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About the Authors

All four authors are active scholars and teachers who have been/are recipients of research
grants from the NIH and the NSF. We have all served in various capacities as grant proposal
reviewers for NSF, NIH, HHMI, and other funding bodies as well as evaluating manuscripts
submitted for publication in immunological journals. In addition, we are all active members
of the American Association of Immunologists and have served our national organization in
a variety of ways.

Judy Owen holds B.A. and M.A. (Hons) degrees from Cambridge University. She pursued
her Ph.D. at the University of Pennsylvania with the late Dr. Norman Klinman and her post-
doctoral fellowship with Dr. Peter Doherty in viral immunology. She was appointed to the
faculty of Haverford College, one of the first undergraduate colleges to offer a course in im-
munology, in 1981. She teaches numerous laboratory and lecture courses in biochemistry and
immunology and has received several teaching and mentorship awards. She is a participant
in the First Year Writing Program and has been involved in curriculum development across
the College.

Jenni Punt received her A.B. from Bryn Mawr College (magna cum laude) majoring in
Biology at Haverford College, She received her VMD (summa cum laude) and Ph.D. in im-
munology from the University of Pennsylvania and was a Damon Runyon-Walter Winchell
Physician-Scientist fellow with Dr. Alfred Singer at the National Institutes of Health. She was
appointed to the faculty of Haverford College in 1996 where she teaches cell biology and im-
munology and performs research in T cell development and hematopoiesis. She has received
several teaching awards and has contributed to the development of college-wide curricular
initiatives.
Together, Jenni Punt and Judy Owen developed and ran the first AAI Introductory Im-
munology course, which is now offered on an annual basis.

Sharon Stranford obtained her B.A. with Honors in Biology from Arcadia University
and her Ph.D. in Microbiology and Immunology from Hahnemann (now Drexel) University,
where she studied autoimmunity with funding from the Multiple Sclerosis Foundation. She
pursued postdoctoral studies in transplantation immunology at Oxford University in England,
followed by a fellowship at the University of California, San Francisco, working on HIV/AIDS
with Dr. Jay Levy. From 1999 to 2001, Sharon was a Visiting Assistant Professor of Biology at
Amherst College, and in 2001 joined the faculty of Mount Holyoke College as a Clare Boothe
Luce Assistant Professor. She teaches courses in introductory biology, cell biology, immunol-
ogy, and infectious disease, as well as a new interdisciplinary course called Controversies in
Public Health.

Pat Jones graduated from Oberlin College in Ohio with Highest Honors in Biology and
obtained her Ph.D. in Biology with Distinction from the Johns Hopkins University. She was a
postdoctoral fellow of the Arthritis Foundation for two years in the Department of Biochem-
istry and Biophysics at the University of California, San Francisco, Medical School, followed
by two years as an NSF postdoctoral fellow in the Departments of Genetics and Medicine/
Immunology at Stanford University School of Medicine. In 1978 she was appointed Assistant
Professor of Biology at Stanford and is now a full professor. Pat has received several under-
graduate teaching awards, was the founding Director of the Ph.D. Program in Immunology,
and in July, 2011, she assumed the position of Director of Stanford Immunology, a position
that coordinates activities in immunology across the university.
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Contents

Chapter 1 SUMMARY 23
REFERENCES 23
Overview of the Immune System 1 USEFUL WEB SITES 23

A Historical Perspective of Immunology 2 STUDY QUESTIONS 24

Early vaccination studies led the way to immunology 2

Vaccination is an ongoing, worldwide enterprise 3 Chapter 2
Immunology is about more than just vaccines
and infectious disease 4 Cells, Organs, and Micro-
Immunity involves both humoral and cellular environments of the Immune
components 6
System 27
How are foreign substances recognized by the
immune system? 9 Cells of the Immune System 27
Hematopoietic stem cells have the ability to
Important Concepts for Understanding
differentiate into many types of blood cells 28
the Mammalian Immune Response 11
Hematopoeisis is the process by which hematopoietic
Pathogens come in many forms and must first stem cells develop into mature blood cells 32
breach natural barriers 12
Cells of the myeloid lineage are the first responders
The immune response quickly becomes tailored to infection 32
to suit the assault 12
Cells of the lymphoid lineage regulate the adaptive
Pathogen recognition molecules can be encoded immune response 37
in the germline or randomly generated 14
Primary Lymphoid Organs—
Tolerance ensures that the immune system avoids Where Immune Cells Develop 41
destroying the host 15
The bone marrow provides niches for hematopoietic
The immune response is composed of two stem cells to self-renew and differentiate into myeloid
interconnected arms: innate immunity and cells and B lymphocytes 41
adaptive immunity 16
The thymus is a primary lymphoid organ where
Adaptive immune responses typically generate T cells mature 41
memory 17
Secondary Lymphoid Organs—
The Good, Bad, and Ugly of the Immune Where the Immune Response Is Initiated 48
System 19
Secondary lymphoid organs are distributed through-
Inappropriate or dysfunctional immune out the body and share some anatomical features 48
responses can result in a range of disorders 19
Lymphoid organs are connected to each other and
The immune response renders tissue transplantation to infected tissue by two different circulatory
challenging 22 systems: blood and lymphatics 48
Cancer presents a unique challenge to the immune The lymph node is a highly specialized secondary
response 22 lymphoid organ 50
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viii Contents

The spleen organizes the immune response against Signal-induced PIP2 breakdown by PLC causes an
blood-borne pathogens 53 increase in cytoplasmic calcium ion concentration 75
MALT organizes the response to antigen that Ubiquitination may inhibit or enhance signal
enters mucosal tissues 53 transduction 76
The skin is an innate immune barrier and also Frequently Encountered Signaling
includes lymphoid tissue 56 Pathways 77
Tertiary lymphoid tissues also organize and maintain The PLC pathway induces calcium release and
an immune response 57 PKC activation 77
SUMMARY 60 The Ras/Map kinase cascade activates transcription
REFERENCES 60 through AP-1 78

USEFUL WEB SITES 61 PKC activates the NF-κB transcription factor 79

STUDY QUESTIONS 61 The Structure of Antibodies 80
Antibodies are made up of multiple
immunoglobulin domains 80
Antibodies share a common structure of two light
Chapter 3 chains and two heavy chains 81
There are two major classes of antibody light chains 85
Receptors and Signaling: B and There are five major classes of antibody heavy chains 85
T-Cell Receptors 65 Antibodies and antibody fragments can serve as
Receptor-Ligand Interactions 66 antigens 86

Receptor-ligand binding occurs via multiple Each of the domains of the antibody heavy and
noncovalent bonds 66 light chains mediate specific functions 88
X-ray crystallography has been used to define
How do we quantitate the strength of receptor-
the structural basis of antigen-antibody
ligand interactions? 66
binding 90
Interactions between receptors and ligands can be
multivalent 67 Signal Transduction in B Cells 91
Receptor and ligand expression can vary during the Antigen binding results in docking of adapter
course of an immune response 68 molecules and enzymes into the BCR-Igα/Igβ
membrane complex 91
Local concentrations of cytokines and other ligands
may be extremely high 68 B cells use many of the downstream signaling
pathways described above 92
Common Strategies Used in Many Signaling
B cells also receive signals through co-receptors 94
Pathways 69
Ligand binding can induce conformational changes T-Cell Receptors and Signaling 95
in, and/or clustering of, the receptor 71 The T-cell receptor is a heterodimer with variable
and constant regions 95
Some receptors require receptor-associated
molecules to signal cell activation 71 The T-cell signal transduction complex includes CD3 98
Ligand-induced receptor clustering can alter The T cell co-receptors CD4 and CD8 also bind
receptor location 71 the MHC 99
Tyrosine phosphorylation is an early step in many Lck is the first tyrosine kinase activated in T cell
signaling pathways 73 signaling 100
Adapter proteins gather members of signaling T cells use downstream signaling strategies similar
pathways 74 to those of B cells 100

Phosphorylation on serine and threonine residues SUMMARY 101

is also a common step in signaling pathways 74
REFERENCES 102
Phosphorylation of membrane phospholipids
USEFUL WEB SITES 102
recruits PH domain-containing proteins to the cell
membrane 75 STUDY QUESTIONS 103
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Chapter 4 Cytokine storms may have caused many deaths in

the 1918 Spanish influenza 137

Receptors and Signaling: Cytokine-Based Therapies 137

Cytokines and Chemokines 105 SUMMARY 138
REFERENCES 138
General Properties of Cytokines and
Chemokines 106 USEFUL WEB SITES 139

Cytokines mediate the activation, proliferation, STUDY QUESTIONS 140

and differentiation of target cells 107
Cytokines have numerous biological functions 107
Chapter 5
Cytokines can elicit and support the activation of
specific T-cell subpopulations 107 Innate Immunity 141
Cell activation may alter the expression of receptors
Anatomical Barriers to Infection 143
and adhesion molecules 109
Epithelial barriers prevent pathogen entry into the
Cytokines are concentrated between secreting and
body’s interior 143
target cells 110
Antimicrobial proteins and peptides kill would-be
Signaling through multiple receptors can fine tune
invaders 145
a cellular response 110
Phagocytosis 147
Six Families of Cytokines and Associated
Receptor Molecules 111 Microbes are recognized by receptors on
phagocytic cells 147
Cytokines of the IL-1 family promote proinflammatory
signals 113 Phagocytosed microbes are killed by multiple
mechanisms 151
Hematopoietin (Class I) family cytokines share
three-dimensional structural motifs, but induce a Phagocytosis contributes to cell turnover and the
diversity of functions in target cells 116 clearance of dead cells 152
The Interferon (Class II) cytokine family was the Induced Cellular Innate Responses 152
first to be discovered 119
Cellular pattern recognition receptors activate
Members of the TNF cytokine family can signal responses to microbes and cell damage 153
development, activation, or death 123
Toll-like receptors recognize many types of
The IL-17 family is a recently discovered, pathogen molecules 153
proinflammatory cytokine cluster 127
C-type lectin receptors bind carbohydrates on the
Chemokines direct the migration of leukocytes surfaces of extracellular pathogens 158
through the body 129
Retinoic acid-inducible gene-I-like receptors bind
Cytokine Antagonists 133 viral RNA in the cytosol of infected cells 160

The IL-1 receptor antagonist blocks the IL-1 Nod-like receptors are activated by a variety of
cytokine receptor 133 PAMPs, DAMPs, and other harmful substances 160

Cytokine antagonists can be derived from cleavage Expression of innate immunity proteins is induced
of the cytokine receptor 134 by PRR signaling 160

