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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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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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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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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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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.
FMTOC Page xxi 12/19/12 10:08 PM user-t044 /Volumes/203/MHR00209/siL52070/disk1of1/0071052070

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.
FMTOC Page xxii 12/19/12 10:08 PM user-t044 /Volumes/203/MHR00209/siL52070/disk1of1/0071052070

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 ([Link]/
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 ([Link]/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.
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 £17 AVCHISTORY ECLECTICISM IN GREEK PHILOSOPHY
TRANSLATED FROM THE GERMAN OF D? E. ZELLER PROFESSOR IN
THE UNIVERSITY OF BERLIN ith the Author's sanction BY Pa GAR |
S. F. ALLEYNE. pA ^ |. LONDON LONGMANS, GREEN, AND CO. 1883
 DENEN /0/8 LONDON : PRINTED BY SPOTTISWOODE AND
CO., NEW-STREET SQUARE AND PARLIAMENT STREET
 TRANSLATOR’S PREFACE. ——-— eS THIS is a translation of
the second section of Dr. Zeller’s ‘Philosophie der Griechen, Dritter
Theil, Erste Abtheilung. The first section of the volume, concerning
the Stoics, Epicureans, and Sceptics, has already been translated by
Dr. Reichel. The present translation has been made from the third
and latest edition of the German work. S. F. ALLEYNE. CLIFTON :
September 1, 1883.
 Errata. Page 83, line 15: for belonged read belongs 95,
116, 162, 205, 206, 207, 210, 294, ,5 1 26 : for fundamental impulse
read impulse 2: for their read its 19: for Í read we 91 : for effects
read affect 6 : for enquires read asks 9: substitute a semicolon for a
comma after ‘doctrine,’ 13: substitute a note of interrogation for a
comma after ‘ourselves.’ 3: for under read in 357, lines 1 and 2: for
that universal, which he claims for all men as their inborn conviction
read that universal conviction which he claims for all men as innate
 CONTENTS. CHAPTER I. ORIGIN AND CHARACTER OF
ECLECTICISM atada blending of the schools of philosophy : internal
causes of this, 1 sg. External causes: diffusion of Greek philosophy
among the Romans, 5. Reaction of that diffusion upon philosophy,
14. Principle and character of eclectic philosophy, 17, Contained the
germs of the later scepticism, 21; and of Neo-Platonism, 22
CHAPTER II. ECLECTICISM IN THE SECOND AND FIRST CENTURIES
BEFORE CHRIST—THE EPICUREANS——ASCLEPIADES Relation of
the later Epicureans to Epicurus, 24. Asclepiades of Bithynia, 29 sq.
CHAPTER III. THE STOICS: BOETHUS, PANJETIUS, POSIDONIUS.
Successors of Chrysippus, 34. Boéthus, 35. Pansetius, 39. Character
of his philosophy, 42. Deviations from Stoicism, 43 sg. Ethics, 47.
Contemporaries and disciples of Paneetius, 52. Posidonius, 56. His
philosophic tendencies, 59. His anthropology, 64. Other Stoics of the
first century before Christ, 70 PAGE
 vi CONTENTS. CHAPTER IV. PAGE THE ACADEMIC
PHILOSOPHERS IN THE FIRST CENTURY BEFORE CHRIST : : 19
Philo of Larissa, 75. His practical bias, 77. Modification of the
scepticism of the Academy, 79. His theory of knowledge, 81.
Antiochus of Ascalon, 85. Polemic against scepticism, 87. Eclecticism:
essential agreement of the various systems, 91 ; theory of
knowledge, 93. Physics and metaphysics, 94. Ethics, 95. School of
Antiochus, 99. Eudorus, 103. Arius Didymus, 106. Potamo, 199
CHAPTER -V. THE PERIPATETIC SCHOOL IN THE FIRST CENTURY
BEFORE CHRIST : : TE Es The Commentators: Andronicus of
Rhodes, 113. Boéthus of Sidon, 117. Aristo, Staseas, Cratippus,
Nicolaus, Xenarchus, and others, 121 sq. The treatise vepl kdopov :
various theories as to its origin, 125, Nature of the ireatise, 132.
