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Janeway’s Immunobiology is a textbook for students studying immunology at the undergraduate, graduate, and
medical school levels. As an introductory text, students will appreciate the book's clear writing and informative
illustrations, while advanced students and working immunologists will appreciate its comprehensive scope and
depth. Immunobiology presents immunology from a consistent point of view throughout—that of the host’s
interaction with an environment full of microbes and pathogens. The Ninth Edition has been thoroughly revised
bringing the content up-to-date with significant developments in the field, especially on the topic of innate
immunity, and improving the presentation of topics across chapters for better continuity.
Kenneth Murphy is the Eugene Opie First Centennial Professor of Pathology and Immunology at Washington
University School of Medicine in St. Louis and Investigator at the Howard Hughes Medical Institute. He received his
MD and PhD degrees from The Johns Hopkins University School of Medicine.
Casey Weaver is the Wyatt and Susan Haskell Professor of Medical Excellence in the Department of Pathology at the
University of Alabama at Birmingham, School of Medicine. He received his MD degree from the University of Florida.
His residency and post-doctoral training were completed at Barnes Hospital and Washington University.
“This is one of the best basic immunology textbooks available. Materials are well
organized and clearly presented. It is a must-have…. The chapters are well ordered and
the language is clear and succinct. Ample, well-designed diagrams and tables illustrate
complex ideas.”
DOODY REVIEWS
9TH EDITION
MURPHY
&
WEAVER
ISBN 978-0-8153-4505-3
Acknowledgments
We would like to thank the following experts who read School of Medicine; John Kearney, University of Alabama
parts or the whole of the eighth edition chapters and pro- at Birmingham; Troy Randall, University of Alabama at
vided us with invaluable advice in developing this new Birmingham; Jeffrey Ravetch, Rockefeller University;
edition. Haley Tucker, University of Texas at Austin.
Chapter 2: Teizo Fujita, Fukushima Prefectural General Chapter 11: Susan Kaech, Yale University School of
Hygiene Institute; Thad Stappenbeck, Washington Medicine; Stephen McSorley, University of California,
University; Andrea J. Tenner, University of California, Davis.
Irvine. Chapter 12: Nadine Cerf-Bensussan, Université Paris
Chapter 3: Shizuo Akira, Osaka University; Mary Dinauer, Descartes-Sorbonne, Paris; Thomas MacDonald, Barts
Washington University in St. Louis; Lewis Lanier, and London School of Medicine and Dentistry; Maria
University of California, San Francisco; Gabriel Nuñez, Rescigno, European Institute of Oncology; Michael Russell,
University of Michigan Medical School; David Raulet, University at Buffalo; Thad Stappenbeck, Washington
University of California, Berkeley; Caetano Reis e Sousa, University.
Cancer Research UK; Tadatsugu Taniguchi, University of Chapter 13: Mary Collins, University College London;
Tokyo; Eric Vivier, Université de la Méditerranée Campus Paul Goepfert, University of Alabama at Birmingham;
de Luminy; Wayne Yokoyama, Washington University. Paul Klenerman, University of Oxford; Warren Leonard,
Chapter 4: Chris Garcia, Stanford University; Ellis National Heart, Lung, and Blood Institute, NIH; Luigi
Reinherz, Harvard Medical School; Robyn Stanfield, Notarangelo, Boston Children’s Hospital; Sarah Rowland-
The Scripps Research Institute; Ian Wilson, The Scripps Jones, Oxford University; Harry Schroeder, University of
Research Institute. Alabama at Birmingham.
Chapter 5: Michael Lieber, University of Southern Chapter 14: Cezmi A. Akdis, Swiss Institute of Allergy and
California Norris Cancer Center; Michel Neuberger, Asthma Research; Larry Borish, University of Virginia
University of Cambridge; David Schatz, Yale University Health System; Barry Kay, National Heart and Lung
School of Medicine; Barry Sleckman, Washington Institute; Harald Renz, Philipps University Marburg;
University School of Medicine, St. Louis; Philip Tucker, Robert Schleimer, Northwestern University; Dale Umetsu,
University of Texas, Austin. Genentech.
Chapter 6: Sebastian Amigorena, Institut Curie; Siamak Chapter 15: Anne Davidson, The Feinstein Institute for
Bahram, Centre de Recherche d’Immunologie et d’He- Medical Research; Robert Fairchild, Cleveland Clinic;
matologie; Peter Cresswell, Yale University School of Rikard Holmdahl, Karolinska Institute; Fadi Lakkis,
Medicine; Mitchell Kronenberg, La Jolla Institute for University of Pittsburgh; Ann Marshak-Rothstein,
Allergy & Immunology; Philippa Marrack, National Jewish University of Massachusetts Medical School; Carson
Health; Hans-Georg Rammensee, University of Tuebingen, Moseley, University of Alabama at Birmingham; Luigi
Germany; Jose Villadangos, University of Melbourne; Ian Notarangelo, Boston Children's Hospital; Noel Rose, Johns
Wilson, The Scripps Research Institute. Hopkins Bloomberg School of Public Health; Warren
Chapter 7: Oreste Acuto, University of Oxford; Francis Shlomchik, University of Pittsburgh School of Medicine;
Chan, University of Massachusetts Medical School; Vigo Laurence Turka, Harvard Medical School.
Heissmeyer, Helmholtz Center Munich; Steve Jameson, Chapter 16: James Crowe, Vanderbilt University; Glenn
University of Minnesota; Pamela L. Schwartzberg, NIH; Dranoff, Dana–Farber Cancer Institute; Thomas Gajewski,
Art Weiss, University of California, San Francisco. University of Chicago; Carson Moseley, University of
Chapter 8: Michael Cancro, University of Pennsylvania Alabama at Birmingham; Caetano Reis e Sousa, Cancer
School of Medicine; Robert Carter, University of Alabama; Research UK.
Ian Crispe, University of Washington; Kris Hogquist, Appendix I: Lawrence Stern, University of Massachusetts
University of Minnesota; Eric Huseby, University of Medical School.
Massachusetts Medical School; Joonsoo Kang, University
We would also like to specially acknowledge and thank
of Massachusetts Medical School; Ellen Robey, University
the students: Alina Petris, University of Manchester;
of California, Berkeley; Nancy Ruddle, Yale University
Carlos Briseno, Washington University in St. Louis;
School of Medicine; Juan Carlos Zúñiga-Pflücker,
Daniel DiToro, University of Alabama at Birmingham;
University of Toronto.
Vivek Durai, Washington University in St. Louis; Wilfredo
Chapter 9: Francis Carbone, University of Melbourne; Garcia, Harvard University; Nichole Escalante, University
Shane Crotty, La Jolla Institute of Allergy and Immunology; of Toronto; Kate Jackson, University of Manchester; Isil
Bill Heath, University of Melbourne, Victoria; Marc Jenkins, Mirzanli, University of Manchester; Carson Moseley,
University of Minnesota; Alexander Rudensky, Memorial University of Alabama at Birmingham; Daniel Silberger,
Sloan Kettering Cancer Center; Shimon Sakaguchi, Osaka University of Alabama at Birmingham; Jeffrey Singer,
University. University of Alabama at Birmingham; Deepica Stephen,
Chapter 10: Michael Cancro, University of Pennsylvania University of Manchester; Mayra Cruz Tleugabulova,
School of Medicine; Ann Haberman, Yale University University of Toronto.