Some viruses have developed strategies to exploit Inflammatory Responses 166

cytokine activity 134
Inflammation results from innate responses
triggered by infection, tissue damage, or harmful
Cytokine-Related Diseases 134 substances 167
Septic shock is relatively common and potentially
Proteins of the acute phase response contribute
lethal 135
to innate immunity and inflammation 168
Bacterial toxic shock is caused by superantigen
induction of T-cell cytokine secretion 135 Natural Killer Cells 168
Cytokine activity is implicated in lymphoid and Regulation and Evasion of Innate and
myeloid cancers 137 Inflammatory Responses 169
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Innate and inflammatory responses can be harmful 169 The Regulation of Complement Activity 210
Innate and inflammatory responses are regulated Complement activity is passively regulated by protein
both positively and negatively 172 stability and cell surface composition 210
Pathogens have evolved mechanisms to evade The C1 inhibitor, C1INH, promotes dissociation
innate and inflammatory responses 173 of C1 components 211
Interactions Between the Innate and Decay Accelerating Factors promote decay of C3
Adaptive Immune Systems 173 convertases 211

The innate immune system activates and regulates Factor I degrades C3b and C4b 212
adaptive immune responses 174 Protectin inhibits the MAC attack 213
Adjuvants activate innate immune responses to Carboxypeptidases can inactivate the anaphylatoxins,
increase the effectiveness of immunizations 175 C3a and C5a 213
Some pathogen clearance mechanisms are common
to both innate and adaptive immune responses 176 Complement Deficiencies 213
Ubiquity of Innate Immunity 176 Microbial Complement Evasion Strategies 214
Plants rely on innate immune responses to combat Some pathogens interfere with the first step of
infections 177 immunoglobulin-mediated complement activation 215
Invertebrate and vertebrate innate immune Microbial proteins bind and inactivate complement
responses show both similarities and differences 177 proteins 215
SUMMARY 180 Microbial proteases destroy complement proteins 215
REFERENCES 181 Some microbes mimic or bind complement
USEFUL WEB SITES 182 regulatory proteins 215
STUDY QUESTIONS 182
The Evolutionary Origins of the Complement
System 215
SUMMARY 219
Chapter 6 REFERENCES 220
USEFUL WEB SITES 220
The Complement System 187 STUDY QUESTIONS 221
The Major Pathways of Complement Activation 189
The classical pathway is initiated by antibody binding 190
The lectin pathway is initiated when soluble proteins Chapter 7
recognize microbial antigens 195
The alternative pathway is initiated in three The Organization and Expression
distinct ways 196
of Lymphocyte Receptor Genes 225
The three complement pathways converge at the
formation of the C5 convertase 200 The Puzzle of Immunoglobulin Gene Structure 226
C5 initiates the generation of the MAC 200 Investigators proposed two early theoretical
models of antibody genetics 226
The Diverse Functions of Complement 201
Breakthrough experiments revealed that multiple
Complement receptors connect complement-
gene segments encode the light chain 227
tagged pathogens to effector cells 201
Complement enhances host defense against infection 204 Multigene Organization of Ig Genes 231
Complement mediates the interface between innate Kappa light-chain genes include V, J, and C segments 231
and adaptive immunities 207
Lambda light-chain genes pair each J segment
Complement aids in the contraction phase of the with a particular C segment 231
immune response 207
Heavy-chain gene organization includes VH, D, JJ,
Complement mediates CNS synapse elimination 210 and CH segments 232
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Contents xi

The Mechanism of V(D)J Recombination 232 Class II molecules have two non-identical
glycoprotein chains 262
Recombination is directed by signal sequences 233
Class I and II molecules exhibit polymorphism in
Gene segments are joined by the RAG1/2 the region that binds to peptides 263
recombinase combination 234
V(D)J recombination results in a functional Ig variable General Organization and Inheritance of
region gene 235 the MHC 267
V(D)J recombination can occur between The MHC locus encodes three major classes of
segments transcribed in either the same or opposite molecules 268
directions 239 The exon/intron arrangement of class I and II genes
Five mechanisms generate antibody diversity in reflects their domain structure 270
naïve B cells 239 Allelic forms of MHC genes are inherited in linked
groups called haplotypes 270
B-Cell Receptor Expression 242
MHC molecules are codominantly expressed 271
Allelic exclusion ensures that each B cell synthesizes
only one heavy chain and one light chain 242 Class I and class II molecules exhibit diversity at
both the individual and species levels 273
Receptor editing of potentially autoreactive
receptors occurs in light chains 243 MHC polymorphism has functional relevance 276

Ig gene transcription is tightly regulated 244 The Role of the MHC and Expression
Mature B cells express both IgM and IgD antibodies Patterns 277
by a process that involves mRNA splicing 246 MHC molecules present both intracellular and
extracellular antigens 278
T-Cell Receptor Genes and Expression 247
MHC class I expression is found throughout the
Understanding the protein structure of the TCR body 278
was critical to the process of discovering the genes 247
Expression of MHC class II molecules is primarily
The β-chain gene was discovered simultaneously restricted to antigen-presenting cells 279
in two different laboratories 249
MHC expression can change with changing
A search for the α-chain gene led to the γ-chain conditions 279
gene instead 250 T cells are restricted to recognizing peptides
TCR genes undergo a process of rearrangement presented in the context of self-MHC alleles 281
very similar to that of Ig genes 251 Evidence suggests different antigen processing
TCR expression is controlled by allelic exclusion 253 and presentation pathways 284

TCR gene expression is tightly regulated 253 The Endogenous Pathway of Antigen
Processing and Presentation 285
SUMMARY 255
Peptides are generated by protease complexes
REFERENCES 256
called proteasomes 285
USEFUL WEB SITES 257
Peptides are transported from the cytosol to the RER 285
STUDY QUESTIONS 258
Chaperones aid peptide assembly with MHC
class I molecules 286

The Exogenous Pathway of Antigen

Chapter 8 Processing and Presentation 288
Peptides are generated from internalized molecules
The Major Histocompatibility in endocytic vesicles 288
Complex and Antigen The invariant chain guides transport of class II
Presentation 261 MHC molecules to endocytic vesicles 289

The Structure and Function of MHC Molecules 262 Peptides assemble with class II MHC molecules
by displacing CLIP 289
Class I molecules have a glycoprotein heavy chain
and a small protein light chain 262 Cross-Presentation of Exogenous Antigens 291
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xii Contents

Dendritic cells appear to be the primary cross- Apoptosis allows cells to die without triggering
presenting cell type 292 an inflammatory response 318
Mechanisms and Functions of Cross-Presentation 292 Different stimuli initiate apoptosis, but all activate
caspases 318
Presentation of Nonpeptide Antigens 293
Apoptosis of peripheral T cells is mediated by the
SUMMARY 295 extrinsic (Fas) pathway 320
REFERENCES 295 TCR-mediated negative selection in the thymus
USEFUL WEB SITES 296 induces the intrinsic (mitochondria-mediated)
apoptotic pathway 321
STUDY QUESTIONS 296
Bcl-2 family members can inhibit or induce apoptosis 321

SUMMARY 324

Chapter 9 REFERENCES 325

USEFUL WEB SITES 326
T-Cell Development 299 STUDY QUESTIONS 327
Early Thymocyte Development 301
Thymocytes progress through four double-negative
stages 301 Chapter 10
Thymocytes can express either TCRαβ or TCRγδ
receptors 302 B-Cell Development 329
DN thymocytes undergo β-selection, which results The Site of Hematopoiesis 330
in proliferation and differentiation 303
The site of B-cell generation changes during gestation 330
Positive and Negative Selection 304 Hematopoiesis in the fetal liver differs from that
in the adult bone marrow 332
Thymocytes “learn” MHC restriction in the thymus 305
T cells undergo positive and negative selection 305 B-Cell Development in the Bone Marrow 332
Positive selection ensures MHC restriction 307 The stages of hematopoiesis are defined by cell-
surface markers, transcription-factor expression,
Negative selection (central tolerance) ensures and immunoglobulin gene rearrangements 334
self-tolerance 310
The earliest steps in lymphocyte differentiation culminate
The selection paradox: Why don’t we delete all cells in the generation of a common lymphoid progenitor 337
we positively select? 312
The later steps of B-cell development result in
An alternative model can explain the thymic commitment to the B-cell phenotype 339
selection paradox 313
Immature B cells in the bone marrow are
Do positive and negative selection occur at the exquisitely sensitive to tolerance induction 344
same stage of development, or in sequence? 314
Many, but not all, self-reactive B cells are deleted
Lineage Commitment 314 within the bone marrow 345

Several models have been proposed to explain B cells exported from the bone marrow are still
lineage commitment 314 functionally immature 345

Double-positive thymocytes may commit to other Mature, primary B-2 B cells migrate to the lymphoid
types of lymphocytes 316 follicles 349

Exit from the Thymus and Final Maturation 316 The Development of B-1 and Marginal-Zone
B Cells 351
Other Mechanisms That Maintain Self-Tolerance 316 B-1 B cells are derived from a separate developmental
TREG cells negatively regulate immune responses 317 lineage 351

Peripheral mechanisms of tolerance also protect Marginal-zone cells share phenotypic and functional
against autoreactive thymocytes 318 characteristics with B-1 B cells and arise at the T2 stage 352

Apoptosis 318 Comparison of B- and T-Cell Development 352

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Contents xiii

SUMMARY 354 Chapter 12

REFERENCES 355
USEFUL WEB SITES 355 B-Cell Activation, Differentiation,
STUDY QUESTIONS 356 and Memory Generation 385
T-Dependent B-Cell Responses 388
T-dependent antigens require T-cell help to
Chapter 11 generate an antibody response 388
Antigen recognition by mature B cells provides a
T-Cell Activation, Differentiation, survival signal 389
and Memory 357 B cells encounter antigen in the lymph nodes and
spleen 390
T-Cell Activation and the Two-Signal Hypothesis 358
B-cell recognition of cell-bound antigen results in
Costimulatory signals are required for optimal T-cell
membrane spreading 391
activation and proliferation 359
What causes the clustering of the B-cell receptors
Clonal anergy results if a costimulatory signal is absent 363
upon antigen binding? 392
Cytokines provide Signal 3 364
Antigen receptor clustering induces internalization
Antigen-presenting cells have characteristic and antigen presentation by the B cell 393
costimulatory properties 365
Activated B cells migrate to find antigen-specific
Superantigens are a special class of T-cell activators 366 T cells 393

T-Cell Differentiation 368 Activated B cells move either into the extra-
follicular space or into the follicles to form germinal
Helper T cells can be divided into distinct subsets 370 centers 395
The differentiation of T helper cell subsets is regulated Plasma cells form within the primary focus 395
by polarizing cytokines 371
Other activated B cells move into the follicles and
Effector T helper cell subsets are distinguished by initiate a germinal center response 396
three properties 372
Somatic hypermutation and affinity selection occur
Helper T cells may not be irrevocably committed within the germinal center 398
to a lineage 378
Class switch recombination occurs within the
Helper T-cell subsets play critical roles in immune germinal center after antigen contact 401
health and disease 378
Most newly generated B cells are lost at the end of
T-Cell Memory 379 the primary immune response 403

