ROITT’S .
`
`ESSENTIAL
`
`IMMUNOLOGY
`
`Ivan Roitt
`
`
`
`Lassen - Exhibit 1045, p. 1
`
`

`

`© 1971, 1974, 1977, 1980, 1984, 1988,
`1991, 1994,1997 by Blackwell Science Ltd
`Editorial Offices:
`Osney Mead, Oxford OX2 GEL
`25 John Street, London WC1 N ZBL
`23 Ainslie Place, Edinburgh EH3 6A]
`350 Main Street, Malden
`MA 02148 5018, USA
`54 University Street, Carlton
`Victoria 3053, Australia
`
`Other Editorial Offices:
`
`Blackwell Wissenscha fts-Verlag Gmbl—l
`Kurfiirstendamm 57
`10707 Berlin, Germany
`Zehetnergasse 6
`A-1140 Wien
`Austria
`
`All rights reserved. No part of
`this publication maybe reproduced,
`stored in a retrieval system, or
`transmitted, in any form or by any
`means, electronic, mechanical,
`photocopying, recording or otherwise,
`except as permitted by the UK
`Copyright, Designs and Patents Act
`1988, without the prior permission
`of the copyright owner.
`
`Set by Excel Typesetters Co., l-Iong Kong
`Printed and bound in Italy
`by Rotolito Lombarda S.p.A., Milan
`
`The Blackwell Science logo is a
`trade mark of Blackwell Science Ltd,
`registered at the United Kingdom
`Trade Marks Registry
`
`First published 1971
`Reprinted 1972 (twice), 1973 (twice)
`Second edition 1974, Reprinted 1975
`Third edition 1977, Reprinted 1978,1979
`Fourth edition 1980, Reprinted 1982, 1983
`Fifth edition 1984
`Sixth edition 1988, Reprinted 1988
`Reprinted with corrections1989
`Seventh edition 1991
`Eighth edition 1994, Reprinted 1996
`Ninth edition 1997
`
`Spanish editions 1972, 1975,1978, 1982,
`1988,1989, 1993
`[talian editions 1973, 1975, 1979, 1986,
`1988,1990, 1993, 1995
`Portuguese editions 1973, 1979, 1983
`French editions 1975, 1979,1990
`Dutch editions 1975, 1978, 1982
`Japanese editions 1976, 1978, 1982, 1986,1988
`German editions 1977, 1984, 1988, 1993
`Polish edition 1977
`Greek editions 1978, 1989, 1992
`Turkish edition 1979
`Slovak edition 1981
`Indonesian editions 1985,1991
`Russian edition 1988
`Korean edition 1991
`ELBS editions 1977, 1982, 1988, Reprinted 1991
`Chinese (Taiwan) editions 1991, 1994
`
`DISTRIBUTORS
`Marston Book Services Ltd
`PO Box 269
`Abingdon
`Oxon OX14 4YN
`(Orders: Tel: 01235 465500
`Fax: 01235 465555)
`
`USA
`Blackwell Science, Inc.
`Commerce Place
`350 Main Street
`Malden, MA 02148 5018
`(Orders: Tel: 800 759 6102
`617 388 8250
`Fax: 617 388 8255)
`
`Canada
`Copp Clark Professional
`200 Adelaide St West, 3rd Floor
`Toronto, Ontario M 51-11W7
`(Orders: Tel: 416 597—1 616
`800 8159417
`Fax: 416 597-1617)
`
`Australia
`Blackwell Science Pty Ltd
`54 University Street
`Carlton, Victoria 3053
`(Orders: Tel: 3 9347 0300
`Fax: 3 9347 5001)
`
`Catalogue records for this title
`are available from the British Library
`and the Library ofCongress
`lSBN 0-86542-729—1
`
`Lassen — Exhibit 1045, p. 2
`
`Lassen - Exhibit 1045, p. 2
`
`

`

`— C
`
`ONTENTS
`
`PREFACE ...........................
`
`ACKNOWLEDGEMENTS ...................
`
`ABBREVIATIONS .......................
`
`USER GUIDE .........................