APPENDICES
I The Immunologist's Toolbox 749
II CD antigens 791
III Cytokines and their Receptors 811
IV Chemokines and their Receptors 814
Biographies 816
Glossary 818
Index 855
Detailed Contents
PART I AN INTRODUCTION TO IMMUNO 1-18 Lymphocytes activated by antigen proliferate in
the peripheral lymphoid organs, generating
BIOLOGY AND INNATE IMMUNITY
effector cells and immunological memory. 23
Chapter 1 Basic Concepts in Immunology 1 Summary. 24
2-11 Complement developed early in the evolution 3-14 TLR and NOD genes have undergone extensive
of multicellular organisms. 61 diversification in both invertebrates and some
2-12 Surface-bound C3 convertase deposits large primitive chordates. 106
numbers of C3b fragments on pathogen surfaces Summary. 106
and generates C5 convertase activity. 62
Induced innate responses to infection. 107
2-13 Ingestion of complement-tagged pathogens by
3-15 Cytokines and their receptors fall into distinct
phagocytes is mediated by receptors for the bound
families of structurally related proteins. 107
complement proteins. 63
3-16 Cytokine receptors of the hematopoietin family
2-14 The small fragments of some complement
are associated with the JAK family of tyrosine
proteins initiate a local inflammatory response. 65
kinases, which activate STAT transcription factors. 109
2-15 The terminal complement proteins polymerize
3-17 Chemokines released by macrophages and
to form pores in membranes that can kill certain
dendritic cells recruit effector cells to sites of
pathogens. 66
infection. 111
2-16 Complement control proteins regulate all three
3-18 Cell-adhesion molecules control interactions
pathways of complement activation and protect
between leukocytes and endothelial cells
the host from their destructive effects. 67
during an inflammatory response. 113
2-17 Pathogens produce several types of proteins 3-19 Neutrophils make up the first wave of cells that
that can inhibit complement activation. 71 cross the blood vessel wall to enter an inflamed
Summary. 72 tissue. 116
Summary to Chapter 2. 73 3-20 TNF-α is an important cytokine that triggers
Questions. 74 local containment of infection but induces
shock when released systemically. 118
References. 75
3-21 Cytokines made by macrophages and dendritic
he Induced Responses of
Chapter 3 T cells induce a systemic reaction known as the
acute-phase response. 118
Innate Immunity 77
3-22 Interferons induced by viral infection make
Pattern recognition by cells of the innate several contributions to host defense. 121
immune system. 77 3-23 Several types of innate lymphoid cells provide
3-1 After entering tissues, many microbes are protection in early infection. 124
recognized, ingested, and killed by phagocytes. 78
3-24 NK cells are activated by type I interferon and
3-2 G-protein-coupled receptors on phagocytes link macrophage-derived cytokines. 125
microbe recognition with increased efficiency of
3-25 NK cells express activating and inhibitory
intracellular killing. 81
receptors to distinguish between healthy and
3-3 Microbial recognition and tissue damage initiate an infected cells. 126
inflammatory response. 85
3-26 NK-cell receptors belong to several structural
3-4 Toll-like receptors represent an ancient pathogen- families, the KIRs, KLRs, and NCRs. 128
recognition system. 87 3-27 NK cells express activating receptors that
3-5 Mammalian Toll-like receptors are activated by recognize ligands induced on infected cells
many different pathogen-associated molecular or tumor cells. 130
patterns. 88 Summary. 131
3-6 TLR-4 recognizes bacterial lipopolysaccharide in Summary to Chapter 3. 131
association with the host accessory proteins
Questions. 132
MD-2 and CD14. 92
References. 133
3-7 TLRs activate NFκB, AP-1, and IRF transcription
factors to induce the expression of inflammatory
cytokines and type I interferons. 92
Part II THe Recognition of Antigen
3-8 The NOD-like receptors are intracellular sensors
of bacterial infection and cellular damage. 96 Chapter 4 Antigen Recognition by B-cell and
3-9 NLRP proteins react to infection or cellular T-cell Receptors 139
damage through an inflammasome to induce
The structure of a typical antibody molecule. 140
cell death and inflammation. 98
4-1 IgG antibodies consist of four polypeptide chains. 141
3-10 The RIG-I-like receptors detect cytoplasmic viral
RNAs and activate MAVS to induce type I interferon 4-2 Immunoglobulin heavy and light chains are
production and pro‑inflammatory cytokines. 101 composed of constant and variable regions. 142
3-11 Cytosolic DNA sensors signal through STING to 4-3 The domains of an immunoglobulin molecule
induce production of type I interferons. 103 have similar structures. 142
3-12 Activation of innate sensors in macrophages and 4-4 The antibody molecule can readily be cleaved
dendritic cells triggers changes in gene expression into functionally distinct fragments. 144
that have far‑reaching effects on the 4-5 The hinge region of the immunoglobulin
immune response. 104 molecule allows flexibility in binding to
3-13 Toll signaling in Drosophila is downstream of a multiple antigens. 145
distinct set of pathogen-recognition molecules. 105 Summary. 145
The interaction of the antibody molecule with specific 5-6 The diversity of the immunoglobulin repertoire is
antigen. 146 generated by four main processes. 184
4-6 Localized regions of hypervariable sequence 5-7 The multiple inherited gene segments are used in
form the antigen-binding site. 146 different combinations. 184
4-7 Antibodies bind antigens via contacts in CDRs that 5-8 Variable addition and subtraction of nucleotides at
are complementary to the size and shape of the junctions between gene segments contributes
the antigen. 147 to the diversity of the third hypervariable region. 185
4-8 Antibodies bind to conformational shapes on Summary. 186
the surfaces of antigens using a variety of
noncovalent forces. 148 T-cell receptor gene rearrangement. 187
5-9 The T-cell receptor gene segments are arranged in
4-9 Antibody interaction with intact antigens is
a similar pattern to immunoglobulin gene segments
influenced by steric constraints. 150
and are rearranged by the same enzymes. 187
4-10 Some species generate antibodies with
5-10 T-cell receptors concentrate diversity in the third
alternative structures. 151
hypervariable region. 189
Summary. 152
5-11 γ:δ T-cell receptors are also generated by gene
Antigen recognition by T cells. 152 rearrangement. 190
4-11 The TCRα:β heterodimer is very similar to a Fab Summary. 191
fragment of immunoglobulin. 153
Structural variation in immunoglobulin constant
4-12 A T-cell receptor recognizes antigen in the form
of a complex of a foreign peptide bound to an MHC
regions. 191
molecule. 155 5-12 Different classes of immunoglobulins are
distinguished by the structure of their heavy-
4-13 There are two classes of MHC molecules with
chain constant regions. 192
distinct subunit compositions but similar three-
dimensional structures. 155 5-13 The constant region confers functional
specialization on the antibody. 193
4-14 Peptides are stably bound to MHC molecules, and
also serve to stabilize the MHC molecule on the 5-14 IgM and IgD are derived from the same pre-mRNA
cell surface. 158 transcript and are both expressed on the surface of
4-15 MHC class I molecules bind short peptides of 8–10 mature B cells. 194
amino acids by both ends. 158 5-15 Transmembrane and secreted forms of immuno-
4-16 The length of the peptides bound by MHC class II globulin are generated from alternative heavy-chain
molecules is not constrained. 160 mRNA transcripts. 195
4-17 The crystal structures of several peptide:MHC:T-cell 5-16 IgM and IgA can form polymers by interacting with
receptor complexes show a similar orientation of the the J chain. 197
T-cell receptor over the peptide:MHC complex. 161 Summary. 198
4-18 The CD4 and CD8 cell-surface proteins of T cells
directly contact MHC molecules and are required Evolution of the adaptive immune response. 198
to make an effective response to antigen. 163 5-17 Some invertebrates generate extensive diversity
4-19 The two classes of MHC molecules are expressed in a repertoire of immunoglobulin-like genes. 198
differentially on cells. 166 5-18 Agnathans possess an adaptive immune system
4-20 A distinct subset of T cells bears an alternative that uses somatic gene rearrangement to diversify
receptor made up of γ and δ chains. 166 receptors built from LRR domains. 200
Summary. 167 5-19 RAG-dependent adaptive immunity based on a
diversified repertoire of immunoglobulin-like genes
Summary to Chapter 4. 168
appeared abruptly in the cartilaginous fishes. 202
Questions. 169
5-20 Different species generate immunoglobulin
References. 170
diversity in different ways. 203
Chapter 5 The Generation of Lymphocyte 5-21 Both α:β and γ:δ T-cell receptors are present in
Antigen Receptors 173 cartilaginous fishes. 206