Naïve, effector, and memory T cells display broad Some germinal center cells complete their
differences in surface protein expression 379 maturation as plasma cells 403

TCM and TEM are distinguished by their locale and B-cell memory provides a rapid and strong
commitment to effector function 380 response to secondary infection 404

How and when do memory cells arise? 380 T-Independent B-Cell Responses 406
What signals induce memory cell commitment? 381 T-independent antigens stimulate antibody
production without the need for T-cell help 406
Do memory cells reflect the heterogeneity of
effector cells generated during a primary response? 381 Two novel subclasses of B cells mediate the response
to T-independent antigens 407
Are there differences between CD4+ and CD8+
memory T cells? 381 Negative Regulation of B Cells 411
How are memory cells maintained over many years? 381 Negative signaling through CD22 shuts down
unnecessary BCR signaling 411
SUMMARY 381
Negative signaling through the FcγRIIb receptor
REFERENCES 382 inhibits B-cell activation 411
USEFUL WEB SITES 383 B-10 B cells act as negative regulators by
STUDY QUESTIONS 383 secreting IL-10 411
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xiv Contents

SUMMARY 412 Naïve lymphocytes sample stromal cells in the

REFERENCES 413 lymph nodes 461

USEFUL WEB SITES 414 Naïve lymphocytes browse for antigen along
reticular networks in the lymph node 461
STUDY QUESTIONS 414
Immune Cell Behavior during the Innate
Immune Response 464
Antigen-presenting cells travel to lymph nodes
Chapter 13 and present processed antigen to T cells 465
Unprocessed antigen also gains access to lymph-
Effector Responses: Cell-and node B cells 465
Antibody-Mediated Immunity 415 Immune Cell Behavior during the Adaptive
Antibody-Mediated Effector Functions 416 Immune Response 467
+
Antibodies mediate the clearance and destruction Naïve CD4 T cells arrest their movements after
of pathogen in a variety of ways 416 engaging antigens 468
+
Antibody isotypes mediate different effector functions 419 B cells seek help from CD4 T cells at the border
between the follicle and paracortex of the Lymph Node 468
Fc receptors mediate many effector functions of
antibodies 423 Dynamic imaging approaches have been used to
address a controversy about B-cell behavior in
Cell-Mediated Effector Responses 427 germinal centers 470
+
Cytotoxic T lymphocytes recognize and kill infected CD8 T cells are activated in the lymph node via a
or tumor cells via T-cell receptor activation 428 multicellular interaction 471

Natural killer cells recognize and kill infected cells and Activated lymphocytes exit the lymph node and
tumor cells by their absence of MHC class I 435 recirculate 472

NKT cells bridge the innate and adaptive immune A summary of our current understanding 472
systems 441 The immune response contracts within 10 to 14 days 474
Experimental Assessment of Cell-Mediated Immune Cell Behavior in Peripheral
Cytotoxicity 444 Tissues 474
Co-culturing T cells with foreign cells stimulates Chemokine receptors and integrins regulate homing
the mixed-lymphocyte reaction 444 of effector lymphocytes to peripheral tissues 474
CTL activity can be demonstrated by cell-mediated Effector lymphocytes respond to antigen in
lympholysis 445 multiple tissues 475
The graft-versus-host reaction is an in vivo indication SUMMARY 480
of cell-mediated cytotoxicity 446
REFERENCES 481
SUMMARY 446 USEFUL WEB SITES 482
REFERENCES 447 STUDY QUESTIONS 482
USEFUL WEB SITES 448
STUDY QUESTIONS 448

Chapter 15
Chapter 14 Allergy, Hypersensitivities, and
The Immune Response Chronic Inflammation 485
in Space and Time 451 Allergy: A Type I Hypersensitivity Reaction 486
Immune Cell Behavior before Antigen IgE antibodies are responsible for type I hypersensitivity 487
Is Introduced 455 Many allergens can elicit a type I response 487
Naïve lymphocytes circulate between secondary IgE antibodies act by cross-linking Fcε receptors on
and tertiary lymphoid tissues 455 the surfaces of innate immune cells 487
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Contents xv

IgE receptor signaling is tightly regulated 491 Chapter 16

Innate immune cells produce molecules responsible
for type I hypersensitivity symptoms 491 Tolerance, Autoimmunity, and
Type I hypersensitivities are characterized by both Transplantation 517
early and late responses 494
Establishment and Maintenance of Tolerance 518
There are several categories of type I hypersensitivity
reactions 494 Antigen sequestration is one means to protect
self antigens from attack 519
There is a genetic basis for type I hypersensitivity 497
Central tolerance limits development of autoreactive
Diagnostic tests and treatments are available for T cells and B cells 520
type I hypersensitivity reactions 498
Peripheral tolerance regulates autoreactive cells
The hygiene hypothesis has been advanced to in the circulation 520
explain increases in allergy incidence 501
Autoimmunity 525
Antibody-Mediated (Type II) Hypersensitivity
Reactions 501 Some autoimmune diseases target specific organs 526

Transfusion reactions are an example of type II Some autoimmune diseases are systemic 529
hypersensitivity 501 Both intrinsic and extrinsic factors can favor
Hemolytic disease of the newborn is caused by susceptibility to autoimmune disease 531
type II reactions 503 Several possible mechanisms have been proposed
for the induction of autoimmunity 533
Hemolytic anemia can be drug induced 504
Autoimmune diseases can be treated by general or
Immune Complex-Mediated (Type III) pathway-specific immunosuppression 534
Hypersensitivity 505
Transplantation Immunology 536
Immune complexes can damage various tissues 505
Graft rejection occurs based on immunologic
Immune complex-mediated hypersensitivity can principles 536
resolve spontaneously 505
Graft rejection follows a predictable clinical course 541
Autoantigens can be involved in immune complex-
mediated reactions 506 Immunosuppressive therapy can be either general
or target-specific 543
Arthus reactions are localized type III hypersensitivity
reactions 506 Immune tolerance to allografts is favored in certain
instances 545
Delayed-Type (Type IV) Hypersensitivity (DTH) 506 Some organs are more amenable to clinical
The initiation of a type IV DTH response involves transplantation than others 546
sensitization by antigen 507
SUMMARY 549
The effector phase of a classical DTH response is REFERENCES 550
induced by second exposure to a sensitizing antigen 507
USEFUL WEB SITES 551
The DTH reaction can be detected by a skin test 508
STUDY QUESTIONS 551
Contact dermatitis is a type IV hypersensitivity response 508

Chronic Inflammation 509

Infections can cause chronic inflammation 509
Chapter 17
There are noninfectious causes of chronic inflammation 510 Infectious Diseases and Vaccines 553
Obesity is associated with chronic inflammation 510
The Importance of Barriers to Infection and
Chronic inflammation can cause systemic disease 510 the Innate Response 554
SUMMARY 513 Viral Infections 555
REFERENCES 515 Many viruses are neutralized by antibodies 556
USEFUL WEB SITES 515 Cell-mediated immunity is important for viral
STUDY QUESTIONS 516 control and clearance 556
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xvi Contents

Viruses employ several different strategies to evade B-cell immunodeficiencies exhibit depressed
host defense mechanisms 556 production of one or more antibody isotypes 601
Influenza has been responsible for some of the Disruptions to innate components may also impact
worst pandemics in history 557 adaptive responses 601

Bacterial Infections 560 Complement deficiencies are relatively common 603

Immune responses to extracellular and intracellular Immunodeficiency that disrupts immune regulation
bacteria can differ 560 can manifest as autoimmunity 603

Bacteria can evade host defense mechanisms at Immunodeficiency disorders are treated by
several different stages 563 replacement therapy 604

Tuberculosis is primarily controlled by CD4+ T cells 564 Animal models of immunodeficiency have been
used to study basic immune function 604
Diphtheria can be controlled by immunization with
inactivated toxoid 565 Secondary Immunodeficiencies 606
Parasitic Infections 565 HIV/AIDS has claimed millions of lives worldwide 607

Protozoan parasites account for huge worldwide The retrovirus HIV-1 is the causative agent of AIDS 608
disease burdens 565 HIV-1 is spread by intimate contact with infected
body fluids 610
A variety of diseases are caused by parasitic
worms (helminths) 567 In vitro studies have revealed the structure and life
cycle of HIV-1 612
Fungal Infections 569
Infection with HIV-1 leads to gradual impairment
Innate immunity controls most fungal infections 569 of immune function 615
Immunity against fungal pathogens can be acquired 571 Active research investigates the mechanism of
Emerging and Re-emerging Infectious Diseases 571 progression to AIDS 616

Some noteworthy new infectious diseases have Therapeutic agents inhibit retrovirus replication 619
appeared recently 572 A vaccine may be the only way to stop the
Diseases may re-emerge for various reasons 573 HIV/AIDS epidemic 621

Vaccines 574 SUMMARY 623

REFERENCES 623
Protective immunity can be achieved by active
or passive immunization 574 USEFUL WEB SITES 624

There are several vaccine strategies, each with STUDY QUESTIONS 624
unique advantages and challenges 578
Conjugate or multivalent vaccines can improve
immunogenicity and outcome 583
Chapter 19
Adjuvants are included to enhance the immune
response to a vaccine 585
Cancer and the Immune System 627
Terminology and Common Types of Cancer 627
SUMMARY 586
REFERENCES 587 Malignant Transformation of Cells 628
USEFUL WEB SITES 588 DNA alterations can induce malignant transformation 629
STUDY QUESTIONS 588 The discovery of oncogenes paved the way for our
understanding of cancer induction 629
Genes associated with cancer control cell
proliferation and survival 630
Chapter 18
Malignant transformation involves multiple steps 633
Immunodeficiency Disorders 593 Tumor Antigens 634
Primary Immunodeficiencies 593 Tumor-specific antigens are unique to tumor cells 636
Combined immunodeficiencies disrupt adaptive Tumor-associated antigens are normal cellular
immunity 597 proteins with unique expression patterns 636
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Contents xvii