`
`PART 1
`
`- THE BASIS OF IMMUNOLOGY
`
`Target cells are told to commit suicide
`Eoslnophlls
`S“ M MARY
`
`19
`20
`20
`
`2 - Specific acquired Immunity, 22
`THE NEED FOR SPECIFIC IMMUNE MECHANISMS
`ANTIBODY — THE SPECIFIC ADAPTOR
`
`Antibody initiates a new complement pathway Cclassical') .....
`Complexed antibody activates phagocytlc cells ..........
`CELLULAR BASIS OF ANTIBODY PRODUCTION
`.
`.
`Antibodies are made by lymphocytes ...............
`Antigen selects the lymphocytes which make antibody
`The need for clonal expansion means humoral Immunity must
`be acquired
`ACQUIRED MEMORY
`Secondary antibody responses are better
`ACQUIRED IMMUNITY HAS ANTIGEN SPECIFICITY . ..
`Discrimination between different antigens
`Discrimination between self and noneelf
`VACCINATION DEPENDS 0N ACOUI RED M EMORY
`CELL-MEDIATED IM MUNITY PROTECTS AGAINST
`INTRACELLULAR ORGANISMS ...............
`
`Cytokine-producing T—cells help macrophages to kill imraoellular
`parasites .........................
`Vlrally infected cells can be killed by cytotoxic T-cells and
`A000
`IMMUNOPATHOLOCY .....................
`SUM MARY
`FURTHER READINI
`General re'adlng
`Reference work
`Historical
`In-depth series for the advanced reader .............
`Current Information .....................
`Multiple choice questions ..................
`Electronic publications (linked to ‘Roltrs Essential
`Immunology)
`Major journals
`
`xiii
`
`xlv
`
`XV
`
`xix
`
`9
`10
`11
`II
`11
`II
`II
`12
`12
`12
`12
`14
`
`14
`14
`15
`
`16
`16
`18
`18
`18
`
`Lassen — Exhibit 1045, p. 3
`
`.
`
`.
`
`.
`
`Innate immunity, 3
`-
`I
`EXTERNAL BARRIERS AGAINST INFECTION .
`PHAGOCYTIC CELLS KILL MICROOROANISMS
`Polymorphs and macrophages are dedicated ‘prafessional'
`phagocytes ........................ .
`The polymorphonuciear neutrophll ...............
`The macrophage .......................
`Microbes are engulfed by phagocytosls ........... _
`.
`.
`.
`There Is an array of killing mechanisms ..............
`Killing by reactive oxygen Intermediates
`Killing by reactive nitrogen intermediates ............
`Kllllng by preformed antlmlcroblals ...............
`COMPLEMENT FACILITATES PHAGOCYTOSIS
`Complement and Its activation ..................
`C3 undergoes slow spontaneous cleavage ......... .
`.
`03b levels are normally tightly controlled ............
`CS convertase ls stabilized an microbial surfaces ........
`The post-03 pathway generates a membrane attack complex
`.
`.
`.
`Complement has a range of defensive biological functions .
`.
`.
`.
`I 03b adheres to complement receptors ............
`2 Biologically active fragments are released
`3 The terminal complex can Induce membrane lesions
`COMPLEM ENT CAN MEDIATE AN ACUTE
`INFLAMMATORY REACTION
`The most cell plays a central role .................
`Macrophages can also do It ...................
`HUMORAL MECHANISMS PROVIDE A SECOND
`DEFENSIVE STRATEGY ...................
`Acute phase proteins Increase In response to Infection .......
`Interferons inhlbltviral replication ................
`EXTRACELLULAR KILLING .................
`Natural killer (NK) cells
`
`Lassen - Exhibit 1045, p. 3
`
`

`

`vi
`
`CONTENTS
`
`PART 2
`
`THE RECOGNITION OF ANTIGEN
`
`3 - Antibodies, 43
`
`43
`
`45
`45
`45
`46
`
`47
`47
`47
`50
`
`59
`59
`
`63
`
`63
`
`64
`65
`65
`85
`
`66
`67
`
`69
`69
`69
`70
`70
`
`.
`
`.
`
`TH E BASIC STRUCTURE IS A FOUR-PEPTIDE UNIT .