5-22 MHC class I and class II molecules are also first
Primary immunoglobulin gene rearrangement. 174 found in the cartilaginous fishes. 206
5-1 Immunoglobulin genes are rearranged in the
Summary. 207
progenitors of antibody-producing cells. 174
Summary to Chapter 5. 207
5-2 Complete genes that encode a variable region
are generated by the somatic recombination of Questions. 208
separate gene segments. 175 References. 209
5-3 Multiple contiguous V gene segments are present
at each immunoglobulin locus. 176 Chapter 6
Antigen Presentation to
5-4 Rearrangement of V, D, and J gene segments is
T Lymphocytes 213
guided by flanking DNA sequences. 178 The generation of α:β T-cell receptor ligands. 214
5-5 The reaction that recombines V, D, and J gene 6-1 Antigen presentation functions both in arming
segments involves both lymphocyte-specific and effector T cells and in triggering their effector
ubiquitous DNA-modifying enzymes. 179 functions to attack pathogen-infected cells. 214
6-2 Peptides are generated from ubiquitinated 7-1 Transmembrane receptors convert extracellular
proteins in the cytosol by the proteasome. 216 signals into intracellular biochemical events. 258
6-3 Peptides from the cytosol are transported by TAP 7-2 Intracellular signal propagation is mediated by large
into the endoplasmic reticulum and further processed multiprotein signaling complexes. 260
before binding to MHC class I molecules. 218
7-3 Small G proteins act as molecular switches in many
6-4 Newly synthesized MHC class I molecules are
retained in the endoplasmic reticulum until they different signaling pathways. 262
bind a peptide. 219 7-4 Signaling proteins are recruited to the membrane by
6-5 Dendritic cells use cross-presentation to present a variety of mechanisms. 262
exogenous proteins on MHC class I molecules to 7-5 Post-translational modifications of proteins can both
prime CD8 T cells. 222 activate and inhibit signaling responses. 263
6-6 Peptide:MHC class II complexes are generated in
7-6 The activation of some receptors generates small-
acidified endocytic vesicles from proteins obtained
through endocytosis, phagocytosis, and autophagy. 223 molecule second messengers. 264
6-7 The invariant chain directs newly synthesized MHC Summary. 265
class II molecules to acidified intracellular vesicles. 225
Antigen receptor signaling and lymphocyte activation. 265
6-8 The MHC class II-like molecules HLA-DM and
7-7 Antigen receptors consist of variable antigen-binding
HLA-DO regulate exchange of CLIP for other
peptides. 226 chains associated with invariant chains that carry
out the signaling function of the receptor. 266
6-9 Cessation of antigen processing occurs in dendritic
cells after their activation through reduced 7-8 Antigen recognition by the T-cell receptor and its
expression of the MARCH-1 E3 ligase. 229 co-receptors transduces a signal across the plasma
Summary. 230 membrane to initiate signaling. 267
7-9 Antigen recognition by the T-cell receptor and its
The major histocompatibility complex and its function. 231 co-receptors leads to phosphorylation of ITAMs by
6-10 Many proteins involved in antigen processing and Src-family kinases, generating the first intracellular
presentation are encoded by genes within the MHC. 231 signal in a signaling cascade. 268
6-11 The protein products of MHC class I and class II 7-10 Phosphorylated ITAMs recruit and activate the
genes are highly polymorphic. 234
tyrosine kinase ZAP-70. 270
6-12 MHC polymorphism affects antigen recognition by
T cells by influencing both peptide binding and the 7-11 ITAMs are also found in other receptors on
contacts between T-cell receptor and MHC molecule. 235 leukocytes that signal for cell activation. 270
6-13 Alloreactive T cells recognizing nonself MHC 7-12 Activated ZAP-70 phosphorylates scaffold proteins
molecules are very abundant. 239 and promotes PI 3-kinase activation. 271
6-14 Many T cells respond to superantigens. 240 7-13 Activated PLC-γ generates the second messengers
6-15 MHC polymorphism extends the range of antigens diacylglycerol and inositol trisphosphate that lead to
to which the immune system can respond. 241 transcription factor activation. 272
Summary. 242 7-14 Ca2+ entry activates the transcription factor NFAT. 273
7-15 Ras activation stimulates the mitogen-activated
Generation of ligands for unconventional
protein kinase (MAPK) relay and induces expression
T-cell subsets. 242
of the transcription factor AP-1. 274
6-16 A variety of genes with specialized functions in
immunity are also encoded in the MHC. 243 7-16 Protein kinase C activates the transcription factors
NFκB and AP-1. 276
6-17 Specialized MHC class I molecules act as ligands
for the activation and inhibition of NK cells and 7-17 PI 3-kinase activation upregulates cellular metabolic
unconventional T-cell subsets. 245 pathways via the serine/threonine kinase Akt. 277
6-18 Members of the CD1 family of MHC class I-like 7-18 T-cell receptor signaling leads to enhanced integrin-
molecules present microbial lipids to invariant mediated cell adhesion. 278
NKT cells. 246 7-19 T-cell receptor signaling induces cytoskeletal
6-19 The nonclassical MHC class I molecule MR1 reorganization by activating the small GTPase Cdc42. 279
presents microbial folate metabolites to MAIT cells. 248 7-20 The logic of B-cell receptor signaling is similar to that
6-20 γ:δ T cells can recognize a variety of diverse ligands. 249 of T-cell receptor signaling, but some of the signaling
components are specific to B cells. 279
Summary. 250
Summary. 282
Summary to Chapter 6. 250
Questions. 251 Co-stimulatory and inhibitory receptors modulate
References. 252 antigen receptor signaling in T and B lymphocytes. 282
7-21 The cell-surface protein CD28 is a required
co-stimulatory signaling receptor for naive T-cell
PART III The development of mature activation. 283
lymphocyte receptor repertoires 7-22 Maximal activation of PLC-γ, which is important for
transcription factor activation, requires a
Chapter 7 Lymphocyte Receptor Signaling 257 co-stimulatory signal induced by CD28. 284
General principles of signal transduction and 7-23 TNF receptor superfamily members augment T-cell
propagation. 257 and B-cell activation. 284
7-24 Inhibitory receptors on lymphocytes downregulate 8-18 T-cell α-chain genes undergo successive rearrange-
immune responses by interfering with co-stimulatory ments until positive selection or cell death intervenes. 326
signaling pathways. 286 Summary. 328
7-25 Inhibitory receptors on lymphocytes downregulate
immune responses by recruiting protein or lipid
Positive and negative selection of T cells. 328
phosphatases. 287 8-19 Only thymocytes whose receptors interact with self
peptide:self MHC complexes can survive and mature. 328
Summary. 288
8-20 Positive selection acts on a repertoire of T-cell
Summary to Chapter 7. 289 receptors with inherent specificity for MHC molecules. 329
Questions. 290 8-21 Positive selection coordinates the expression of
References. 291 CD4 or CD8 with the specificity of the T-cell receptor
and the potential effector functions of the T cell. 330
Chapter 8 The Development of B and
8-22 Thymic cortical epithelial cells mediate positive
T Lymphocytes 295 selection of developing thymocytes. 331
Development of B lymphocytes. 296 8-23 T cells that react strongly with ubiquitous self
8-1 Lymphocytes derive from hematopoietic stem cells antigens are deleted in the thymus. 332
in the bone marrow. 297 8-24 Negative selection is driven most efficiently by
8-2 B-cell development begins by rearrangement of the bone marrow-derived antigen-presenting cells. 334
heavy-chain locus. 299 8-25 The specificity and/or the strength of signals for
8-3 The pre-B-cell receptor tests for successful negative and positive selection must differ. 334
production of a complete heavy chain and signals 8-26 Self-recognizing regulatory T cells and innate T cells
for the transition from the pro-B cell to the pre-B develop in the thymus. 335
cell stage. 302
8-27 The final stage of T-cell maturation occurs in the
8-4 Pre-B-cell receptor signaling inhibits further thymic medulla. 336
heavy-chain locus rearrangement and enforces
8-28 T cells that encounter sufficient quantities of self
allelic exclusion. 303
antigens for the first time in the periphery are
8-5 Pre-B cells rearrange the light-chain locus and eliminated or inactivated. 336
express cell-surface immunoglobulin. 304
Summary. 337
8-6 Immature B cells are tested for autoreactivity
Summary to Chapter 8. 337
before they leave the bone marrow. 305
Questions. 339
8-7 Lymphocytes that encounter sufficient quantities
of self antigens for the first time in the periphery References. 340
are eliminated or inactivated. 308
8-8 Immature B cells arriving in the spleen turn over PART IV the adaptive immune
rapidly and require cytokines and positive signals
through the B-cell receptor for maturation and