The Immune Response to Cancer 638 Hemagglutination inhibition reactions are used to detect
the presence of viruses and of antiviral antibodies 658
Immunoediting both protects against and
promotes tumor growth 639 Bacterial agglutination can be used to detect
antibodies to bacteria 659
Key immunologic pathways mediating tumor
eradication have been identified 639 Antibody Assays Based on Antigen Binding to
Some inflammatory responses can promote cancer 642 Solid-Phase Supports 659
Some tumor cells evade immune recognition Radioimmunoassays are used to measure the
and activation 643 concentrations of biologically relevant proteins
and hormones in bodily fluids 659
Cancer Immunotherapy 644
ELISA assays use antibodies or antigens covalently
Monoclonal antibodies can be targeted to tumor cells 644 bound to enzymes 660
Cytokines can be used to augment the immune The design of an ELISA assay must consider various
response to tumors 646 methodological options 662
Tumor-specific T cells can be expanded and ELISPOT assays measure molecules secreted by
reintroduced into patients 647 individual cells 663
New therapeutic vaccines may enhance the anti-tumor Western blotting can identify a specific protein
immune response 647 in a complex protein mixture 664
Manipulation of costimulatory signals can improve Methods to Determine the Affinity of Antigen-
cancer immunity 647
Antibody Interactions 664
Combination cancer therapies are yielding
Equilibrium dialysis can be used to measure
surprising results 648
antibody affinity for antigen 665
SUMMARY 649
Surface plasmon resonance is commonly used
REFERENCES 650 for measurements of antibody affinity 667
USEFUL WEB SITES 650 Microscopic Visualization of Cells and
STUDY QUESTIONS 651 Subcellular Structures 668
Immunocytochemistry and immunohistochemistry
use enzyme-conjugated antibodies to create images
Chapter 20 of fixed tissues 668
Immunoelectron microscopy uses gold beads
Experimental Systems to visualize antibody-bound antigens 669

and Methods 653 Immunofluorescence-Based Imaging

Techniques 669
Antibody Generation 654
Fluorescence can be used to visualize cells
Polyclonal antibodies are secreted by multiple clones
and molecules 669
of antigen-specific B cells 654
Immunofl uorescence microscopy uses antibodies
A monoclonal antibody is the product of a single
conjugated with fluorescent dyes 669
stimulated B cell 654
Confocal fluorescence microscopy provides three-
Monoclonal antibodies can be modified for use in
dimensional images of extraordinary clarity 670
the laboratory or the clinic 655
Multiphoton fluorescence microscopy is a variation
Immunoprecipitation- Based Techniques 656
of confocal microscopy 670
Immunoprecipitation can be performed in solution 656
Intravital imaging allows observation of immune
Immunoprecipitation of soluble antigens can be responses in vivo 671
performed in gel matrices 656
Flow Cytometry 672
Immunoprecipitation allows characterization of
cell-bound molecules 657 Magnetic Activated Cell Sorting 677
Agglutination Reactions 658 Cell Cycle Analysis 678
Hemagglutination reactions can be used to detect any Tritiated (3H) thymidine uptake was one of the
antigen conjugated to the surface of red blood cells 658 first methods used to assess cell division 678
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xviii Contents

Colorimetric assays for cell division are rapid and Transgenic animals carry genes that have been
eliminate the use of radioactive isotopes 678 artificially introduced 684
Bromodeoxyuridine-based assays for cell division use Knock-in and knockout technologies replace an
antibodies to detect newly synthesized DNA 678 endogenous with a nonfunctional or engineered
gene copy 685
Propidium iodide enables analysis of the cell cycle
status of cell populations 678 The cre/lox system enables inducible gene deletion in
selected tissues 687
Carboxyfluorescein succinimidyl ester can be used
to follow cell division 679 SUMMARY 689
REFERENCES 690
Assays of Cell Death 679
USEFUL WEB SITES 690
The 51Cr release assay was the first assay used
STUDY QUESTIONS 691
to measure cell death 679
Fluorescently labeled annexin V measures phosphatidyl
serine in the outer lipid envelope of apoptotic cells 680
The TUNEL assay measures apoptotically generated Appendix I
DNA fragmentation 680
Caspase assays measure the activity of enzymes
CD Antigens A-1
involved in apoptosis 681

Biochemical Approaches Used to Elucidate

Signal Transduction Pathways 681 Appendix II
Biochemical inhibitors are often used to identify
intermediates in signaling pathways 681
Cytokines B-1
Many methods are used to identify proteins
that interact with molecules of interest 682
Appendix III
Whole Animal Experimental Systems 682
Animal research is subject to federal guidelines Chemokines and Chemokine
that protect nonhuman research subjects 682 Receptors C-1
Inbred strains can reduce experimental variation 683
Congenic resistant strains are used to study the
effects of particular gene loci on immune Glossary G-1
responses 684
Answers to Study Questions AN-1
Adoptive transfer experiments allow in vivo
examination of isolated cell populations 684 Index I-1
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Feature Boxes in Kuby 7e

Clinical Focus Classic Experiment
Box 1.1 Vaccine Controversy: What’s Truth and What’s Box 2.1 Isolating Hematopoietic Stem Cells p. 29
Myth? p. 5 Box 2.3 The Discovery of a Thymus—and Two p. 46
Box 1.2 Passive Antibodies and the Iditarod p. 8 Box 3.1 The Elucidation of Antibody Structure p. 82
Box 1.3 The Hygiene Hypothesis p. 20 Box 3.3 The Discovery of the T-Cell Receptor p. 96
Box 2.2 Stem Cells—Clinical Uses and Potential p. 42 Box 6.1 The Discovery of Properdin p. 198
Box 3.2 Defects in the B-Cell Signaling Protein Btk Lead Box 7.1 Hozumi and Tonegawa’s Experiment: DNA
to X-Linked Agammaglobulinemia p. 93 Recombination Occurs in immunoglobulin
Box 4.2 Therapy with Interferons p. 120 Genes in Somatic Cells p. 227
Box 4.4 Cytokines and Obesity p. 136 Box 8.3 Demonstration of the Self-MHC Restriction of
Box 5.2 Genetic Defects in Components of Innate CD8⫹ T Cells p. 282
and Inflammatory Responses Associated with Box 9.1 Insights about Thymic Selection from the First
Disease p. 170 TCR Transgenic Mouse Have Stood the Test of
Box 6.2 The Complement System as a Therapeutic Time p. 308
Target p. 208 Box 10.3 The Stages of B-Cell Development:
Box 7.3 Some Immunodeficiencies Result from Impaired Characterization of the Hardy Fractions p. 342
Receptor Gene Recombination p. 255 Box 11.1 Discovery of the First Costimulatory Receptor:
Box 8.2 MHC Alleles and Susceptibility to Certain CD28 p. 362
Diseases p. 277 Box 12.1 Experimental Proof That Somatic
Box 8.4 Deficiencies in TAP Can Lead to Bare Hypermutation and Antigen- Induced Selection
Lymphocyte Syndrome p. 287 Occurred Within the Germinal Centers p. 399
Box 9.2 How Do T Cells That Cause Type 1 Diabetes Box 13.2 Rethinking Immunological Memory: NK Cells
Escape Negative Selection? p. 311 Join Lymphocytes as Memory-Capable
Box 9.3 Failure of Apoptosis Causes Defective Cells p. 442
Lymphocyte Homeostasis p. 322 Box 15.1 The Discovery and Identification of IgE as the
Box 10.1 B-Cell Development in the Aging Carrier of Allergic Hypersensitivity p. 488
Individual p. 333 Box 16.3 Early Life Exposure to Antigens Favors Tolerance
Box 11.2 Costimulatory Blockade p. 364 Induction p. 546
Box 11.4 What a Disease Reveals about the Physiological
Role of TH17 Cells p. 376 Advances
Box 13.1 Monoclonal Antibodies in the Treatment of Box 4.1 Methods Used to Map the Secretome p. 111
Cancer p. 420 Box 4.3 How Does Chemokine Binding to a Cell-Surface
Box 15.2 The Genetics of Asthma and Allergy p. 498 Receptor Result in Cellular Movement Along the
Box 15.3 Type 2 Diabetes, Obesity, and Chemokine Gradient? p. 130
Inflammation p. 511 Box 5.1 Inflammasomes p. 162
Box 16.1 It Takes Guts to Be Tolerant p. 523 Box 6.3 Staphylococcus aureus Employs Diverse Methods
Box 16.2 Why Are Women More Susceptible Than Men to Evade Destruction by the Complement
to Autoimmunity? Gender Differences in System p. 216
Autoimmune Disease p. 528 Box 10.2 The Role of miRNAs in the Control of B-Cell
Box 16.4 Is There a Clinical Future for Development p. 336
Xenotransplantation? p. 548 Box 11.3 How Many TCR Complexes Must Be Engaged to
Box 17.1 The 1918 Pandemic Influenza Virus: Should It Trigger T-Cell Activation? p. 368
Publish or Perish? p. 557 Box 12.2 New Ideas on B-Cell Help: Not All Cells That Help
Box 18.1 Prevention of Infant HIV Infection by Anti- B Cells Make Antibodies Are T Cells p. 408
Retroviral Treatment p. 610 Box 14.1 Dynamic Imaging Techniques p. 452
Box 19.1 A Vaccine to Prevent Cervical Cancer, and Box 14.2 Molecular Regulation of Cell Migration Between
More p. 637 and Within Tissues p. 456
Box 17.2 A Prime and Pull Vaccine Strategy for Preventing
Evolution Sexually Transmitted Diseases p. 586
Box 2.4 Variations on Anatomical Themes p. 57 Box 20.1 Flow Cytometry Under the Hood p. 674
Box 5.3 Plant Innate Immune Responses p. 178
Box 7.2 Evolution of Recombined Lymphocyte
Receptors p. 240
Box 8.1 The Sweet Smell of Diversity p. 275
FMTOC Page xx 12/19/12 10:08 PM user-t044 /Volumes/203/MHR00209/siL52070/disk1of1/0071052070

Preface

Like all of the previous authors of this book, we are dedicated 2a Lymph
to the concept that immunology is best taught and learned in 1 P node
an experimentally-based manner, and we have retained that 3
P B
emphasis with this edition. It is our goal that students should P
B
complete an immunology course not only with a firm grasp T
of content, but also with a clear sense of how key discoveries
were made, what interesting questions remain, and how they T B
5a T
might best be answered. We believe that this approach ensures
4
that students both master fundamental immunological con- 5b
cepts and internalize a vision of immunology as an active and Memory
ongoing process. Guided by this vision, the new edition has
been extensively updated to reflect the recent advances in all
2b T
aspects of our discipline. N B

OVERVIEW FIGURE 1-9 Collaboration between innate and

New Authorship adaptive immunity in resolving an infection.

As a brand-new team of authors, we bring experience in both A new capstone chapter (Chapter 14) integrates the events
research and undergraduate teaching to the development of this of an immune response into a complete story, with particu-
new edition, which continues to reflect a dedication to peda- lar reference to the advanced imaging techniques that have
gogical excellence originally modeled by Janis Kuby. We remain become available since the writing of the previous edition.
deeply respectful of Kuby’s unique contribution to the teaching In this way, the molecular and cellular details presented in
of immunology and hope and trust that this new manifestation Chapters 2-13 are portrayed in context, a moving landscape
of her creation will simply add to her considerable legacy. of immune response events in time and space (Figure 14-5).