`AMINO ACID SEOUENCES REVEAL VARIATIONS IN
`IMMUNOGLOBULIN STRUCTURE ,,,,,,,,,,,,,,
`IM MUNOGLOBULIN GENES .................
`lmmunoglobulins are encoded by multiple gene segments .....
`A special mechanism etiects VDJ recombination
`STRUCTURAL VARIANTS OF THE BASIC
`IMMUNOGLOBULIN MOLECULE ..............
`lsotypes
`Allotypes ............................
`Idiotypes ............................
`IMMUNOGLOBULINS ARE FOLDED INTO GLOBULAR
`DOMAINS WHICH SUBSERVE DIFFERENT
`FUNCTIONS.
`.
`.
`lmmunoglobulln domains have a characteristic structure .....
`The variable domain binds antigen ................
`constant region domains determine secondary biological tunctlon
`.
`IM MUNOGLOBULIN GLASSES AND SUBCLASSES
`lmmunoglobulln G has major but varled roles in extracellular
`defenses
`Activation of the classical complement pathway
`The diversity at FCy receptors .................
`Nonprecipltoting ‘univalent’ antibodies ,,,,,,,,,,,,,
`lmmunoglobulln A guards the mucosal suriaces .........
`lmmunoglobulln M provides a defense against bacteremta .....
`lmmunoglobulln D is a cell surtcce receptor ............
`lmmunoglobulln E triggers inilammatory reactions ........
`lmmunoglobulins are turther subdivided into subclasses
`SUMMARY ..........................
`FURTHER READING .....................
`
`.
`
`4 - Membrane receptors tor antigen, 63
`THE B-CELL SURFACE RECEPTOR FOR ANTIGEN .
`The B-cell inserts a transmembrane lmmunoglobulln into
`its surtace ..........................
`The surtace lmmunoglobulln ls complexed with associated
`membrane proteins .......................
`THE T-CELL SURFACE RECEPTOR FOR ANTIGEN
`.
`.
`The receptor for antigen Is a transmembrane heterodlmer .....
`There are two classes at T-celi receptors .............
`The encoding of T-cell receptors is similar to that or
`lmmunoglobultns ........................
`The CDS complex is an integral part or the T-cell receptor ......
`THE GENERATION OF DIVERSITY FDR ANTIGEN
`RECOGNITION
`.......................
`lntrachaln amplification of diversity ................
`Random VDJ combination increases diversity geometrically .
`.
`.
`Playing with the junctions ..................
`Interchaln amplltlcotlon .....................
`Somatic hypermalation .....................
`THE MAJOR HISTOCOMPATIBILITY COMPLEX
`(M NO)
`Class I and class II molecules are membrane-bound
`heterodlmers ........................
`MHC class I
`MHC class II
`
`Complement genes contribute to the remaining class lll region
`of the MHC ......................... 72
`Gene map at the MHC ..................... 72
`The genes at the MHC display remarkable polymorphism ..... 75
`Nomenclature ....................
`75
`Inheritance of the MHC ...................
`77
`The tissue distribution of MHC molecules
`............ 77
`MHC iunctlons
`................
`77
`SUMMARY ........................
`78
`FURTHER READING .................
`79
`
`5 - The primary Interaction with antigen, 80
`80
`.
`WHAT IS AN ANTIGEN? .................
`Otepitopes and amlgen determinants .............. 81
`ldentitlcation of B—cell epitopes ................. 81
`ANTIGENS AND ANTIBODIES INTERACT BY SPATIAL
`83
`.
`.
`COMPLEMENTARITY NOT BY COVALENT BONDING .
`Variation In hapten structure shows impedance at shape ..... 83
`Spatial complementarity of epitope and paratape can be
`demonstrated ......................... 83
`Antigen—antibody bonds are readily reversible .........
`84
`THE FORCES BINDING ANTIGEN TO ANTIBODY
`BECOME LARGE As INTERMOLECULAR DISTANCES
`86
`.
`BECOME SMALL .................. .
`86
`i Electrostatic
`......................
`2 Hydrogen bonding ..................... 87
`3 Hydrophobic
`....................... B7
`4Van derWaale ..............