Origin and date of composition, 138. Treatise on virtues and vices,
145 CHAPTER VI. CICERO—VARRO ^ : . 146 Cicero, 146. His
scepticism, 149. Its limits, 151. Practical view of philosophy, 156.
Eclecticism : doctrine of innate knowledge, 159. Ethics, 162.
"Theology, 167. Anthropology, 169. Varro, 171. His view of
philosophy and the various schools, 172. Ethics, 173. Anthropology
and philosophy, 176 CHAPTER VIL THE ACHOOL OF THE SEXTII : ~
90 History of the school, 80. Its philosophie character and
standpoint, 153
 CONTENTS. vii CHAPTER VIII. PAGE THE FIRST
CENTURIES AFTER CHRIST — THE SCHOOL OF THE STOICS—
SENECA . . 189 Philosophy in the Imperial period: study of the
ancient philosophers, 189. Endowment of public chairs of philosophy,
190. The school of the Stoics from the first to the third century, 194
sg. Cornutus, 199. Seneca, 202. His conception of the problem of
philosophy, 205. Uselessness of merely theoretic inquiries, 206.
Opinion of dialectic, 207. Physics, 209. Metaphysical and theological
views, 212. The world and nature, 217. Man, 219. Uncertainty of
Seneca’s speculative theories, 225. His ethics essentially Stoic in
principle, 226. Modification of Stoic dogmas, 227. Application of
particular moral doctrines, 235. Independence of things external,
236. Love of mankind, 239. Religious temperament, 242 CHAPTER
IX. THE STOICS CONTINUED: MUSONIUS, EPICTETUS, MARCUS
AURELIUS ji ; . 246 Musonius, 246. His practical standpoint, 248. His
ethics, 255. Epictetus and Arrian, 256. Practical end of philosophy,
258. Inferior value of knowledge, 260. Religious view of the world,
263. Man, 266. Ethics, 268. Independence of things external ;
resignation to destiny and the course of the universe, 270 sg.
Inclination to Cynicism, 272. Gentleness and love of mankind, 274,
275. Marcus Aurelius Antoninus, 276, ° His practical view of
philosophy, 277. His theoretic opinions ; flux of all things, 279 ; the
Deity, Providence, order of the world, 280 sg. Kinship of man to God,
283. Ethics, 284. Withdrawal into self, 284. Resignation to the will of
God, 285. Love of mankind, 286
 viii CONTENTS. CHAPTER: X: PAGE THE CYNICS OF THE
IMPERIAL ERA. EM eje Revival of Cynicism, 289. Its adherents, 290
sq. Demetrius, 291. (Enomaus, 294. Demonax, 296. Peregrinus, 299.
Later Cynics, 301 CHAPTER. XL THE PERIPATETICS OF THE FIRST
CENTURIES AFTER CHRIST : , . 904 The Peripatetic school of the
first and second century, 304. Commentators of Aristotle's works:
Aspasius, Adrastus, Herminus, Achaicus, Sosigenes, 306. Aristocles
of Messene, 314. Alexander of Aphrodisias, 318. Apologies for
Aristotle's writings and commentaries on them, 322. The Particular
and the Universal, Form and Matter, 324. The soul and vois, 324.
God and the world, 329. Extinction of the Peripatetic School, 332
CHAPTER XII. THE PLATONIC SCHOOL IN THE FIRST CENTURIES
AFTER THE CHRISTIAN ERA. f . oot Platonists of this period, 334.
Commentators of Platonic writings, 337. Introduction of alien
doctrines opposed by Taurus and Atticus, 340. Eclecticism
exemplified in Theo, Nigrinus, Severus, Albinus, 344 CHAPTER XII.