Understanding
Immunology As a Whole
We recognize that the immune system is an integrated network
of cells, molecules, and organs, and that each component relies
on the rest to function properly. This presents a pedagogical
challenge because to understand the whole, we must attain
working knowledge of many related pieces of information,
and these do not always build upon each other in simple lin-
ear fashion. In acknowledgment of this challenge, this edition
presents the “big picture” twice; first as an introductory over-
view to immunity, then, thirteen chapters later, as an integra-
tion of the details students have learned in the intervening text.
Specifically, Chapter 1 has been revised to make it more
approachable for students who are new to immunology. The
chapter provides a short historical background to the field and
an introduction to some of the key players and their roles in
the immune response, keeping an eye on fundamental con-
cepts (Overview Figure 1-9). A new section directly addresses
some of the biggest conceptual hurdles, but leaves the cellular FIGURE 14-5 A T cell (blue) on a fibroblastic reticular network
and molecular details for later chapters. (red and green) in the lymph node.
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Preface xxi

Focus on the Fundamentals signaling, as well as to specific molecules and pathways

involved in signaling through antigen receptors. Chapter
The order of chapters in the seventh edition has been revised 4 includes a more thorough introduction to the roles of
to better reflect the sequence of events that occurs naturally cytokines and chemokines in the immune response.
during an immune response in vivo. This offers instructors • An expanded and updated treatment of innate immunity
the opportunity to lead their students through the steps of (Chapter 5), which now includes comprehensive cover-
an immune response in a logical sequence, once they have age of the many physical, chemical, and cellular defenses
learned the essential features of the tissues, cells, molecular that constitute the innate immune system, as well as
structures, ligand-receptor binding interactions, and signal- the ways in which it activates and regulates adaptive
ing pathways necessary for the functioning of the immune immunity.
system. The placement of innate immunity at the forefront • Substantial rewriting of chapters concerned with
of the immune response enables it to take its rightful place complement (Chapter 6) and antigen receptor gene
as the first, and often the only, aspect of immunity that an rearrangement (Chapter 7). These chapters have been ex-
organism needs to counter an immune insult. Similarly, the tensively revised for clarity in both text and figures. The
chapter on complement is located within the sequence in a description of the complement system has been updated
place that highlights its function as a bridge between innate to include the involvement of complement proteins in
and adaptive immune processes. However, we recognize that both innate and adaptive aspects of immunity.
a course in immunology is approached differently by each
• A restructured presentation of the MHC, with the addi-
instructor. Therefore, as much as possible, we have designed
tion of new information relevant to cross-presentation
each of the chapters so that it can stand alone and be offered
pathways (Chapter 8) (Figure 8-22b).
in an alternative order.

(b) DC cross-presentation and activation of CTL

Challenging All Levels Cross-presenting

dendritic cell Exogenous
While this book is written as a text for students new to im- antigen
munology, it is also our intent to challenge students to reach
deeply into the field and to appreciate the connections with TLR
other aspects of biology. Instead of reducing difficult top- Crossover
ics to vague and simplistic forms, we instead present them pathway
with the level of detail and clarity necessary to allow the Class I MHC
beginning student to find and understand information they CD8
may need in the future. This offers the upper level student CD3
a foundation from which they can progress to the inves- CD80/CD86
tigation of advances and controversies within the current CD28
immunological literature. Supplementary focus boxes have
been used to add nuance or detail to discussions of particu- IL-2 Naïve
lar experiments or ideas without detracting from the flow TC cell
of information. These boxes, which address experimental
approaches, evolutionary connections, clinical aspects, or FIGURE 8-22b Exogenous antigen activation of naïve Tc cells re-
advanced material, also allow instructors to tailor their use quires DC licensing and cross-presentation
appropriately for individual courses. They provide excellent
launching points for more intensive in class discussions • The dedication of specialized chapters concerned with
relevant to the material. T cell development and T cell activation (Chapters 9
Some of the most visible changes and improvements and Chapter 11, respectively). Chapter 11 now includes
include: current descriptions of the multiple helper T cell subsets
• A rewritten chapter on the cells and organs of the im- that regulate the adaptive immune response.
mune system (Chapter 2) that includes up to date images • Substantially rewritten chapters on B cell development
reflecting our new understanding of the microenviron- and B cell activation (Chapters 10 and 12, respectively)
ments where the host immune system develops and that address the physiological locations as well as the na-
responds. ture of the interacting cells implicated in these processes.
• The consolidation of signaling pathways into two • An updated discussion of the role of effector cells and
chapters: Chapter 3 includes a basic introduction to molecules in clearing infection (Chapter 13), including a
ligand:receptor interactions and principles of receptor more thorough treatment of NK and NKT cells.
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xxii Preface

• A new chapter that describes advances in understand- 2

Inhibitory
ing and visualizing the dynamic behavior and activi- T cell cytokines T cell

ties of immune cells in secondary and tertiary tissue

TGF␤
(Chapter 14).
• Substantial revision and updating of the clinical chapters 1 3
Cytokine IL–2R TCR Inhibiting antigen
(Chapters 15-19) including the addition of several new deprivation FoxP3 APC presenting cells
clinically relevant focus boxes. MHC

• Revised and updated versions of the final methods chap-

4
ter (Chapter 20), and the appendices of CD antigens, Cytotoxicity
chemokines, and cytokines and their receptors. T cell T cell

Throughout the book, we attempt to provide a “big picture”

context for necessary details in a way that facilitates greater FIGURE 9-10 How regulatory T cells inactivate traditional T cells.
student understanding.
• The roles of the microbiome and commensal organisms in
Recent Advances and Other Additions the development and function of immunity, as well as the
connections between these and many chronic diseases.
Immunology is a rapidly growing field, with new discoveries, • A new appreciation for the micro environmental
advances in techniques, and previously unappreciated con- substructures that guide immune cell interactions with
nections coming to light every day. The 7th edition has been antigen and with one another (Figure 14-11a).
thoroughly updated throughout, and now integrates the fol-
lowing new material and concepts: Antigen delivery to T cells

• New immune cell types and subtypes, as well as the Subcapsular DC presenting
phenotypic plasticity that is possible between certain Lymph node Afferent
sinus (SCS) antigen
subtypes of immune cells. lymphatic

• A greater appreciation for the wide range of mechanisms

responsible for innate immunity and the nature and roles
Antigen
of innate responses in sensing danger, inducing inflam- B cell follicle
mation, and shaping the adaptive response (Figure 5-18).

Bacteria
Naïve T H1 IFN-γ
TLR4 or
Dectin-1 TLR5 IL-12

TLR3, 7, 9
Tricellular complex
Fungi
IL-6 (CD8+ T cell, CD4+ T cell zone
IL-23 TH17 IL-17
Virus
Naïve T cell, and DC) FRC network (paracortex)
FIGURE 14-11a How antigen travels into a lymph node.
IL-10
TLR2/1
IL-4
Helminth
Naïve TH2 IL-5 • Many technical advances, especially in the areas of imag-
IL-13
TLR2/6 ing and sequencing, which have collectively enhanced
our understanding of immune function and cellular
Fungi IL-10
interactions, allowing us to view the immune response
Naïve Treg
IL-10 TGF-β in its natural anatomical context, and in real time (see
RA
CD28 CD80/86
TGF-β Figure 14-5).
TCR MHC II with peptide

FIGURE 5-18 Differential signaling through dendritic cell PRRs

influences helper T cell functions. Connections to the Bench,
the Clinic, and Beyond
• Regulation of immunity, including new regulatory cell
types, immunosuppressive chemical messengers and We have made a concerted effort in the 7th edition to integrate
the roles these play, for example, in tolerance and in experimental and clinical aspects of immunology into the
the nature of responses to different types of antigens text. In Chapter 2, illustrations of immune cells and tissues are
(Figure 9-10). shown alongside histological sections or, where possible, electron
FMTOC Page xxiii 12/19/12 10:08 PM user-t044 /Volumes/203/MHR00209/siL52070/disk1of1/0071052070