`.
`.
`.
`.
`.
`.
`87
`AFFINITY MEASURES STRENGTH OF BINDING OF
`ANTIGEN AND ANTIBODY ...............
`The avidity of antiserum tor antigen — the bonus etiect
`oi multlvalency ...................... .
`THE SPECIFICITY OF ANTIGEN RECOGNITION
`BY ANTIBODY IS NOT ABSOLUTE ............. 90
`WHAT THE T-CELL SEES .................
`91
`Haplotype restriction reveals the need tor MHC participation
`.
`.
`.
`91
`T-celisrecognlzeaIlnearpeptidesequenoe tromtheantlgen .
`.
`.
`91
`PROCESSING OF INTRAOELLULAR ANTIGEN
`FOR PRESENTATION BY CLASS! MHC
`......... 92
`PROCESSING OF ANTIGEN FOR CLASS II MHC
`.
`PRESENTATION FOLLOWS A DIFFERENT PATHWAY .
`.
`THE NATURE OF THE ‘GROOVY’ PEPTIDE .
`.
`.
`.
`.
`.
`Binding to MHC class I ....................
`Binding to MHC class It ...................
`THE up T-CELL RECEPTOR FORMS A TERNARY
`98
`.
`.
`.
`COMPLEX WITH MHO AND ANTIGENIC PEPTIDE .
`Topology of the ternary complex ................. 99
`T-CELLS WITH A DIFFERENT OUTLOOK ......... 99
`Non-classical class I molecules can also present antigen ...... 99
`MHC class I-llke molecules .................... 99
`The family or CD] non-MHC class l-like molecules can
`99
`present exotic antigens .................... .
`75 Time have some features of antibody .......... .
`.
`. 100
`SUPERANTIGENS STIMULATE WHOLE FAMILIES
`OF LYMPHOCYTE RECEPTORS ............... too
`Bacterial toxins represent one major group of T-cetl
`superantigens ......................... 100
`Endogenous mouse mammary tumor viruses (MMTV) act
`as superantigens ........................ 100
`Microbes can also provide B-eell superantlgens
`......... iOi
`
`.
`
`.
`.
`
`.
`.
`
`.
`
`88
`
`88
`
`93
`96
`96
`97
`
`Lassen — Exhibit 1045, p. 4
`
`Lassen - Exhibit 1045, p. 4
`
`

`

`CONTENTS
`
`vll
`
`THE RECOGNITION OF DIFFERENT FORMS OF ANTIGEN
`BY 3- AND T-GELLS IS ADVANTAGEOUS TO THE
`Hosr ............................. 101
`suMMARY .......................... 102
`FURTHER READING ..................... 103
`
`PART 3 - TECHNOLOGY
`
`6 - Immunochemlcaltechnlques.107
`
`ESTIMATION OF ANTIBODY ................ 107
`Antlgen~ontlbody interactions in solution
`............ 1 07
`What does serum ‘antibody confenl’ mean? .......... 107
`The classical preclpitin reaction ................ 1 09
`Nonprecipltating antibodies can be detected by nephelometry .
`. 109
`Complexes formed by nonprecipiiating antibodies can
`be precipitated ........................ 1 10
`Enhancement of precipitation by countercurrent
`immunoelectrophoresls .................... 1 1 0
`Measurement of antibody affinity ............... 1 10
`Agglutlnatlon of antigen-coated particles ............ r 111
`Immunoassay for antibody using solid-phase antigen ....... 1 12
`The principle ......................... 112
`A wide variety of labels is available .............. 1 13
`ELISA (enzyme-linked immunosorbent assay) ........ 113
`Other labels ........................ 1 13
`Surface plasmon resonance .................. 114
`IDENTIFICATION AND MEASUREMENT OF ANTIGEN.
`.
`. 114
`Precipitation reactionccn be carried out In gels
`......... 114
`Characterization of antigens by electrophoresis and
`immunafixation ....................... 114
`Quantification by single radial lmmunodli‘fusion (SRID)
`.
`.
`.
`.
`.