ECLECTICS WHO BELONG TO NO DEFINITE SCHOOL 351 Dio
Chrysostom, 353. Lucian, 357. Galen, 360. Character of his
philosophy, 362. Theory of knowledge, 362 sq. Logic, 363. Physics
and metaphysics, 365. Contempt for theoretic enquiry, 369. Ethics,
370 INDEX e SI w
 ECLECTICISM. CHAPTER I. ORIGIN AND CHARACTER OF
ECLECTICISM. THaT form of philosophy which appeared about the
beginning of the post-Aristotelian period had, in the course of the
third and second centuries, perfected itself in its three principal
branches. These three schools had hitherto existed side by side,
each striving to maintain itself in its purity, and merely adopting
towards the others, and towards the previous philosophy, an
aggressive or defensive attitude. But it lies in the nature of things
that mental tendencies, which have sprung from a kindred soil,
cannot very long continue in this mutuyt ally exclusive position. The
first founders of a school and their immediate successors, in the
fervour of original enquiry, usually lay excessive weight upon that
which is peculiar to their mode of thought ; in their opponents they
see only deviations from this their truth: later members, on the
contrary, who have not sought this peculiar’ element with the same
zeal, and therefore have not grasped it with B CHAP. I. A. Gradual
blending of the three post-Aristotelian schools of philosophy. i.
Internal causes of this.
 to ECLECTICISM. the same rigidity and one-sidedness,
more easily perceive, even in adverse statements, that which is
common and akin, and are more ready to sacrifice subordinate
peculiarities of their own standpoint ; the strife of schools will itself
oblige them to repel exaggerated accusations and unqualified
condemnations, by the stronger enforcement of that in which they
coincide with others, to give up or put aside untenable assertions, to
soften offensive propositions, and to break off from their systems
the sharpest angles ; many an objection of the adversary maintains
its ground, and in seeking to elude it by another interpretation, it is
found that the presuppositions of the objection have been partially
conceded, together with the objection itself. It is, therefore, a
natural and universal experience that in the conflict of parties and
schools their oppositions gradually become blunted, that the
common principle which underlies them all is in time more clearly
recognised, and a mediation and fusion is attempted. Now, so long
as philosophie productivity is still living and active in a people, the
case will either never arise or arise only temporarily, that its whole
science is infected by this eclecticism, because already in its youthful
course, new directions are attempted before those immediately
preceding them have decidedly begun to grow old. As soon, on the
contrary, as the scientific spirit is exhausted, and a long space of
time, devoid of new creations, is merely filled with discussions
among the existing schools, the natural result of these
 ITS ORIGIN. discussions, the partial blending of the hostile
parties, will appear to a greater extent, and the whole philosophy
will assume that eclectic character which, in its universal diffusion, is
always the premonitory sign either of a deeply seated revolution, or
of scientific decay. This was precisely the position in which Greek
philosophy found itself in the last centuries before Christ. All the
causes which led, generally speaking, to the dissolution of classical
culture, had also had a paralysing influence on the philosophic spirit;
for centuries after the transformation of philosophy, which marks the
end of the fourth and the beginning of the third century no new
system arose; and if the postAristotelian systems in and for
themselves had already lost the purely theoretic interest in the
contemplation of things, and by their restriction to the life and aims
of men, had announced the discontinuance of scientific endeavour,
the long cessation of philosophic production could only serve to dull
the scientific sense still more, and to call in question the possibility
of scientific knowledge in general, This state of things found its
proper expression in scepticism, which opposed the dogmatic
systems with more and more signal success. The eclecticism which
since the beginning of the first century before Christ had repressed
scepticism and united together the previously separate tendencies of
thought, was, however, merely the reverse side of scepticism itself.
Scepticism had B 2 CHAP.