Preface xxiii

micrographs, so students can see what they actually look like. assessment, and helpful course management features into one
Throughout the text, experimental data are used to dem- convenient, fully customizable space.
onstrate the bases for our knowledge (Figure 3-4b), and the
clinical chapters at the end of the book (Chapters 15 through ImmunoPortal Features:
19) describe new advances, new challenges, and newly appre- NEW! Kuby Immunology Seventh Edition e-Book—also
ciated connections between the immune system and disease. available as a standalone resource (ebooks.bfwpub.com/
immunology7e)
This online version of the textbook combines the contents
of the printed book, electronic study tools, and a full comple-
ment of student media, including animations and videos.
Students can personalize their e-Book with highlighting,
bookmarking, and note-taking features. Instructors can cus-
FIGURE 3-4b Targeted delivery of cytokines (pink). tomize the e-Book to focus on specific sections, and add their
own notes and files to share with their class.
Featured Boxes NEW! LearningCurve—A Formative
Quizzing Engine
Associated with each chapter are additional boxed materials
that provide specialized information on historically-important With powerful adaptive quizzing, a game-like format, and the
studies (Classic Experiments) that changed the way immu- promise of significantly better grades, LearningCurve gives
nologists viewed the field, noteworthy new breakthroughs instructors a quickly implemented, highly effective new way
(Advances) that have occurred since the last edition, the to get students more deeply involved in the classroom. De-
clinical relevance of particular topics (Clinical Focus) and veloped by experienced teachers and experts in educational
the evolution of aspects of immune functioning (Evolution). technology, LearningCurve offers a series of brief, engaging
Examples of such boxes are “The Prime and Pull Vaccine activities specific to your course. These activities put the con-
strategy,” “Genetic defects in components of innate and in- cept of “testing to learn” into action with adaptive quizzing
flammatory responses associated with disease,” “The role of that treats each student as an individual with specific needs:
miRNAs in the control of B cell development” and an updated • Students work through LearningCurve activities one
“Stem cells: Clinical uses and potential.” We have involved our question at a time.
own undergraduate students in the creation of some of these
boxes, which we believe have greatly benefitted from their • With each question, students get immediate feedback.
perspective on how to present interesting material effectively Responses to incorrect answers include links to book
to their fellow students. sections and other resources to help students focus on
what they need to learn.
• As they proceed toward completion of the activity, the
Critical Thinking and Data Analysis level of questioning adapts to the level of performance.
The questions become easier, harder, or the same de-
Integration of experimental evidence throughout the book pending on how the student is doing.
keeps students focused on the how and why. Detailed and • And with a more confident understanding of assigned
clear descriptions of the current state of the field provide material, students will be more actively engaged during
students with the knowledge, skills, and vocabulary to read classtime.
critically in the primary literature. Updated and revised study
questions at the end of the chapter range from simple recall of
information to analyzing original data or proposing hypothe- Resources
ses to explain remaining questions in the field. Classic Experi-
ment boxes throughout the text help students to appreciate The Resources center provides quick access to all instructor
the seminal experiments in immunology and how they were and student resources for Kuby Immunology.
conducted, providing a bridge to the primary research articles
and emphasizing data analysis at every step. For Instructors—
All instructor media are available in the ImmunoPortal and on
the Instructor Resource DVD.
Media and Supplements
NEW! test bank—over 500 dynamic questions in PDF and
NEW! ImmunoPortal (courses.bfwpub.com/immunology7e) editable Word formats include multiple-choice and short-
This comprehensive and robust online teaching and answer problems, rated by level of difficulty and Bloom’s
learning tool combines a wealth of media resources, vigorous Taxonomy level.
Another Random Scribd Document
with Unrelated Content
quanto rerum minus tanto minus cupiditatis erat. Nuper divitiae
avaritiam at abundantes voluptates desiderium per luxum atque
libidinem pereundi perdendique omnia invexere." It is always safer
to accuse those that are dead than those with whom we live; and
surely, the historian that did not dread to attack the living, would
not have failed to arraign the dead, had the dead deserved it. The
expulsion and cause of expelling Tarquin, consecrated an individual
self-respect which evermore remained an important element in the
Roman character. This self-respect is the bulwark of individual
freedom, and the most indestructible foundation of a social edifice.
From it arose the acquisition by the populace of the jus suffragii,
jus commercii, jus connubii, jus honorum. It was the mine
which blew up, first, the patricians, and then the nobles. Where did
Dr. Lord learn that patricians and nobles are synonymous terms?
This self-respect imparted fortitude to the soldier, wisdom to the
statesman, honor to the merchant. The individual was clothed with
the majesty of his country. To uphold that majesty was the first
duty of the Roman. Allied with self-respect, unchangeableness of
purpose appears as a trait of the Roman character. Athens might
have been a Rome, had the Athenian spirit the persistency of the
Roman. There was, perhaps, no formative element of the Roman
character so prominent as the practical common sense which made
them learners in all the departments of life. The Romans admitted
the perfectibility of their institutions and practices, so as to adopt
from foreigners whatever they deemed an improvement. The
Spartan loved his country as intensely and as devotedly as the
Roman, but Sparta, rejecting the eclecticism of Rome, remained
cramped and undeveloped in its exclusiveness. These qualities of
the mind, together with a physical strength, such as appears from
the saying of Pyrrhus, "Had I the Romans for soldiers, I could
conquer the world," led Rome along the highway of glory and
power.

It would be folly to follow Dr. Lord through the many subjects on

which he speaks. We take the first chapter of his work as a
specimen of the wild, thoughtless, rambling manner in which he
writes. It is headed "The Conquests of the Romans;" but in it one
finds a paragraph on "the lawfulness of war," a paragraph on "the
evils of war," a few pages on "Providence," a disquisition on the
immediate and ultimate consequences of the Crusades, a paragraph
on Providence again, something on the aspirations of the South, a
paragraph to show "how petty legends indicate the existence of
great virtues," a paragraph to show "how petty wars with
neighboring states develop patriotism," something on morals and
Cato, whom he characterizes as "a hard, narrow statesman," a
chronicon Romanum, the history of the helepolis, a paragraph to
show the necessity for the empire. Would any one imagine that the
same man wrote of Rome under the emperors the following
passages: "The real (page 13) grandeur of Rome is associated with
the emperors. Great works of art appear, and they become
historical. The city is changed from brick to marble, and palaces,
and theatres, and temples become colossal. There are more marble
busts than living men. A liberal patronage is extended to artists.
Medicine, law, and science flourish. … The highest state of
prosperity is reached that the ancient world knew." Again "Rome
(p. 69) yields her liberties, and imperial despotism begins its reign
—hard, immovable, resolute— under which genius is crushed.
Empire is added, but prosperity is undermined. The machinery
is perfect, but life is fled." Dr. Lord tells us that he loves to ponder
on the sacred geese, but we would respectfully direct his pondering
to the inconsistencies, contradictions, and false pronouncements
with which his volume teems. He considers the Crusades the worst
wars in history, uncalled for, unscrupulous, fanatical; but, though
they were uncalled for, unscrupulous, and fanatical, he styles
Bernard, Urban, Philip, and Richard, great men, far-sighted
statesmen, and asserts that "the hand which guided that warfare
between Europe and Asia was the hand that led the Israelites out
of Egypt across the Red Sea;" and those wars which he pronounces
worst he declares to have developed the resources of Europe, built
free cities, opened the horizon of knowledge, and given a new
stimulus to all the energies of the European nations. There are few
who will agree with Dr. Lord when he says that the Romans
"despised literature, art, philosophy, agriculture, and even luxury
when they were making their grand conquests." He need only read
his own description of the heroes who made the conquests to see
the falsehood of his statements. There are few, too, who will say
that he describes the characters of the ancients with accuracy. We
would especially notice his defect of appreciation in the case of
Homer, of Sophocles, and of the Latin historians. The grand
excellence of Homer remains unseen by him. The raising up of hero
after and over hero, and the transference of a collective glory to
Achilles may be said to constitute the greatest marvel of the Iliad.
This generates the oneness which has been noticed and praised by
all the ancients. The Doctor praises extravagantly Virgil's epic, but
every candid reader will confess that he feels unconcerned, and, it
may be, weary, as he wades though the last half of the AEneid,
whereas he becomes more and more enraptured as he advances
through the books of the Iliad. Diomedes is as grand a warrior as
AEneas, and we doubt very much whether Virgil could have raised
a higher model than AEneas, whereas Homer has worked the
climax through four or five to Achilles. Who believes, or has
believed, that Demosthenes' Philippics are more brilliant than his De
Corona? To us Dr. Lord seems, in judging of the ancients, to have
acted as a compiler rather than to stand boldly before the extant
originals and pronounce his own judgment. When he does speak
for himself, he seems to be more anxious to make himself singular
than to see and tell the truth with accuracy. Speaking of "the
solitary grandeur of the Jewish muse and the mythological
myths of the ante-Homeric songsters," he looks rather in the light
of a foolish fool than a serious writer communicating truth to a
criticising world.

It is curious, touchy, and, we might say, laughable, to read over Dr.

Lord's notions of the connection of the old Roman world with the
church. Bossuet's idea of the old Roman empire being an
instrument in the hands of God to propagate Christianity, has a
deep fascination for our author; but Bossuet never gets the credit
of it. We err very much if, in writing The Old Roman World, Dr.
Lord did not intend to elaborate this conception in a work which
the world would recognize as the rival of Gibbon's Decline and
Fall. How does he do it? He discovers that there had existed an
ineffable fatalism, according to which the Roman empire was
doomed to die. What was old and heathen should disappear, that
what was new and Christian might arise. The fading away of the
Roman reign was unworthy to be compared with the glories about
to be manifested. What were they? Were they the beauties of a
grand society whose teaching authority as to the things of eternity
was to be the Holy Spirit, whose head and sanctifier was to be
Christ—of a society to be sustained by the hand of God, elevated
above all societies, extended and visible through the world such as
Bossuet conceived? Dr. Lord opines that, when Christianity is
embraced by all, it is corrupted, and may be said to be dead except
with a few chosen spirits; and when Christianity is embraced only
by a few and is pure, it is valueless for the mass of mankind, being
limited and uninfluential. On either horn of the dilemma,
Christianity may be regarded as an unimportant and unprofitable
school for the multitude. Yet he says that the world marches on in
Christian progress. There are always some revivalists, some
believers, as the Puritans, in a pure and personal God; and
Providence, which "grandly and mournfully" eliminates the Roman
world, consoles the human race by casting up, here and there,
some select ones, some pure ones, some godly ones. But, if Dr.
Lord merely wished to act the part of a noonday somnambulist or a
dreamy rhapsodist, we would fain permit him to revel undisturbed
in his reveries. We have, however, a right, as Catholics, to object to
misrepresentations of Catholic doctrine. There are many honest and
righteous Protestant minds whose vision may become jaundiced by
the assertions of this writer. Where has he learned that the Virgin
has been made the object of absolute worship? When he speaks of
ceremonies, and festivals, and pomps, he ought to look upon them
as those do who use them. We have always been at a loss to
understand what special enmity some people have against a special
sense. If the senses are channels for communicating thought, why
decry the legitimate use of any one of them performing its own
function? Why instruct through the ear and not through the eye?
Does not a map surpass all language in communicating
geographical knowledge? Logically, one ought to praise God
through the intuition of spirit vis-a-vis spirit and disown corporeal
agents, eyes, tongue, ears, hands, physical actions; or recognize
all, provided they be means of communicating thought. There is
not and there never has been in the church, any imposing altar
typical of Jewish sacrifices. As to the monks, either Lord admits the
truth of what are called evangelical counsels, or he does not; if he
does, he should not be at war with the monks for actuating what is
true; if he does not, how does he get rid of the texts of the Bible
which contain them? Did the monks effect nothing for the good of
humanity? Were all the monks in pursuit of a purely contemplative
life? Were there no teachers, no benefactors of the poor, no
cultivators of deserts, and woods, and wildernesses amongst them?
Were there no founders of cities, no evangelizers of savages?
Surely, the disciples of Columbanus, of Benedict, of Basil, deserve
something better than the following turgid rigmarole of a visionary
fanfaron: "Monastic life (p. 559) ripened also in a grand system of
penance and expiatory rights, such as characterized oriental
asceticism. Armies of monks retired to gloomy and isolated places,
and abandoned themselves to rhapsodies, and fastings, and self-
expiations in opposition to the grand doctrine of Christ's expiation.
They despaired of society and abandoned the world to its fate—a
dismal and fanatical set of men overlooking the practical aims of
life. They lived more like beasts and savages than enlightened
Christians—wild, fierce, solitary, superstitious, ignorant, fanatical,
filthy, clothed in rags, eating the coarsest food, practising gloomy
austerities, introducing a false standard of virtue, regardless of the
comforts of civilization, and careless of those great interests which
were entrusted to them to guard.