response 345
long-term survival. 309 Chapter 9 T-cell-Mediated Immunity 345
8-9 B-1 B cells are an innate lymphocyte subset that
arises early in development. 312
Development and function of secondary lymphoid
organs—sites for the initiation of adaptive immune
Summary. 313
responses. 347
Development of T lymphocytes. 315 9-1 T and B lymphocytes are found in distinct locations
8-10 T-cell progenitors originate in the bone marrow, in secondary lymphoid tissues. 347
but all the important events in their development 9-2 The development of secondary lymphoid tissues is
occur in the thymus. 315 controlled by lymphoid tissue inducer cells and
8-11 Commitment to the T-cell lineage occurs in the proteins of the tumor necrosis factor family. 349
thymus following Notch signaling. 317 9-3 T and B cells are partitioned into distinct regions of
8-12 T-cell precursors proliferate extensively in the secondary lymphoid tissues by the actions of
thymus, but most die there. 317 chemokines. 350
8-13 Successive stages in the development of 9-4 Naive T cells migrate through secondary lymphoid
thymocytes are marked by changes in cell-surface tissues, sampling peptide:MHC complexes on
molecules. 319 dendritic cells. 351
8-14 Thymocytes at different developmental stages are 9-5 Lymphocyte entry into lymphoid tissues depends
found in distinct parts of the thymus. 321 on chemokines and adhesion molecules. 352
8-15 T cells with α:β or γ:δ receptors arise from a common 9-6 Activation of integrins by chemokines is responsible
progenitor. 322 for the entry of naive T cells into lymph nodes. 353
8-16 T cells expressing γ:δ T-cell receptors arise in two 9-7 The exit of T cells from lymph nodes is controlled
distinct phases during development. 322 by a chemotactic lipid. 355
8-17 Successful synthesis of a rearranged β chain allows 9-8 T-cell responses are initiated in secondary
the production of a pre-T-cell receptor that triggers lymphoid organs by activated dendritic cells. 356
cell proliferation and blocks further β-chain gene 9-9 Dendritic cells process antigens from a wide array
rearrangement. 324 of pathogens. 358
9-10 Microbe-induced TLR signaling in tissue-resident 9-32 Cytotoxic T cells are selective serial killers of targets
dendritic cells induces their migration to lymphoid expressing a specific antigen. 391
organs and enhances antigen processing. 361
9-33 Cytotoxic T cells also act by releasing cytokines. 392
9-11 Plasmacytoid dendritic cells produce abundant
Summary. 392
type I interferons and may act as helper cells for
antigen presentation by conventional dendritic cells. 363 Summary to Chapter 9. 392
9-12 Macrophages are scavenger cells that can be induced Questions. 393
by pathogens to present foreign antigens to naive
References. 395
T cells. 363
9-13 B cells are highly efficient at presenting antigens Chapter 10 The Humoral Immune Response 399
that bind to their surface immunoglobulin. 364
Summary. 366 B-cell activation by antigen and helper T cells. 400
10-1 Activation of B cells by antigen involves signals from
Priming of naive T cells by pathogen-activated the B-cell receptor and either TFH cells or microbial
dendritic cells. 366 antigens. 400
9-14 Cell-adhesion molecules mediate the initial
10-2 Linked recognition of antigen by T cells and B cells
interaction of naive T cells with antigen-
presenting cells. 367 promotes robust antibody responses. 402
9-15 Antigen-presenting cells deliver multiple signals for 10-3 B cells that encounter their antigens migrate toward
the clonal expansion and differentiation of naive the boundaries between B-cell and T-cell areas in
T cells. 368 secondary lymphoid tissues. 403
9-16 CD28-dependent co-stimulation of activated T cells 10-4 T cells express surface molecules and cytokines that
induces expression of interleukin-2 and the activate B cells, which in turn promote TFH-cell
high-affinity IL-2 receptor. 368 development. 406
9-17 Additional co-stimulatory pathways are involved in 10-5 Activated B cells differentiate into antibody-secreting
T-cell activation. 369 plasmablasts and plasma cells. 406
9-18 Proliferating T cells differentiate into effector T cells
10-6 The second phase of a primary B-cell immune
that do not require co-stimulation to act. 370
response occurs when activated B cells migrate into
9-19 CD8 T cells can be activated in different ways to follicles and proliferate to form germinal centers. 408
become cytotoxic effector cells. 372
10-7 Germinal center B cells undergo V-region somatic
9-20 CD4 T cells differentiate into several subsets of
hypermutation, and cells with mutations that improve
functionally different effector cells. 372
affinity for antigen are selected. 410
9-21 Cytokines induce the differentiation of naive CD4
T cells down distinct effector pathways. 375 10-8 Positive selection of germinal center B cells involves
contact with TFH cells and CD40 signaling. 412
9-22 CD4 T-cell subsets can cross-regulate each other’s
differentiation through the cytokines they produce. 377 10-9 Activation-induced cytidine deaminase (AID)
9-23 Regulatory CD4 T cells are involved in controlling introduces mutations into genes transcribed
adaptive immune responses. 379 in B cells. 413
Summary. 380 10-10 Mismatch and base-excision repair pathways
contribute to somatic hypermutation following
General properties of effector T cells and initiation by AID. 414
their cytokines. 380
10-11 AID initiates class switching to allow the same
9-24 Effector T-cell interactions with target cells are
assembled VH exon to be associated with different
initiated by antigen-nonspecific cell-adhesion
CH genes in the course of an immune response. 415
molecules. 381
9-25 An immunological synapse forms between effector 10-12 Cytokines made by TFH cells direct the choice of
T cells and their targets to regulate signaling and to isotype for class switching in T-dependent antibody
direct the release of effector molecules. 381 responses. 418
9-26 The effector functions of T cells are determined by 10-13 B cells that survive the germinal center reaction
the array of effector molecules that they produce. 383 eventually differentiate into either plasma cells or
memory cells. 419
9-27 Cytokines can act locally or at a distance. 383
9-28 T cells express several TNF-family cytokines as 10-14 Some antigens do not require T-cell help to induce
trimeric proteins that are usually associated with B-cell responses. 419
the cell surface. 386 Summary. 421
Summary. 386
The distributions and functions of immunoglobulin
T-cell-mediated cytotoxicity. 387 classes. 422
9-29 Cytotoxic T cells induce target cells to undergo 10-15 Antibodies of different classes operate in distinct
programmed cell death via extrinsic and intrinsic places and have distinct effector functions. 423
pathways of apoptosis. 387 10-16 Polymeric immunoglobulin receptor binds to the
9-30 The intrinsic pathway of apoptosis is mediated by Fc regions of IgA and IgM and transports them
the release of cytochrome c from mitochondria. 389 across epithelial barriers. 425
9-31 Cytotoxic effector proteins that trigger apoptosis are 10-17 The neonatal Fc receptor carries IgG across the
contained in the granules of CD8 cytotoxic T cells. 390 placenta and prevents IgG excretion from the body. 426
10-18 High-affinity IgG and IgA antibodies can neutralize 11-11 Differentiated effector T cells continue to respond
toxins and block the infectivity of viruses and to signals as they carry out their effector functions. 466
bacteria. 426 11-12 Effector T cells can be activated to release
10-19 Antibody:antigen complexes activate the classical cytokines independently of antigen recognition. 467
pathway of complement by binding to C1q. 429 11-13 Effector T cells demonstrate plasticity and
10-20 Complement receptors and Fc receptors both cooperativity that enable adaptation during
contribute to removal of immune complexes from anti-pathogen responses. 468
the circulation. 430
11-14 Integration of cell- and antibody-mediated
Summary. 431 immunity is critical for protection against many
The destruction of antibody-coated pathogens types of pathogens. 469
via Fc receptors. 432 11-15 Primary CD8 T-cell responses to pathogens can
10-21 The Fc receptors of accessory cells are signaling occur in the absence of CD4 T-cell help. 470
receptors specific for immunoglobulins of different 11-16 Resolution of an infection is accompanied by the
classes. 432 death of most of the effector cells and the
10-22 Fc receptors on phagocytes are activated by generation of memory cells. 471
antibodies bound to the surface of pathogens Summary. 472
and enable the phagocytes to ingest and
destroy pathogens. 433 Immunological memory. 473
11-17 Immunological memory is long lived after infection
10-23 Fc receptors activate NK cells to destroy
or vaccination. 473
antibody-coated targets. 435
11-18 Memory B-cell responses are more rapid and have