 ECLECTICISM. placed all dogmatie theories on an equality
in such . a manner as to deny scientific truth to all alike. This *
neither one nor another’ ( Weder-noch) became in eclecticism ‘One
as well as the other’ (Sowohlals-auch); but for that very transition
scepticism had paved the way; for it had not been able to rest in
pure negation, and had therefore, in its doetrine of probability, set
up once more a positive conviction as a practical postulate. This
conviction was not indeed to come forward with a claim to full
certainty; but we cannot fail to perceive in the development of the
sceptical theory, from Pyrrho to Arcesilaus, and from Arcesilaus to
Carneades, a growing estimation of the value of the knowledge of
probability: it was only necessary to advance one step further, to
bring forward practical necessity more decidedly as against the
sceptical theory, and the probable would reeeive the significance of
the true —seeptieism would be transformed into a dogmatic
acceptance of truth (Furwahrhalten). In this dogmatism, however,
doubt would inevitably continue to exercise such an influence that
no individual system as such would be recognised as true, but the
true out of all systems would be separated according to the measure
of subjective necessity and opinion. This had been exactly the
procedure of the sceptics in the ascertainment of the probable; as
they develop their doubt in the criticism of existing theories, so do
they seek the probable primarily in the existing systems, among
which they have reserved to themselves the right to
 ITS ORIGIN. decide. Carneades, as we know,! had so
treated the ethical questions to which, we are told, aban- _ doning
his former predilection for combating hostile opinions, he more and
more restricted himself with advancing years? Similarly Clitomachus,
while contending with the dogmatic schools, seems to have sought a
positive relation to them ;? and we learn that /Eschines, another
disciple of Carneades, adhered to that side only of his master’s
teaching. Thus scepticism forms the bridge from the one-sided
dogmatism of the Stoic and Epicurean philosophy to eclecticism ;
and in this respect we cannot regard it as a mere accident that from
the followers of Carneades this mode of thought chiefly emanated,
and that in them it was immediately connected with the point on
which the Stoies and Epicureans had sustained their dogmatism, and
even the Platonists, in the last resort, their doctrine of probability,
viz. the necessity of definite theories for practical life. It was,
however, generally speaking, the condition of philosophy at that
time, and the strife of the philosophic schools, which first caused the
rise and spread of scepticism, and in the sequel, the eclectic
tendency in philosophy. The most important external impulse to this
! Zeller, Philosophie der Griechen, 3° Theil, 1° Abtheilung, p- 517 sq.
2 Plut. An seni 8. ger. resp. 13, 1. p. 791: ó uiv ody 'Akaðnpalkós
Aisxlyns, codi TOV tive Ae'yyóvrov, Üri TpocTtoievTOA yeyoveya:
Kapveddov, mh -yeyovüs, pa8nrís* GAG TéTE Ye, eImev, éyà
Kapveddov Üvfjkovov bre thy paxlav kal toy wWó$ov apenas ó
Adyos abrod Sia Tb yijpas eis rò XPhoimov ovviKTo kal Kowwvrixdy.
? Phil. der Griechen, III. i. p. 524, note 2, 1 Vide note 2. li. Ecternal
causes. ;
 Diffusion of Greek philosophy «mong the Lèomans.
ECLECTICISM. change was given by the relation in which Greek
science and culture stood to the Roman world.’ The first knowledge
of Greek philosophy doubtless came to the Romans from Lower Italy
: the founder of the Italian School (Pythagoras) is the first
philosopher whose name is mentioned in Rome.? But the doctrines
of the Greek philosophers can only have been heard of there in an
entirely superficial and fragmentary manner before the beginning of
the second century before Christ. This ştate of things must have
changed, however, when, after the second Punic War, the Roman
policy and Roman arms pressed forward farther and farther towards
the east; when the wars with Macedonia and Syria brought
distinguished Romans in great numbers to Greece, while, on the
other hand, Greek ambassadors and state prisoners, and soon also
slaves, appeared more and more commonly in Rome; when men of
the importance of the elder Scipio Africanus, T. Quinctius Flamininus,
and Æmilius Paulus, applied themselves ! For what follows, cf. Ritter,
iv. 79 sq. ? The arguments for this are given in Phil. der Griech. Part
I. pp. 287, 3; 450, 15 c£. iid. 213, 24 and Part HI. np sq. A still
earlier date (if this statement is historical) must be fixed for the
presence in Rome of Hermodorus the Ephesian, who assisted the
decemviri in the drawing up of the twelve tables (Part I. 566, 2): but
even if he were indeed the celebrated friend of Heracleitus, we have
no ground for the supposition that he discoursed to the Romans on
the physics of that philosopher. ? Such as the thousand Achzans
who, 168 B.C., were carried away into Italy, and kept there for
seventeen years, all of them men of repute and culture (among
them we know was Polybius), whose long residenee in the country
could not have been without influence on Rome if even the least
considerable of them had their actual abode in that city.