The monks and hermits sought to save themselves by climbing to

heaven by the same ladder that had been sought by the soofis and
fakirs, which delusion had an immense influence in undermining the
doctrines of grace. Christianity was fast merging itself into an
oriental theosophy." It is a sad thing to see, and a tormenting thing
to have to follow, through over six hundred pages, a man, rushing
madly from subject to subject. We have no interest, except in the
cause of truth and right, to censure Dr. Lord; and could we fairly, in
the capacity of critic, have awarded him praise, we should have,
without reluctance, and with warmth, performed the task. We
should say that he must have labored long to compile his work; but
if anything distinguishes that work, it is an unlikeness to the
sources from which it is presumed to have been gotten up. The
ancients conceived of a whole, and elaborated the natural
component parts to form that whole; in the work before us the
formative materials produce as grotesque a union as that in the
minotaur, or centaur, or gorgon, or chimaera, or hydra, or sphinx.
In the ancients, we are pleased with a modesty which dreads alike
the overstatement or the withholding of the truth; Dr. Lord
astounds us with an unblushing and unthinking recklessness of
assertion. In presenting their thoughts to the world, the Greeks and
Romans were scrupulous down to the collocation of a particle; Dr.
Lord's production is overgrown with expletives, ambiguities,
redundancies, and repetitions. To any one accustomed to gaze on
the chaste, crystal, and refreshing pages of classic lore, his volume
is an unendurable eyesore.
The Divine Loadstone.
 "And I, if I be lifted up from the earth,
will draw all things to myself."

The Disciple.

"Ah me! what doth my feet restrain,

That I thy cross behold—
A loadstone all divine—
Drawing men's hearts with mystic chain
As misers lured by gold,
And yet it draws not mine?"

The Master.

"My word is very truth, my son;

All hearts to me should freely run;
And if I draw not thee
As sweetly as the rest,
'Tis thou who wouldst the loadstone be,
And draw the hearts of men to thee—
Their love doth mine contest."

The Disciple.

"Nay, Lord; 'tis only for thy heart I pine."

The Master.

"Say'st so? Then give me, also, all of thine."

 Translated From The German.

The Rival Composers.

Late one afternoon, in the autumn of the year 1779, a gentleman,
walking in the garden of the Tuileries, was observed by the guard
near the gate of the palace private grounds, gesticulating in a
manner to excite suspicion. He was plainly dressed, and advanced
in years. When the sentinel saw him, after walking briskly to and
fro, and muttering half aloud, stop and lift his hand in a threatening
manner toward the royal abode, he promptly arrested him. Calling
two gens d'armes, he put the suspected man, supposed guilty of
designs against the king, into their hands, to be conveyed to
prison.

At the gate they met a richly gilded open carriage, in which sat two
ladies, with a child and nurse. The taller of the ladies wore a hat of
dark velvet, with drooping plumes, and a mantle of the same, with
a flowing dress of satin, the sleeves trimmed with rich lace. The
soldiers stopped to salute the young Queen Marie Antoinette, and
the prisoner removed his hat and bowed low. At the same instant
the lady leaned from the carriage, exclaiming, "Ah! Master Gluck!"

The queen laughed heartily when she heard her old music-master
had just been arrested for disloyal practices near the palace; when
he was only declaiming a passionate recitative out of his new
opera! She insisted on his entering the carriage and going to the
palace with her; while the astonished guards went to report their
mistake.

Not unfrequently had the celebrated composer been the guest of

the royal lady. He was wont to visit her in the garden of the
Trianon, talking German with her, and exchanging reminiscences of
Vienna. When the opera-house in Paris had resounded with the
applause called forth by the representation of one of his operas,
and he was sent for to the royal box, the queen's own hand had
crowned him with the chaplet his genius had won.

At this period the music-loving population of Paris was divided into

partisans of the two rival composers, Gluck and Piccini. The merits
of each were discussed in every circle, and comparisons were
made, often with a confused war of tongues; the dispute being, to
whom the palm of superior greatness should be awarded. Each had
composed a piece on the same subject, which was shortly to be
represented; the success deciding which of the two should keep the
field.

Late the same evening a number of the Parisian connoisseurs and

artists were assembled in the brilliantly illuminated salon of the
Café du Feu. Many of the noblesse were to be seen, surrounded
by critics, amateurs, etc., and the company was in a Babel of
declamation and argument; the battle-cries all over Paris being
"Gluck" and "Piccini." Three young men, who had just entered,
secured a place in a quiet side-room, where three others were
seated; one in a corner, deep in the shadow of a pillar. Comfortably
ensconced in an arm-chair, this man sat with head leaning back,
drumming with the fingers of one hand on the table, and taking no
notice of anything that passed. Another occupant of the room was
a handsome young Frenchman, with deep blue eyes shaded with
heavy brown lashes, and complexion of the rich brown of Provence;
he was poorly dressed, but his manner was graceful and spirited.
His companion at the table was a long, thin, middle-aged man, with
an air of discontent and spite in his whole demeanor. He wore a
rough brown peruke; his features were heavy, and he had a pair of
keen, squinting eyes, with a peevish, sinister twist about the
mouth. He spoke French badly, his accent betraying the Saxon. He
was speaking of Gluck, and ended his remarks by saying: "I cannot
understand what a people of so much judgment and taste as the
French find so great in this man!"
"Are you speaking," cried the young Frenchman, "of the creator of
Armida, of Orpheus, of Iphigenia?"

"Ahem! yes. He is not esteemed highly among us in Germany, for

he knows little or nothing of art-rules, as the learned Herr Forhel in
Göttingen and other distinguished critics have proved."

"And you, a musician, a composer, a German, speak thus!"

exclaimed the young man. "I know little of art-rules; but one thing
I know and feel, the Chevalier Gluck has a grand and noble spirit.
His music awakens elevated feeling; no low or common thought
can approach me while I listen to it; even when spiritless and
dejected, my despondency takes flight before the lofty joy I feel in
Gluck's creations."

"And think you," cried young Arnaut, who belonged to the other
faction, "that the great Piccini would enter into a contest with your
chevalier, did he not know he was to strive with a worthy
adversary!"

The German, nettled at the question, shuffled a little as he

answered, "Hem! I suppose not; I only maintain that M. Gluck is
not the best composer, as the learned Herr Forhel has proved. With
regard to a church style—"

"Who is talking of church styles!" interrupted the brown youth, with

vivacity. "The point is, a grand opera style! Would your learned
critics change Gluck's Armida into a nun's hymn, or have his wild
motets of Tauris sung in the style of Palestrina?"

The squinting man moved in his seat, sipped his orangeade, and
muttered: "The learned Herr Forhel has proved that the Chevalier
Gluck understands nothing of songs."

"Nothing of songs!" echoed all the company, in surprise. The

German continued: "He cannot carry through an ordinary melody
according to rule; his song is but an extravagant declamation."
The brown youth started to his feet in glowing indignation. "You
are not worthy to be a German, sir," he cried, "thus to speak of
your great countryman. All Paris acknowledges in Gluck a mighty
artist; the dispute is only whether he or Piccini is the greater.
Gluck's music is the true expression of feeling, alike removed from
the cold constraint of rules and from capricious innovation! Whether
he would excel in church or concert music—or would attempt it—
we cannot tell! He has set himself one glorious task, and pursues
that with all the strength of a great spirit!"

"What is your name, young man?" sounded a sonorous voice from

the corner behind him.

The stranger, whom all turned to look at, had risen from his seat,
and the light of the candles shone full upon his face.

"The Chevalier Gluck!" exclaimed several voices. Gluck smiled and

bowed; then turning to the brown youth, he repeated his question.

"My name is Etienne Mehul," was the modest reply.

"You are a musician, I perceive," said Gluck. "Will you call at my

house? Here is my address."

Handing him the card, he turned to the squinting German, who sat
embarrassed, and spoke to him with undisguised contempt:

"Mr. Elias Hegrin! It is an unexpected pleasure to see you in Paris;

yet a pleasure—for I like to tell you honestly what a miserable
rascal you are! You think I understand nothing of the rules of music
or of songs—eh! You thought differently in Vienna, when you
almost lived at my house, and received instructions in music from
me, and took what I procured for you from patrons, and what I
gave you out of my own pocket! You became my enemy because I
candidly told you you could master only the lifeless form, not the
spirit. You seek what you can never obtain—not for the sake of art,
but for your own temporary advantage. You would do better as an
honest tailor or shoemaker, than a mean musician! You could not
forgive my telling you this! and so you go and abuse me in
Göttingen! Go and do better, if you can; but I think that will be
difficult; for he who belies art because he cannot compass her, will
be likely to remain the rascal he has shown himself! Adieu,
Messieurs!"

Gluck nodded to young Mehul, and went out.

Queen Marie Antoinette had a private morning reception of her

friends at her favorite Trianon. Comte d'Artois, just returned to Paris
from his hunting castle, had come with his brother, the Comte de
Provence, to pay his respects to his beautiful sister-in-law. They
talked of the latest news in the capital, the balls, flirtations,
witticisms, spectacles, etc., and of the new entertainment expected
in the contest between Gluck and Piccini; the anticipations of which
kept all Paris in dispute.

D'Artois declared himself for Gluck. "Your countryman," he cried to

the queen, "is a splendid fellow! He went on the chase with me,
and made five shots one after the other. As to the Italians, they do
not know how to hold a gun!"

"I like the Italian music best," said the Comte de Provence. "You
cannot well sing or dance to the German, as Noverre justly
observes."

"Noverre had to dance to German music, though!" cried the queen,

laughing. Then she told the story of the great dancing-master's visit
to Gluck, and how he had ventured to tell him that no dancer in
the grand opera could dance to his music in the Scythian ballets;
and how Gluck, enraged, had seized the little man, and danced him
through the whole house, up-stairs and down-stairs, singing the
Scythian ballets; and had asked him, when the breath was nearly
knocked out of Noverre, "Well, sir, think you, now, a dancer in the
grand opera can dance to my music?" to which the poor panting
victim had gasped out an eager affirmative! The story was much
laughed at, and the arrogance of the opera artists commented on.

A page entered and announced, "The Chevalier Gluck, come to give

the queen a lesson on the piano."

Marie Antoinette ordered him to be admitted.

"We were talking of you, M. Gluck," said the Princess Elizabeth;

"and her majesty praised you for an excellent dancing-master."

"And my brother thinks you an expert in hunting, and on that

account he belongs to your party," remarked the Comte de
Provence.

"Come," cried the queen, "you must not tease my good master!
Leave him to save all his patience for his pupil—myself! He will
have need of it, I assure you!"

"Because, Antoinette," said Gluck gravely, speaking in German, "you

do not play half so well as queen, as when you were archduchess."

The queen laughed as she answered in the same language, "Wait

but a little, Christophe! your ears shall ring presently. Ladies and
gentlemen, will you be quiet?" She spoke to them in French, as she
went to open the piano.

She inserted the key and turned it, perhaps too hastily; for she
could not open the instrument. After several vain attempts, she
called impatiently:

"Come hither, Gluck, and help me!"

