemagglutination and blood typing.......Page 777
A-6 Coombs tests and the detection of rhesus
incompatibility.......Page 778
A-7 Monoclonal antibodies.......Page 779
A-8 Phage display libraries for antibody V-region
production.......Page 780
A-9 Generation of human monoclonal antibodies from
vaccinated individuals.......Page 781
A-10 Microscopy and imaging using fluorescent dyes.......Page 782
A-11 Immunoelectron microscopy.......Page 783
A-13 Immunoprecipitation and co-immunoprecipitation.......Page 784
A-15 Use of antibodies in the isolation and
characterization of multiprotein complexes
by mass spectrometry.......Page 786
A-17 Isolation of lymphocytes from tissues other than
blood.......Page 788
A-18 Flow cytometry and FACS analysis.......Page 789
A-20 Isolation of homogeneous T-cell lines.......Page 792
A-21 Limiting-dilution culture.......Page 793
A-23 Identification of functional subsets of T cells based
on cytokine production or transcription factor
expression.......Page 795
A-24 Identification of T-cell receptor specificity using peptide:MHC
tetramers.......Page 798
A-25 Biosensor assays for measuring the rates of
association and dissociation of antigen receptors
for their ligands.......Page 799
A-26 Assays of lymphocyte proliferation.......Page 800
A-27 Measurements of apoptosis.......Page 801
A-28 Assays for cytotoxic T cells.......Page 802
A-30 Transfer of protective immunity.......Page 804
A-31 Adoptive transfer of lymphocytes.......Page 805
A-32 Hematopoietic stem-cell transfers.......Page 806
A-33 In vivo administration of antibodies.......Page 807
A-35 Gene knockout by targeted disruption.......Page 808
A-36 Knockdown of gene expression by
RNA interference (RNAi).......Page 812
Appendix II CD antigens......Page 813
Appendix III Cytokines and their Receptors......Page 833
Appendix IV Chemokines and their Receptors......Page 836
Biographies......Page 838
Photograph Acknowledgments......Page 839
Glossary......Page 840
Movie List......Page 877