 GREEK PHILOSOPHY IN ROME. with delight to Greek
literature; when, from the beginning of the second century, Greek
poetry was transplanted to Roman soil in the more or less free
imitations of Ennius, Pacuvius, Statius, Plautus, and their suecessors
; and Roman history was related in the Greek language by Fabius
Pictor and other annalists. 'The philosophie literature of Greece
stood in far too close a connection with the other branches—
philosophy occupied far too important a place in the whole Hellenic
sphere of culture, as a means of instruction and object of universal
interest —to make it possible for such as had once found pleasure in
Greek intellectual life to shut themselves up from it very long,
however small the need for scientific enquiry might be in them. We
find, then, even before the middle of the second century, many and
various traces of the commencement of a knowledge of Greek
philosophy among the Romans. Ennius shows that he was
acquainted with it, and adopts from it isolated propositions. In the
year 181 B.C. an attempt was made, in the so-called Books of Numa,
to introduce dogmas of Greek philosophy into the Roman religion?
Twenty-six years later (aecording to others only eight) the activity of
the Epieurean philosophers in teaching caused their banishment
from Rome. In 161 B.c., by a decree of the senate, residence in
Rome was forbidden to the philosophers and rhetoricians ; * and
this always ! Cf. Phil. der. Griech. III. * This decree of the senate is
ii. p. 83. to be found in Suetonius, De 2 Cf. [. c. III. ii. p. 85. Cl.
Rhetor. 1; Gell. N.A. xv. 11 3 Cf. 7.0. IIL. i. p. 372, 1. (cf. also
Clinton, Fasti Hellen.
 ECLECTICISM. proves that there was reason for anxiety in
regara to their influence upon the education of youth. /Emilius
Paulus, the conqueror of Macedonia, gave his sons Greek instructors,
and for that purpose took with him on his expeditions the
philosopher Metrodorus.! His companion in the Macedonian
campaign, Sulpicius Gallus, besides the astronomical knowledge for
which he was distinguished, may, perhaps, have also adopted certain
philosophie theories of the Greeks? But all these are merely isolated
signs of the movement which from the middle of the second century
manifested itself to a much greater extent. Hitherto comparatively
few had occupied themselves with Greek philosophy ; now the
interest in that philosophy was more universally diffused. Greek
philosophers come to Rome in order to try 161 B.C). These authors
tell us of another similar enactment: an edict of the censor Cn.
Domitius Ahenobarbus and L. Licinius Crassus, in which they express
their serious displeasure with the teachers and frequenters of the
newly-arisen Latin schools of rhetoricians on account of this
departure from the consuetudo majorum. But, not to mention that
the rhetores Latini, who were alone affected by this decree,
according also to Cicero, De Orat. iii. 24, 93 sq., were only indirectly
connected with Greek philosophy, the decree was not promulgated
until the year 95 B.C., as we see from a comparison of Cicero, loc.
cit. with i. 7, 24. Clinton, Fasti Hellen: dates itin 92 B.C; Pn fist; Nat.
xxsv, 1895 cf. Plut. 4m. P.6. The latter mentions among the Greeks
with whom At milius surrounded his sons, grammarians, sophists,
and rhetoricians. Pliny gives the more definite information, that after
the victory over Perseus (168 B.C.) he requested from the Athenians
a good painter and an able philosopher. They sent him Metrodorus,
who was both in one person. CL Phil. d. Gr. ILA. p.525: ? Cicero
praises his knowledge of astronomy, Cic. Off. i. 6, 19. According to
Livy, xliv. 37; and Plin. Hist. Nat. ii. 12, 53, he foretold an eclipse of
the sun before the battle of Pydna. A more detailed account of the
authorities in regard to this event is given by Martin, Revue
Archéolog. 1864, No. 3.