10-24 Mast cells and basophils bind IgE antibody via
higher affinity for antigen compared with responses
the high‑affinity Fcε receptor. 436
of naive B cells. 475
10-25 IgE-mediated activation of accessory cells has
11-19 Memory B cells can reenter germinal centers and
an important role in resistance to parasite infection. 437
undergo additional somatic hypermutation and
Summary. 438 affinity maturation during secondary immune
Summary to Chapter 10. 439 responses. 476
11-20 MHC tetramers identify memory T cells that persist
Questions. 440
at an increased frequency relative to their frequency
References. 441 as naive T cells. 477
11-21 Memory T cells arise from effector T cells that
Chapter 11 Integrated Dynamics of maintain sensitivity to IL-7 or IL-15. 478
Innate and Adaptive Immunity 445 11-22 Memory T cells are heterogeneous and include
Integration of innate and adaptive immunity in central memory, effector memory, and tissue-
response to specific types of pathogens. 446 resident subsets. 480
11-1 The course of an infection can be divided into 11-23 CD4 T-cell help is required for CD8 T-cell memory
several distinct phases. 446 and involves CD40 and IL-2 signaling. 482
11-2 The effector mechanisms that are recruited to 11-24 In immune individuals, secondary and subsequent
clear an infection depend on the infectious agent. 449 responses are mainly attributable to memory
Summary. 452 lymphocytes. 484
Summary. 485
Effector T cells augment the effector functions of
innate immune cells. 452 Summary to Chapter 11. 486
11-3 Effector T cells are guided to specific tissues and Questions. 487
sites of infection by changes in their expression of
References. 488
adhesion molecules and chemokine receptors. 453
11-4 Pathogen-specific effector T cells are enriched at Chapter 12 The Mucosal Immune System 493
sites of infection as adaptive immunity progresses. 457
The nature and structure of the mucosal
11-5 TH1 cells coordinate and amplify the host response
immune system. 493
to intracellular pathogens through classical
activation of macrophages. 458 12-1 The mucosal immune system protects the internal
surfaces of the body. 493
11-6 Activation of macrophages by TH1 cells must be
12-2 Cells of the mucosal immune system are located
tightly regulated to avoid tissue damage. 460
both in anatomically defined compartments and
11-7 Chronic activation of macrophages by TH1 cells scattered throughout mucosal tissues. 496
mediates the formation of granulomas to contain
12-3 The intestine has distinctive routes and
intracellular pathogens that cannot be cleared. 461
mechanisms of antigen uptake. 499
11-8 Defects in type 1 immunity reveal its important
12-4 The mucosal immune system contains large
role in the elimination of intracellular pathogens. 461
numbers of effector lymphocytes even in the
11-9 TH2 cells coordinate type 2 responses to expel absence of disease. 500
intestinal helminths and repair tissue injury. 462 12-5 The circulation of lymphocytes within the mucosal
11-10 TH17 cells coordinate type 3 responses to enhance immune system is controlled by tissue-specific
the clearance of extracellular bacteria and fungi. 465 adhesion molecules and chemokine receptors. 501
12-6 Priming of lymphocytes in one mucosal tissue may 13-4 SCID can also be due to defects in the purine
induce protective immunity at other mucosal salvage pathway. 538
surfaces. 502 13-5 Defects in antigen receptor gene rearrangement
12-7 Distinct populations of dendritic cells control can result in SCID. 538
mucosal immune responses. 503 13-6 Defects in signaling from T-cell antigen receptors
12-8 Macrophages and dendritic cells have different can cause severe immunodeficiency. 539
roles in mucosal immune responses. 505 13-7 Genetic defects in thymic function that block T-cell
12-9 Antigen-presenting cells in the intestinal mucosa development result in severe immunodeficiencies. 539
acquire antigen by a variety of routes. 505 13-8 Defects in B-cell development result in deficiencies
12-10 Secretory IgA is the class of antibody associated in antibody production that cause an inability to
with the mucosal immune system. 506 clear extracellular bacteria and some viruses. 541
12-11 T-independent processes can contribute to IgA 13-9 Immune deficiencies can be caused by defects in
production in some species. 509 B-cell or T-cell activation and function that lead to
12-12 IgA deficiency is relatively common in humans but abnormal antibody responses. 543
may be compensated for by secretory IgM. 509 13-10 Normal pathways for host defense against different
12-13 The intestinal lamina propria contains antigen- infectious agents are pinpointed by genetic deficiencies
experienced T cells and populations of unusual of cytokine pathways central to type 1/TH1 and type
innate lymphoid cells. 510 3/TH17 responses. 546
12-14 The intestinal epithelium is a unique compartment 13-11 Inherited defects in the cytolytic pathway of
of the immune system. 511 lymphocytes can cause uncontrolled lympho-
proliferation and inflammatory responses to viral
Summary. 514 infections. 548
The mucosal response to infection and regulation 13-12 X-linked lymphoproliferative syndrome is associated
of mucosal immune responses. 514 with fatal infection by Epstein–Barr virus and with the
development of lymphomas. 550
12-15 Enteric pathogens cause a local inflammatory
response and the development of protective 13-13 Immunodeficiency is caused by inherited defects
immunity. 515 in the development of dendritic cells. 551
12-16 Pathogens induce adaptive immune responses 13-14 Defects in complement components and complement-
when innate defenses have been breached. 518 regulatory proteins cause defective humoral immune
function and tissue damage. 552
12-17 Effector T-cell responses in the intestine protect
the function of the epithelium. 518 13-15 Defects in phagocytic cells permit widespread
bacterial infections. 553
12-18 The mucosal immune system must maintain
tolerance to harmless foreign antigens. 519 13-16 Mutations in the molecular regulators of inflammation
can cause uncontrolled inflammatory responses that
12-19 The normal intestine contains large quantities of
result in ‘autoinflammatory disease.’ 556
bacteria that are required for health. 520
13-17 Hematopoietic stem cell transplantation or gene
12-20 Innate and adaptive immune systems control therapy can be useful to correct genetic defects. 557
microbiota while preventing inflammation without
compromising the ability to react to invaders. 521 13-18 Noninherited, secondary immunodeficiencies are
major predisposing causes of infection and death. 558
12-21 The intestinal microbiota plays a major role in
Summary. 559
shaping intestinal and systemic immune function. 522
12-22 Full immune responses to commensal bacteria Evasion and subversion of immune defenses. 560
provoke intestinal disease. 524 13-19 Extracellular bacterial pathogens have evolved
Summary. 525 different strategies to avoid detection by pattern
recognition receptors and destruction by antibody,
Summary to Chapter 12. 525 complement, and antimicrobial peptides. 560
Questions. 526 13-20 Intracellular bacterial pathogens can evade the
References. 527 immune system by seeking shelter within phagocytes. 563
13-21 Immune evasion is also practiced by protozoan
parasites. 565
PART V the immune System in Health
13-22 RNA viruses use different mechanisms of antigenic
and Disease variation to keep a step ahead of the adaptive
Chapter 13 Failures of Host Defense immune system. 566
Mechanisms 533 13-23 DNA viruses use multiple mechanisms to subvert
NK-cell and CTL responses. 568
Immunodeficiency diseases. 533
13-24 Some latent viruses persist in vivo by ceasing to
13-1 A history of repeated infections suggests a
replicate until immunity wanes. 571
diagnosis of immunodeficiency. 534
Summary. 573
13-2 Primary immunodeficiency diseases are caused
by inherited gene defects. 534 Acquired immune deficiency syndrome. 573
13-3 Defects in T-cell development can result in severe 13-25 HIV is a retrovirus that establishes a chronic
combined immunodeficiencies. 535 infection that slowly progresses to AIDS. 574
13-26 HIV infects and replicates within cells of the 14-10 Allergen introduced into the bloodstream can cause
immune system. 576 anaphylaxis. 619
13-27 Activated CD4 T cells are the major source of 14-11 Allergen inhalation is associated with the
HIV replication. 578 development of rhinitis and asthma. 621
13-28 There are several routes by which HIV is 14-12 Allergy to particular foods causes systemic
transmitted and establishes infection. 579 reactions as well as symptoms limited to the gut. 624
13-29 HIV variants with tropism for different co-receptors 14-13 IgE-mediated allergic disease can be treated by
play different roles in transmission and progression inhibiting the effector pathways that lead to