Gluck tried, but with no better success; the others took their turn;
but the lock resisted all their efforts. The queen looked vexed.

"What fool can have made such a lock?" exclaimed Gluck.

"Take care, chevalier, what you say," said the Comte de Provence;
"the lock is of the king's own making—of a new sort, I believe."

D'Artois went out, and in a few moments returned with the king.
Louis XVI. wore a short jacket, his head covered with an unsightly
leathern cap, his face glowing and begrimed with soot, his hands
were rough as those of a locksmith, and a bundle of keys and
picklocks were fastened to his belt. He went up to the piano, and
examined the lock with the earnest manner of an artisan, tried
several keys without success, shook his head dissatisfied, and tried
others. Finding the right one at last, the lock yielded, and with an
air of triumph, as if he had won a battle, he said, smiling on his
wife,

"There, the piano is open! Now, madame, you can play!"

But so long a time had passed, that the queen had lost the
inclination. As she would not take her lesson, the Princess Elizabeth
asked Gluck to play them something from his Iphigenia. He
played the frenzy scene of Orestes. When he had finished it, the
king exclaimed: "Excellent, chevalier! I am delighted. I will have
your opera produced first, with all the care you like; and I hope the
success will gratify you."

Two more visitors were announced—Signor Piccini and the Chevalier

Noverre, who started and colored in some embarrassment when he
saw Gluck. The king commanded the two composers to salute each
other, which they did with dignity, cordiality, and easy grace. After
the queen had spoken to them, the Chevalier Noverre reminded her
majesty that she had been pleased to grant permission to Signor
Piccini to play some new airs from his Iphigenia before her.

Marie Antoinette assented, and asked Piccini what selection he had

made; to which he replied that Noverre had wished him to play the
first Scythian dance.
D'Artois burst into a laugh; but the others restrained their mirth. At
the queen's command, Piccini seated himself at the piano, the
Comte de Provence and Noverre beating time to his music. All the
company thought Piccini's Scythian dance more pleasing and better
adapted to the grace of motion than that of Gluck. But D'Artois
whispered to the king that the dance, though admirable and full of
melody, was better suited for a masked ball in the salon of the
grand opera than for a private abode in Tauris. Gluck listened with
earnest attention, evidently appreciating the merits of his opponent;
but a light curl of his lips was seen, when Piccini indulged too freely
in his pretty quaverings and tinklings. There was great applause
when it was ended. Noverre praised the performance as displaying
the inspiriting rhythmus which alone would enable the dancer to
give true expression to his pirouettes and enterchats.

"I agree with you, Monsieur Noverre," interrupted Louis, "that

Signor Piccini's music is admirable; but I hope you will also make
yourself acquainted with the music of the Chevalier Gluck."

Noverre replied timidly, that the Chevalier Gluck and he were on

the most friendly terms.

After the artists had left the royal abode, Gluck and Piccini took a
courteous leave of each other. As Gluck stepped into his carriage,
he said to Noverre: "Do not, chevavalier, forget his majesty's
command. If I made you dance against your will, it was to
introduce you to my music. I regret I am not a proficient in the art
of dancing; yet I am, like yourself, chevalier of the order de
l'Esprit, and in that character I wish you a good morning."

Piccini laughed at this, but Noverre looked vexed as Gluck drove

away.

The rehearsals and preparations for the representation of the two

Iphigenias were nearly complete, and the day was appointed
when the masterpiece of Gluck was to receive the sentence of the
Parisians. It was to be performed first; the preference having been
yielded to him as the oldest of the two composers. He was at that
time sixty-five.

Treatises, learned and superficial, were published, upon Gluck and

Piccini, the differences in their style and in the two operas; all
tinctured with party spirit, and many showing gross ignorance of
music. The performers, too, fell into dissension. Piccini had hard
work to propitiate, by attentions and favors, some who were
opposed to him, that his work might not be spoiled by their
perversity. Gluck resorted to threats, and made his enemies afraid
of him. He trusted to the excellence of his motto, "Truth makes its
way through all things;" and reflected that the worst success would
not make a good work a bad one.

On the morning of the final rehearsal, the day before the first
representation, young Mehul was announced. Gluck cordially
welcomed him, and asked why he had not seen him before.

"I feared to disturb you," answered the young man. "But to-day my
anxiety brings me."

"Anxiety?" questioned Gluck.

"You have enemies; your opera is to be produced to-morrow!

Should the success fall short of its merits—"

"Then be it so," said the master, smiling.

"You can say that so calmly?"

"Why not? Do you think of devoting yourself to dramatic

composition?"

"It is my wish to do so."

"Work, then, with bold heart! Lay hold on what glowing inspiration
brings you, and mould it with earnest heed! The great thing is, to
stand firm, and go on with spirit and strength. The world makes
this hard for the artist, and many fall in the conflict."

"You have won!"

"If I have gone through life neither a fool nor a knave, still I have
my faults. To some the All-Benevolent has granted to know but
little, till what they have attained is wasted, or in danger of being
lost. Happy he who apprehends the better part, and holds it fast,
though his heart be torn in the struggle! What will you say when I
confess to you, that perception of the highest—the only good,
came late—fearfully late to me! Music was all to me from earliest
youth. When a boy, in lovely Bohemia, I heard her voice in the
dense forest, the gloomy ravine, or the romantic valley; on the
bold, stark cliff; in the cheerful hunter's call, or the hoarse song of
stream and torrent. I thought there was nothing so great and
glorious, that man, impotent man, could not achieve it. Too soon I
learned that something was impossible. How soon are the spirit's
wings clipped! Then come harassing doubts, false ambition, thirst
of gain, envy, disappointed vanity, worldly cares; the hateful
gnomes of earth, that cling to you and drag you downward, when
you would soar like the eagle toward the sun. Thus it is in youth, in
manhood, in old age. One among many, redeemed from folly,
discerns and appreciates the right, and might create the beautiful.
But by that time the ardor and vigor of youth are gone; and to his
enthusiasm, his newly acquired knowledge, there remains a grave!"

"More—much more—to you!" cried Mehul in deep emotion.

"Perhaps it is true; for when I burst the fetters of the unworthy and
the base, there came to me a radiant vision from the pure, bright
Grecian age. The work of holding it fast, and shaping it in the
external world, is my last. And melancholy it is that a whole
vigorous lifetime could not be consecrated alone to such a theme—
or to yet higher ones. But I must submit in repentance and
humility, for my shortcomings! I will bear it, whether these Parisians
adjudge me fame and wealth, or hiss down my work."

The hour struck for the rehearsal, and Gluck, accompanied by his
young friend, went to the Royal Academy of Music.

Nicolo Piccini, morose and out of humor, was walking up and down
his room, glancing now and then at the manuscript of his opera
that lay upon his writing-desk. At times he would go to the desk as
if a happy thought had struck him, to add something to the notes;
but the next instant he would let fall the pen, shake his head with
a dissatisfied and melancholy air, and resume his walk through the
room.

A knocking was heard; and after it was repeated twice, Piccini

opened the door. Elias Hegrin came in. The composer seemed
disturbed at his presence, and gloomily asked what he wanted.
Hegrin answered that the Chevalier Noverre had informed him
Signor Piccini wished to see him.

After a pause, Piccini admitted that he had sent for him.

"And in what can I serve my honored patron?" asked Elias.

"By speaking the truth!" sternly answered Piccini. "Confess that

you spoke falsely, when you told me Gluck stirred up all his friends
to make a party against me!"

Elias Hegrin changed color, but he collected himself, and answered,

"I spoke the truth."

"It is false, Elias! It was the same when you told me you had read
the manuscript of my adversary, and that the work hardly deserved
the honors of mediocrity."
"It was the truth, Signor Piccini, and I repeat my opinion of the
opera of the Chevalier Gluck."

"So much the worse for your judgment! I have heard five
rehearsals, and I must—ay, and will declare before all the world,
that Gluck's Iphigenia is the greatest opera I know, and that in its
author I acknowledge my master."

Elias stared in amazement.

"I believed I had accomplished something worthy in my own work,"

continued Piccini; "and, indeed, my design was pure; nor is my
work altogether without merit; but oh! how void and cold, how
weak and insignificant does it seem to me, compared with Gluck's
gigantic creation! Yes, creation! mine is only a work! a work that
will vanish without a trace; while Gluck's Iphigenia will endure as
long as feeling for the grand and the beautiful is not dead in the
hearts of men!"

"But, Signor Piccini," stammered Elias.

"Silence!" interrupted Piccini. "Why have you slandered the noble

chevalier, and striven to bring down his works and his character to
your own level? Are you not ashamed of such pitiful behavior? In
spite of Noverre's recommendation, I have never fully trusted you;
for I know that Noverre hated Gluck for having wounded his
ridiculous vanity. But I never thought you capable of such
meanness as I find you guilty of. Gluck stir up his friends to make a
party against me! Look at these letters in Gluck's own hand, written
to Arnaud, Rollet, Maurepas, wherein he judges my work
thoroughly, dwelling upon the best parts, and entreats them to
listen impartially to my opera as to his own, and to give an
impartial judgment, as he is anxious only for the truth! My patron,
the Comte de Provence, persuaded those gentlemen to send me
these letters, to remove my groundless suspicions. I am deeply
mortified that I ever condescended to make common cause with
you! You have deceived me! Now, tell me, what induced you to act
in this dishonorable manner toward your benefactor?"

Elias, shrunk into himself, replied in a lachrymose tone, "Ah! I am

an unhappy man, and deserve your sympathy! From boyhood I
heard it said at home that I had extraordinary talent for music, and
would become a great composer, and win both wealth and fame. I
studied zealously; my first work was praised in the town where I
lived; but when I went to Vienna, I could do nothing."

"Gluck took you by the hand in Vienna, supported you, gave you
instruction, and corrected your works."

"He did so; but he likewise told me I had no genius, and that I
never could be a great composer."

"And did he deceive you? What have you proved yourself? You hate
and slander him, then, because he honestly advised you to desist
from useless efforts?"

Elias squinted sullenly, and shrugged his shoulders.

"Yes, I hate him!" he exclaimed fiercely. "Confound him! All the

fame and gold are for him, and none for me! I will do him all the
harm I can! I will embitter his life!"

"Begone!" cried Piccini, full of horror. "We have nothing more in

common. Honor, religion, guide the true man; your divinities are
vanity, envy, cowardly malice! Such as you deserve no sympathy!"

Full of spite and vexation, Elias Hegrin left the house.

Piccini's opera was admired, but that of Gluck obtained the victory,
awakening universal enthusiasm. After its third representation,
Gluck left the opera-house, followed by the acclamations of the
enraptured multitude. Mehul was with him, going to sup at his
house.
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