 GREEK PHILOSOPHY IN ROME. their fortune, or are sent
for thither by distinguished men. Young Romans, desirous of playing
a part in the state, or of gaining distinction in cultivated society,
think that they cannot do without the instruction of a philosopher,
and it’ soon became usual to seek this not only in Rome, but in
Athens itself, the chief school of Greek science. Already the famous
deputation of philosophers in the year 156 B.C.) showed, by the
extraordinary influenee whieh Carneades especially obtained, how
favourably Greek philosophy was regarded in Rome; and though we
should not overrate the effect of this passing event, we may,
nevertheless, suppose that it gave a considerable impetus to the
previously awakened interest in philosophy, and spread it abroad in
wider circles. More permanent, no doubt, was the influence of the
Stoic Panzetius during his residenee, prolonged as it would seem to
have been for many years, in the capital of the Roman empire, he
being a man peculiarly fitted by the character of his philosophy to
effect an entrance for Stoicism among his Roman auditors.? Soon
after him Caius Blossius of Cumæ, a disciple of Antipater the Stoic,
was in. Rome, the friend and counsellor of Tiberius Graechus, who
through him must likewise have ! The authorities for this are of
Gracchus (133 B.c.) Blossius cited Phil. d. Gr. II. ii. p. 928, was also
in danger. He left 1; cf, p. 498, 1; cf. Part III. ii Rome, and went into
Asia p. 498, 1. Minor to Andronicus, after ? Further details infra,
chap- whose fall (130 B.C.) he killed ter iii. himself, A thorough
examina3 Plut. Tib. Gracch. 8, 17, tion of him is to be found in 20;
Val. Max. iv. 7, 1; Cicero, ‘Pemepi wept BAocaíov kal Aio$dLel.11,37.
After themurder »vovs (Leipzig, 1873). MeanCHAP. 9
 ECLECTICISM. become acquainted with Stoicism.! And now
that immigration of Greek learned men begins, which, in time,
assumed greater and greater proportions.’ Among the Romans
themselves, men who by their intellect and position were so
decidedly pre-eminent as the younger Scipio Africanus, his friend the
wise Lelius, L. Furius Philus and Tiberius Gracchus, took philosophic
studies under their protection. With them are connected Scipio’s
nephew Tubero, a disciple of Panætius, who, while he himself calls
his work €pevvat kal eikacgíai, and the latter so decidedly
preponderate, that our historical knowledge of the man is scarcely
extended by the treatise. ! That Gracchus, through the care of his
mother, had distinguished Greeks for his instructors (Cic. Brut: 97,
104^ ct, Plut. Tib. Gracch. 20) is well known. ? Polybius (xxxii.10),
however, relates that much earlier, when Scipio was only eighteen
(166 B.C.), he said to him and his brother: zepl wev yap rà
paðhuaTa, mepl & viv ópà omovddcorras juas «ai piAoTimoupEvous,
OÙK ATOPNTETE Ttv gcuvepynaóvrov viv éroluws, «al gol Kakeivw’
T0ÀU yap ÖN Tt pvarov amd tis ‘EAAdSos émippéov Óp® karà TÒ
Tapüv TÕV TOLOÚTWV avOpérwy, which agrees with what is quoted
supra, p. 7, note 4. 3 Cicero, De Orat. ii. 37, 154 : Et certe non tulit
ullos hec civitas aut gloria clariores, aut auctoritate graviores, aut
humanitate politiores P. Africano, C. Lelio, L. Furio, qui secum '
Grecia palam semper habuerunt. De Rep. ii. 3, 5: Quid P. Scipione,
quid C. Leliv, quid L. Philo perfectius cogitari potest ? qui . ad
domesticum majorumque morem etiam hane a Socrate adventiciam
doctrinam adhibuerunt. Cicero there puts the substance of
Carneades’ discourse against justice, which he himself had heard,
into the mouth of Furius Philus, while he makes him at the same
time folow the Academic philosopher in the consuetudo contrarias in
partes disserendi; loc. Cit 0. 5, 8 409.5 Lact. Tnstosv: 14.