of disease. 580 symptoms or by desensitization techniques
13-30 A genetic deficiency of the co-receptor CCR5 that aim at restoring biological tolerance to
confers resistance to HIV infection. 582 the allergen. 625
13-31 An immune response controls but does not Summary. 627
eliminate HIV. 583
Non-IgE-mediated allergic diseases. 628
13-32 Lymphoid tissue is the major reservoir of
HIV infection. 585 14-14 Non-IgE dependent drug-induced hypersensitivity
reactions in susceptible individuals occur by binding
13-33 Genetic variation in the host can alter the rate of of the drug to the surface of circulating blood cells. 628
disease progression. 585
14-15 Systemic disease caused by immune-complex
13-34 The destruction of immune function as a result of
formation can follow the administration of large
HIV infection leads to increased susceptibility to
quantities of poorly catabolized antigens. 628
opportunistic infection and eventually to death. 587
14-16 Hypersensitivity reactions can be mediated by TH1
13-35 Drugs that block HIV replication lead to a rapid
cells and CD8 cytotoxic T cells. 630
decrease in titer of infectious virus and an
increase in CD4 T cells. 588 14-17 Celiac disease has features of both an allergic
13-36 In the course of infection HIV accumulates many response and autoimmunity. 634
mutations, which can result in the outgrowth of Summary. 636
drug-resistant variants. 590
Summary to Chapter 14. 636
13-37 Vaccination against HIV is an attractive solution
but poses many difficulties. 591 Questions. 637
13-38 Prevention and education are important in References. 638
controlling the spread of HIV and AIDS. 592
Summary. 593
Chapter 15 Autoimmunity and Transplantation 643
Summary to Chapter 13. 594
The making and breaking of self-tolerance. 643
15-1 A critical function of the immune system is to
Questions. 594 discriminate self from nonself. 643
References. 595 15-2 Multiple tolerance mechanisms normally prevent
autoimmunity. 645
Chapter 14 Allergy and Allergic Diseases 601
15-3 Central deletion or inactivation of newly formed
IgE and IgE-mediated allergic diseases. 602 lymphocytes is the first checkpoint of self-tolerance. 646
14-1 Sensitization involves class switching to IgE 15-4 Lymphocytes that bind self antigens with relatively
production on first contact with an allergen. 603 low affinity usually ignore them but in some
14-2 Although many types of antigens can cause circumstances become activated. 647
allergic sensitization, proteases are common 15-5 Antigens in immunologically privileged sites do not
sensitizing agents. 605 induce immune attack but can serve as targets. 648
14-3 Genetic factors contribute to the development of 15-6 Autoreactive T cells that express particular
IgE‑mediated allergic disease. 607 cytokines may be nonpathogenic or may
14-4 Environmental factors may interact with genetic suppress pathogenic lymphocytes. 649
susceptibility to cause allergic disease. 609 15-7 Autoimmune responses can be controlled at
14-5 Regulatory T cells can control allergic responses. 611 various stages by regulatory T cells. 650
Summary. 612 Summary. 652
Effector mechanisms in IgE-mediated Autoimmune diseases and pathogenic mechanisms. 652
allergic reactions. 612 15-8 Specific adaptive immune responses to self
14-6 Most IgE is cell-bound and engages effector antigens can cause autoimmune disease. 652
mechanisms of the immune system by pathways 15-9 Autoimmunity can be classified into either organ-
different from those of other antibody isotypes. 613 specific or systemic disease. 653
14-7 Mast cells reside in tissues and orchestrate allergic 15-10 Multiple components of the immune system are
reactions. 613 typically recruited in autoimmune disease. 654
14-8 Eosinophils and basophils cause inflammation and 15-11 Chronic autoimmune disease develops through
tissue damage in allergic reactions. 616 positive feedback from inflammation, inability to
14-9 IgE-mediated allergic reactions have a rapid onset clear the self antigen, and a broadening of the
but can also lead to chronic responses. 617 autoimmune response. 657
15-12 Both antibody and effector T cells can cause 15-37 Regulatory T cells are involved in alloreactive
tissue damage in autoimmune disease. 659 immune responses. 692
15-13 Autoantibodies against blood cells promote their 15-38 The fetus is an allograft that is tolerated repeatedly. 693
destruction. 661
Summary. 694
15-14 The fixation of sublytic doses of complement to
Summary to Chapter 15. 694
cells in tissues stimulates a powerful inflammatory
response. 661 Questions. 695
15-15 Autoantibodies against receptors cause disease by References. 696
stimulating or blocking receptor function. 662
15-16 Autoantibodies against extracellular antigens cause Chapter 16 Manipulation of the
inflammatory injury. 663 Immune Response 701
15-17 T cells specific for self antigens can cause direct Treatment of unwanted immune responses. 701
tissue injury and sustain autoantibody responses. 665 16-1 Corticosteroids are powerful anti-inflammatory
Summary. 668 drugs that alter the transcription of many genes. 702
16-2 Cytotoxic drugs cause immunosuppression by
The genetic and environmental basis of autoimmunity. 669
killing dividing cells and have serious side-effects. 703
15-18 Autoimmune diseases have a strong genetic
component. 669 16-3 Cyclosporin A, tacrolimus, rapamycin, and JAK
inhibitors are effective immunosuppressive agents
15-19 Genomics-based approaches are providing new that interfere with various T-cell signaling pathways. 704
insight into the immunogenetic basis of autoimmunity. 670
16-4 Antibodies against cell-surface molecules can be
15-20 Many genes that predispose to autoimmunity fall used to eliminate lymphocyte subsets or to inhibit
into categories that affect one or more tolerance lymphocyte function. 706
mechanisms. 674
16-5 Antibodies can be engineered to reduce their
15-21 Monogenic defects of immune tolerance. 674 immunogenicity in humans. 707
15-22 MHC genes have an important role in controlling 16-6 Monoclonal antibodies can be used to prevent
susceptibility to autoimmune disease. 676 allograft rejection. 708
15-23 Genetic variants that impair innate immune 16-7 Depletion of autoreactive lymphocytes can treat
responses can predispose to T-cell-mediated autoimmune disease. 710
chronic inflammatory disease. 678
16-8 Biologics that block TNF-α, IL-1, or IL-6 can
15-24 External events can initiate autoimmunity. 679 alleviate autoimmune diseases. 711
15-25 Infection can lead to autoimmune disease by 16-9 Biologic agents can block cell migration to sites of
providing an environment that promotes lymphocyte inflammation and reduce immune responses. 712
activation. 680 16-10 Blockade of co-stimulatory pathways that activate
15-26 Cross-reactivity between foreign molecules on lymphocytes can be used to treat autoimmune
pathogens and self molecules can lead to antiself disease. 713
responses and autoimmune disease. 680 16-11 Some commonly used drugs have
15-27 Drugs and toxins can cause autoimmune syndromes. 682 immunomodulatory properties. 713
15-28 Random events may be required for the initiation 16-12 Controlled administration of antigen can be used
of autoimmunity. 682 to manipulate the nature of an antigen-specific
Summary. 682 response. 714
Summary. 714
Responses to alloantigens and transplant rejection. 683
15-29 Graft rejection is an immunological response Using the immune response to attack tumors. 716
mediated primarily by T cells. 683 16-13 The development of transplantable tumors in mice
15-30 Transplant rejection is caused primarily by the strong led to the discovery of protective immune
immune response to nonself MHC molecules. 684 responses to tumors. 716
15-31 In MHC-identical grafts, rejection is caused by 16-14 Tumors are ‘edited’ by the immune system as they
peptides from other alloantigens bound to graft evolve and can escape rejection in many ways. 717
MHC molecules. 685 16-15 Tumor rejection antigens can be recognized by
15-32 There are two ways of presenting alloantigens on the T cells and form the basis of immunotherapies. 720
transplanted donor organ to the recipient’s 16-16 T cells expressing chimeric antigen receptors are
T lymphocytes. 686 an effective treatment in some leukemias. 723
15-33 Antibodies that react with endothelium cause 16-17 Monoclonal antibodies against tumor antigens,
hyperacute graft rejection. 688 alone or linked to toxins, can control tumor growth. 724
15-34 Late failure of transplanted organs is caused by 16-18 Enhancing the immune response to tumors by
chronic injury to the graft. 688 vaccination holds promise for cancer prevention
15-35 A variety of organs are transplanted routinely in and therapy. 726
clinical medicine. 689 16-19 Checkpoint blockade can augment immune
15-36 The converse of graft rejection is graft-versus- responses to existing tumors. 727
host disease. 691 Summary. 728