`i 15
`The nepheiometric assay for antigen ............... 115
`Sodium dodecyl sulfate-polyacryiomide gel electrophoresis
`(SDS—PAGE) for analysis of lmmunoprecipiiates and
`immunoblotting ........................ 118
`The immunoassay otontigens
`................. 117
`immunoassay on multiple mlcrospots
`.......... .
`. 118
`Epliope mapping ........................ 118
`T-celi epitopes ........................ I 18
`B-ceil epitopes ........................ 1 19
`DETECTION OF IMMUNE COMPLEX FORMATION .
`.
`.
`. 120
`MAKING ANTIBODIES TO ORDER
`............ 120
`The monoclonal antibody revolution ............... 120
`First in rodents ........................ 120
`Catalytic antibodies ..................... 121
`Human monoclonals can be made ............... 123
`Engineering antibodies ..................... 124
`Fields of antibodies
`..................... 125
`Drugs can be based on the (mm: of minibodles ......... i215
`PURIFICATION OF ANTIGENS AND ANTIBODIES
`BY AFFINITY CHROMATOGRAPHY ............ 126
`NEUTRALIZATION OF BIOLOGICAL ACTIVITY ...... 127
`To detect antibody ...................... 127
`Using antibody as an inhibitor ................. 127
`SD M MARY .......................... 123
`FURTHER READING ..................... 129
`
`7 - Cellularteclrnlques. 130
`ISOLATION OF LEUKOCYTE SUBPOPULATIONS ..... 130
`
`Bulk techniques ......................... 130
`Separation based on physical parameters ........... 130
`Separation exploiting biological parameters ..... .
`.
`.
`.
`. 131
`Selection by antibody mating ..... .
`. .......... 131
`Cell selection by the FACS .................... 131
`Enrichment of antigen-specific populations ............ 131
`IMMUNOHISTOCHEMISTRY — LOCALIZATION
`OF ANTIGENS IN CELLS AND TISSUES
`......... 133
`lmmunofluorescence techniques ................ 133
`Direct test with labeled antibody ............... 134
`Indirect testforantlbody ................. . 134
`High resolution with the confocal microscope ..... .
`.
`.
`r 135
`Flow cytofluorimetry ..................... 135
`The detection and isolation of rare cells ...... . ..... 137
`Other labeled antibody methods ................. 139
`Localization in tissues of a gene product
`........... . 139
`ASSESSMENT OF FUNCTIONAL AGTIVITY ........ 140
`The activity of phagocytic cells .................. 140
`Lymphocyte responsiveness ................... 140
`Limiting dilution analysis .................... 140
`Enumeration of antibody-forming cells ........ . ..... 140
`The immunofluorsscence sandwich test ............ 140
`Plaque techniques ...................... 141
`Analysis of functional activity by cellular reconstitution
`. ..... 142
`Radiation chimeras ...................... 142
`Mice with severe combined immunodeficiency (SCID) ...... 142
`Cellular intercclions In vitro .................. 142
`Probing function With antibodies . ................ 143
`GENETIC ENGINEERING 0F CELLS ............ 144
`insertion and modification of genes in mammalian cells
`.
`.
`.
`.
`.
`. 144
`introducing new genes into animals ......... .
`.
`.
`.
`.
`. 144
`Establishing ‘designer mice’ bearing new genes ........ 144
`Transgenes introduced Into embryonic stem cells ........ 144
`Gene therapy in humans .................. 145
`SUMMARY .............. - ............ 147
`FURTHER READING ..................... 148
`
`PART 4 - THE ACQUIRED IMMUNE
`R E S P 0 N S E
`
`8 ' The anatomy 01'th Immune response, 151
`THE SURFACE MARKERS OF CELLS IN THE IMMUNE
`SYSTE M ........................... 1 51
`THE NEED FOR ORGANIZED LYMPHOID TISSUE ..... 151
`LYMPHOCYTES TRAFFIC BETWEEN LYMPHDID
`TISSUES ........................... 153
`
`Lymphocytes home to their specific tissues ............ 153
`Tronsmlgratlon occurs in three stages .............. 153
`Step 1 : Tethering and rolling
`................. 153
`Step 2: [12 lntegrln activation and cell flattening
`........ 154
`Step 3:Transmlgratlan Into the tissue (diapedesls)
`.