Concerning the connection of Scipio and Lalius with Panetius we
shall have to speak later on. Lelius, according to Cic. Fin: H8 24; had
also attended the lectures of Diogenes, which we must, no doubt,
connect with his presence in Rome in the year 156 B.C. * Q. #lius
Tubero, through his mother a grandson of JEmilius Paulus, was a
very zealous. Stoic, who carried out eruditissimos homines ex
 i GREEK PHILOSOPHY IN ROME. with the sons-in-law of
Lælius, Quintus Mucius Scævola,! and Caius Fannius,’ P. Rutilius
Rufus,’ Lucius Ælius Stilo, and others, open the long his principles in
his life, not without exaggeration. Cf. concerning him Cic. Brut. 31,
117 ; De Orat. iii. 23, 87; Pro Mur. 36, 75 sq.; Acad. ii. 44, 135;
Tuse. iv. 2, 4 ; Sen. Lp. 95, 72 sq. ; 98, 13; 104, 21; 120,19; Plut.
Luculli. 39; Pompon. De Orig. Juris, i. 40; Gell. JV. A. i. 22, 7; xiv. 2,
20; Val. Max. vii. 5,1. Cic. Off. iii. 15, 63, mentions a treatise of
Hecato addressed to him, and another of Panstius, ibid. Acad. ii. 44,
135; Tuso. iv. 2, 4; against which the pseudo-Plutarch, De Nobilit.
18, 3, is not any historical testimony ; cf. Bernays, Dial. d. Arist. 140.
1 One of the most celebrated of the ancient jurists and founders of
scientific jurisprudence among the Romans ( Bernhardy, Grundr. d.
Rom. Lit. 676, &c.), son-in-law of Laelius (Cic. De Orat.i.9, 35).
According to Cicero, he had heard Panetius lecture, and (J. e. 10,
43) he calls the Stoics Stoici nostri. ? C. Fannius, son of Marcus, son-
in-law of Laelius, was brought by Lelius to hear Pansetius (Cic. Brut.
26, 101), and is designated by Cicero (Brut. 31, 18) as a Stoic.
Cicero often mentions an historical work composed by him. Similarly
Plut. Tib. Gracch. 4. With regard to his consulate, cf. id. C. Gracch. 8,
11, 12. 3 This is the Rutilius who was famous for his services in war
(Val. Max. ii. 3,2; Sallust, Jug. 54, 56 sq.), but principally for the
purity of his character. On account of the impartiality with which, as
proconsul, he defended the inhabitants of Asia Minor against the
extortions of the Roman equites, one of the most shameless
sentences of banishment was passed upon him, which he bore with
the cheerfulness of a sage. He went to Smyrna, where he died,
having refused to return, which was offered him by Sulla. Cf. on this
subject Cic. Brut. 30, 115; N. D. iii. 82, 80; im ` Pison. 39, 95; Rabir.
Post. 10, 27 ; Pro Balbo, 11, 28 (cf. Tacit. Ann. iv. 43); Sen.*Eyp. 24,
4; 79, 14; 82, 11; Benef. vi. 97, 2, &c.; Val. Max. ii. 10, 5, &c. Cicero
(Brut. 30, 114) calls him doctus vir et Graecis literis eruditus, Panetii
auditor, prope perfectus in Stoicis. Concerning his admiration of his
teacher Panetius and his acquaintance with Posidonius, cf. Cic. Off.
iii. 2,10. He left behind him memorials and historical works: vide
Bernbardy, loc. cit. 203, 506; also Cicero, Fin. i. 3, 7. t Vide
concerning this philosopher, the predecessor and teacher of Varro,
Cic. Brut. 56, 205 sq.; also Acad.i. 2, 8; Ad Herenn. iv. 12;
Bernhardy, loc. cit. 857. * Such as Marcus Vigellius (Cic. Orat. iii. 21,
78) and Sp. CHAP.
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