Fighting infectious diseases with vaccination. 729 A-14 Immunoblotting (Western blotting). 764
16-20 Vaccines can be based on attenuated pathogens A-15 Use of antibodies in the isolation and
or material from killed organisms. 730 characterization of multiprotein complexes
16-21 Most effective vaccines generate antibodies that by mass spectrometry. 764
prevent the damage caused by toxins or that A-16 Isolation of peripheral blood lymphocytes by density-
neutralize the pathogen and stop infection. 731 gradient fractionation. 766
16-22 Effective vaccines must induce long-lasting A-17 Isolation of lymphocytes from tissues other than
protection while being safe and inexpensive. 732 blood. 766
16-23 Live-attenuated viral vaccines are usually more A-18 Flow cytometry and FACS analysis. 767
potent than ‘killed’ vaccines and can be made safer A-19 Lymphocyte isolation using antibody-coated
by the use of recombinant DNA technology. 732 magnetic beads. 770
16-24 Live-attenuated vaccines can be developed by A-20 Isolation of homogeneous T-cell lines. 770
selecting nonpathogenic or disabled bacteria or by
A-21 Limiting-dilution culture. 771
creating genetically attenuated parasites (GAPs). 734
A-22 ELISPOT assay. 773
16-25 The route of vaccination is an important
determinant of success. 735 A-23 Identification of functional subsets of T cells based
on cytokine production or transcription factor
16-26 Bordetella pertussis vaccination illustrates the
expression. 773
importance of the perceived safety of a vaccine. 736
A-24 Identification of T-cell receptor specificity using peptide:MHC
16-27 Conjugate vaccines have been developed as a
tetramers. 776
result of linked recognition between T and B cells. 737
A-25 Biosensor assays for measuring the rates of
16-28 Peptide-based vaccines can elicit protective
association and dissociation of antigen receptors
immunity, but they require adjuvants and must
for their ligands. 777
be targeted to the appropriate cells and cell
compartment to be effective. 738 A-26 Assays of lymphocyte proliferation. 778
16-29 Adjuvants are important for enhancing the A-27 Measurements of apoptosis. 779
immunogenicity of vaccines, but few are approved A-28 Assays for cytotoxic T cells. 780
for use in humans. 739 A-29 Assays for CD4 T cells. 782
16-30 Protective immunity can be induced by DNA-based A-30 Transfer of protective immunity. 782
vaccination. 740
A-31 Adoptive transfer of lymphocytes. 783
16-31 Vaccination and checkpoint blockade may be
A-32 Hematopoietic stem-cell transfers. 784
useful in controlling existing chronic infections. 741
A-33 In vivo administration of antibodies. 785
Summary. 742
A-34 Transgenic mice. 786
Summary to Chapter 16. 742
Questions. 743 A-35 Gene knockout by targeted disruption. 786
References. 744 A-36 Knockdown of gene expression by
RNA interference (RNAi). 790
APPENDICES
Appendix II CD antigens 791
Appendix I The Immunologist's Toolbox 749 Appendix III Cytokines and their Receptors 811
A-1. Immunization. 749
Appendix IV Chemokines and their Receptors 814
A-2 Antibody responses. 752
A-3 Affinity chromatography. 753 Biographies 816
A-4 Radioimmunoassay (RIA), enzyme-linked
immunosorbent assay (ELISA), and competitive
Photograph Acknowledgments 817
inhibition assay. 753 Glossary 818
A-5 Hemagglutination and blood typing. 755
A-6 Coombs tests and the detection of rhesus
Index 855
incompatibility. 756
A-7 Monoclonal antibodies. 757
A-8 Phage display libraries for antibody V-region
production. 758
A-9 Generation of human monoclonal antibodies from
vaccinated individuals. 759
A-10 Microscopy and imaging using fluorescent dyes. 760
A-11 Immunoelectron microscopy. 761
A-12 Immunohistochemistry. 762
A-13 Immunoprecipitation and co-immunoprecipitation. 762
Basic Concepts in
Immunology
Immunology is the study of the body’s defense against infection. We are con-
1
IN THIS CHAPTER
tinually exposed to microorganisms, many of which cause disease, and yet The origins of vertebrate immune
become ill only rarely. How does the body defend itself? When infection does cells.
occur, how does the body eliminate the invader and cure itself? And why do we
develop long-lasting immunity to many infectious diseases encountered once Principles of innate immunity.
and overcome? These are the questions addressed by immunology, which we Principles of adaptive immunity.
study to understand our body’s defenses against infection at the cellular and
The effector mechanisms
molecular levels. of immunity.
The beginning of immunology as a science is usually attributed to Edward
Jenner for his work in the late 18th century (Fig. 1.1). The notion of immunity—
that surviving a disease confers greater protection against it later—was known
since ancient Greece. Variolation—the inhalation or transfer into superficial
skin wounds of material from smallpox pustules—had been practiced since
at least the 1400s in the Middle East and China as a form of protection against
that disease and was known to Jenner. Jenner had observed that the relatively
mild disease of cowpox, or vaccinia, seemed to confer protection against the
often fatal disease of smallpox, and in 1796, he demonstrated that inoculation
with cowpox protected the recipient against smallpox. His scientific proof
relied on the deliberate exposure of the inoculated individual to infectious
smallpox material two months after inoculation. This scientific test was his
original contribution.
Jenner called the procedure vaccination. This term is still used to describe
the inoculation of healthy individuals with weakened or attenuated strains of
disease-causing agents in order to provide protection from disease. Although
Jenner’s bold experiment was successful, it took almost two centuries for
smallpox vaccination to become universal. This advance enabled the World
Health Organization to announce in 1979 that smallpox had been eradicated
(Fig. 1.2), arguably the greatest triumph of modern medicine.
Immunobiology
Fig. 1.1 Edward | chapter 1 | 01_001
Jenner. Portrait by John
Jenner’s strategy of vaccination was extended in the late 19th century by the Murphy et al | Ninth edition
Raphael Smith. Reproduced courtesy of
© Garland Science design by blink studio limited
discoveries of many great microbiologists. Robert Koch proved that infectious Yale University, Harvey Cushing/John Hay
diseases are caused by specific microorganisms. In the 1880s, Louis Pasteur Whitney Medical Library.
the lymphatic system. The lymphatic system drains extracellular fluid and
immune cells from tissues and transports them as lymph that is eventually
emptied back into the blood system.
All the cellular elements of blood, including the red blood cells that transport
oxygen, the platelets that trigger blood clotting in damaged tissues, and the
white blood cells of the immune system, ultimately derive from the hemato-
poietic stem cells (HSCs) of the bone marrow. Because these can give rise
to all the different types of blood cells, they are often known as pluripotent
hematopoietic stem cells. The hematopoietic stem cells give rise to cells of
more limited developmental potential, which are the immediate progenitors
of red blood cells, platelets, and the two main categories of white blood cells,
the lymphoid and myeloid lineages. The different types of blood cells and
their lineage relationships are summarized in Fig. 1.3.
N UIT douce, ai-je dit. Nuit fade, sur une campagne d’une simplicité
décourageante. Ces paysages berrichons n’ont rien de romantique. Ils
serviraient mal de cadre à des héros de tragédie. Une âme tourmentée
n’y trouve pas matière à s’émouvoir, sauf par contraste. C’est un pays de
tout repos.
Par ma fenêtre ouverte, je n’entendais que le cri morne du crapaud qui
chantait dans le jardin. L’eau de la Creuse luisait à peine.
Je m’assis à ma table pour y fixer un croquis. J’aurais pu me croire seul
dans la maison, tant le silence y était parfait. Un écrivain eût mieux
apprécié que moi les ressources d’une nuit pareille en une pareille solitude.
Nous autres, sculpteurs et peintres, qui travaillons au grand jour, nous
ignorons la volupté du travail nocturne et l’orgueil de penser ou de souffrir
pour la multitude qui sommeille.
A mesure que ma main combinait des harmonies de lignes, je m’enivrais
de la docilité de mes doigts à jouer du crayon. Pour la première fois depuis
mon arrivée, je me sentais dispos. Étais-je enfin conquis par la douceur
modeste du climat? Dix projets différents pour ma fontaine naissaient en
moi l’un de l’autre, et le dernier me séduisait toujours plus que le précédent.
Combien de temps passai-je ainsi, à noter les démarches pressées de
mon imagination jusque-là si rétive? Je ne sais pas. Les trois fleurs, que
mon amie avait placées sur ma table, enchantaient de leur parfum mon
allégresse. Le cri du crapaud persistait dans le jardin, morne et fidèle. Toute
la maison semblait endormie.
J’avais l’impression qu’en me levant je troublerais d’un bruit intempestif
la quiétude qui m’environnait. Je n’osais plus bouger de ma chaise. Je
crayonnais d’une main lente. Le moindre geste maladroit eût sans doute
éveillé de lointains échos.
Derrière moi, le bois de l’armoire craqua. Je tournai la tête, surpris qu’un
effet si grand n’eût pas de cause plus considérable. Et j’eus envie de me
coucher, afin de ne point me gagner près de mes hôtes une réputation
d’importun.
Mais, comme machinalement je traçais quelques dernières lignes, un
autre bruit soudain m’arrêta, un autre craquement, moins proche, puis un
autre, et un autre, et un autre, et un autre, puis un autre, puis d’autres
encore; et tout à coup je crus que ma respiration allait s’arrêter aussi; mon
cœur battit avec violence contre la table.
Une plainte sourde m’arrivait. Une plainte, rythmée comme le bruit qui
avait arrêté ma main. Cette voix... Des mots dominèrent la plainte. Je les
entendis. Une voix, une seule. Des mots d’extase. La voix haletait. Elle cria.
Deux cris légers. Silence.
Les craquements duraient. J’aurais été incapable de me lever. Quel coup
de matraque venait de me frapper à la nuque? Ces bruits qui m’arrivaient
prenaient une ampleur de cauchemar. La plainte recommençait. La même
faible voix geignit, geignit longtemps, râla, encouragea, témoigna, se rendit,
s’oublia, cria. Toute la maison aurait dû entendre comme j’entendais. Mais
non, rien. Silence. Silence partout. Seuls les craquements premiers se
prolongeaient, étouffés, mais réguliers, tenaces, lancinants.
J’étais rivé à ma table, les épaules lourdes, les oreilles bourdonnantes,
paralysé, anéanti. Une troisième fois,—oui, une troisième fois, alors que
l’homme, pas une fois, ne se révéla d’aucune façon,—je subis le supplice de
ces cris de femme en plaisir, puis tout se tut. Silence complet. Silence enfin
total. Silence définitif. J’ai connu de pareils silences pendant la guerre, la
nuit, après des fusillades inopinées.
Qu’ajouterais-je? Rien. Il faut qu’ici le même silence pèse, comme là-
bas sur toute la maison endormie, comme il pèse encore à cette heure sur
mon cœur battant. Rien. Il ne faut rien ajouter.
Ma longue détresse qui s’ensuivit, elle n’importe pas. Ni le désordre des
mille résolutions qui m’éblouirent et m’épuisèrent. Ni mon accablement. Ni
ma honte. Ni rien. Rien. Silence.
L’aube à la cime des tilleuls blémit. J’étais toujours prostré à ma table.
J’eus froid. Un coq appela.
Le soleil parut. Des oiseaux, jetant au jour leur joie en paquets de sifflets
confus, marquèrent la fin du silence. Tout peu à peu se réveilla, au loin, plus
près, à la ferme, dans la maison. Ce fut comme un flux de vie qui monta
vers ma stupeur.
Courbatu, je me levai, et j’allai vers un miroir. Mes cheveux n’étaient
point devenus blancs, mais quel désarroi trahissaient mes yeux!
Quand je sortis de ma chambre, vers huit heures, le beau-frère de mon
amie sortait de la chambre voisine. En costume d’appartement, et la main
sur le bouton de la porte, il disait, vers l’intérieur:
—Je vous envoie le chocolat et des rôties, mais levez-vous, hein? Vous
avez assez dormi, petite paresseuse.
Après quoi:
—A la bonne heure au moins! me dit-il. Voilà qui est d’un campagnard,
de ne pas s’attarder au lit. Comment allez-vous, ce matin?
E LLE avait compris. Pendant plusieurs jours, elle n’essaya pas une fois
de forcer mon indécision. Elle se plaignit seulement, dès le premier, au
dîner, d’être souffrante. Et, plusieurs jours durant, elle traîna de vagues
migraines et des mines fatiguées. C’était sans doute une façon de se montrer
à mes yeux humble et repentante. Un homme plus cruel que moi l’eût
accusée de sentiments plus habiles. La discrétion qu’elle observa
m’attendrit. Tels sont les effets de la présence. Si j’avais fui tout de suite,
chaque heure d’absence nous aurait éloignés davantage l’un de l’autre: tout
rapprochement eût été désormais impossible.
Que désirais-je? J’étais dans l’état d’un blessé qui ne se rend même plus
compte de la gravité de sa blessure, que la fièvre alimente, que d’étranges
rêves soutiennent, et qui ne sait point s’il guérira ni s’il a peut-être envie de
guérir, tant un retour à la vie normale de tous les hommes n’est pas toujours
pour les hommes désirable.
Les jours, lents, se succédaient. Je m’enfermais dans mon atelier.
N’ayant encore fixé mon choix sur aucun de mes projets, je n’avais pas
encore commandé le marbre convenable. Pour éviter des questions, je
m’étais empressé de manier quelques blocs de glaise, au hasard, et, couvert
par cette apparence, je ne faisais rien, que de ruminer des pensées
débilitantes.
Quelquefois, les enfants entraient dans l’atelier. Ils avaient l’air
contraint. Obscurément, ils pressentaient peut-être en moi un ennemi, et ils
ne cherchaient pas mon amitié; ils demeuraient distants, comme il arrive à
l’ordinaire à ces pauvres petits êtres devant ceux qui menacent de leur
dérober une part de l’affection maternelle qu’ils veulent toute pour eux.
Le mari, quand il venait me voir, ne laissait percer aucune gêne. Il avait,
comme on dit, des idées arrêtées, mais, quand l’éducation de ses enfants
n’était pas en jeu, il n’essayait pas de les imposer. A mon égard, il montrait
de la sympathie. Je ne m’en réjouissais pas. Il m’interrogeait volontiers,
s’intéressait à ce qu’il nommait mon labeur secret d’artiste; mais, en
homme de méthode, il ne me parlait de mon art que dans mon atelier. Il était
intelligent, curieux, et n’affichait qu’un goût modéré pour les spéculations
philosophiques, se retranchant derrière sa seule compétence de technicien
qui regrette que tout le monde ne l’imite pas. Au demeurant, un homme de
bonne compagnie.
Quant au beau-frère, il ne me dérangeait presque jamais. Il prétendait,
disait-il, ne pas violer les mystères de mon temple. Et je lui savais gré de ne
m’infliger que rarement, et rapidement, son intrusion. C’est à cause de lui,
on le comprend, que je retardais de plus en plus l’instant où j’ouvrirais mes
bras à mon amie pardonnée, si je devais les lui ouvrir jamais.
Quelle certitude attendais-je?
Mon amie ne semblait pas pressée d’obtenir malgré moi son pardon.
Discrète, humble, digne, et douloureuse, elle attendait, elle aussi. Depuis la
nuit affreuse, je ne montais dans ma chambre que fort tard, après de longues
et desséchantes heures passées au fond de mon atelier, lorsque je présumais
que je pouvais enfin sans risque gagner mon lit, où d’ailleurs le sommeil
m’échappait longtemps. Nuits détestables. Nuits atroces. Réveils pénibles.
Je descendais de ma chambre vers midi, pour ne pas risquer non plus de
trouver encore le beau-frère sur le seuil de sa belle-sœur, ou de rencontrer
l’un de mes hôtes au sortir du lit, alors que les yeux et tout le visage ont une
franchise indécente.
Quand je revoyais mon amie, elle me regardait tristement, puis elle
baissait la tête. Rien de plus. Selon mon humeur, c’était beaucoup, ou
c’était peu. Certains jours, j’avais envie de la prendre dans mes bras, devant
tout le monde; d’autres jours, je serrais les poings, et je l’aurais frappée
avec plaisir.
Orgueil! Orgueil! Lequel fut le plus coupable, du sien ou du mien?
Pourquoi n’avait-elle pas le courage de me tendre des mains chéries?
Pourquoi n’eus-je pas la force d’être lâche encore, aveuglément? Le même
orgueil nous retenait tous deux. Aurais-je persévéré? Je ne crois pas. Du
plus profond de ma misère, je songeais souvent à cet enfant qu’elle avait