`.
`.
`.
`.
`.
`. 154
`A closer look atthe interacting receptors and their ligands ..... 156
`ENCAPSULATED LYMPII NODES .............. 156
`B-cell areas ........................... I56
`T-ceil areas ........................... 157
`SPLEEN ............................ 158
`MUCOSAL-ASSOCIATED LYMPHOID TISSUE (MALT).
`.
`, 161
`Intestinal lymphocytes ..................... 162
`BONE MARROW CAN BE A MAJOR SITE OF ANTIBODY
`SYNTHESIS .......................... 162
`
`Lassen — Exhibit 1045, p. 5
`
`Lassen - Exhibit 1045, p. 5
`
`

`

`vIli
`
`CONTENTS
`
`. 163
`THE ENJOYMENT OF PRIVILEGED SITES ....... .
`THE HANDLING OF ANTIGEN ............... 163
`Macrophages are general antigen-presenting cells ........ 163
`Interdlgltctlng dendritic cells present antigentoT—Iymphocytes
`.
`.
`. 164
`Follicular dendrlllc cells stimulate B-celis in germinal centers
`.
`.
`. 165
`M-celis provide the gateway to the mucosal lymphoid system .
`.
`. 166
`SUMMARY ........................
`166
`FURTHER READING ....................
`167
`
`9 - Lymphocyte activation. 168
`IMMUNOCOMPETENT T- AND B-CELLS DIFFER IN
`MANY RESPECTS ...................... 168
`T-LYMPHOCYTES AND ANTIGEN-PRESENTING CELLS
`INTERACT THROUGH SEVERAL PAIRS OF ACCESSORY
`MOLECULES ......................... 169
`THE ACTIVATION OF T-CELLS REGUIRES
`TWO SIGNALS
`. ..................... 169
`PROTEIN TYROSINE PHOSPHORYLATION IS AN EARLY
`EVENT IN T-CELL SIGNALING ............... 170
`DOWNSTREAM EVENTS FOLLOWING TCR
`171
`SIGNALING ....................
`The phosphattdylinosltol pathway ................ 171
`p21 rastunction ........................ 171
`Control at iL-2 gene transcription ................. 171
`Further thoughts on the control at T-celi trl|gering ......... 171
`A serial TOR engagement model for T—cell activation
`...... 171
`Damping T-cell enthusiasm ................ ,
`I73
`B-CELLS RESPOND TO THREE DIFFERENT TYPES
`OF ANTIGEN ......................... 173
`I Type‘l thymus-Independentantlgsns .............. I73
`2 Type 21hymus-independent antigens ............. .
`I73
`3 Thymus~dependentantigens .................. 174
`The need for collaboration with T-helper cells
`......... 174
`Antigen processing by B—cells ................. 174
`THE NATURE OF II-CELL ACTIVATION ........... 176
`B-cells are stimulated by cross-linking surface lg ......... 176
`T—helper cells activate resting B-ceils ............... 177
`SUMMARY .
`.
`. ...................... I77
`FURTHER READING ..................... 178
`
`10 ~ The production of effectors. 179
`A SUCCESSION OF GENES ARE UPREGULATED
`. 179
`SY T-CELL ACTIVATION ............... .
`. 179
`CYTOKINES A01 A5 INTERCELLULAR MESSENGERS .
`Cytcklne action to transient and usually short range ........ 180
`Cytokines act through cell surface receptors ........... 180
`The gp 130 subfamily .................... 182
`The [to and ya receptor subfamilies .............. 182
`Signal transduction through cytoklne receptors .......... 182
`Cytokines often have multiple effects .............. , 182
`Network Interactions ...................... 1 83
`DIFFERENT CD4 T-CELL SUSSETS CAN MAKE
`DIFFERENT CYTOKINE PATTERNS ............. 184
`
`The bipolarTHr/Tuz concept ................
`Interactions with cells of the Innate immune system may bias
`the Trn/Trrz response ..................
`ACTIVATED T-CELLS PROLIFERATE IN RESPONSE
`TO CYTOKINES ......................
`
`.
`
`184
`
`. 185
`
`186
`
`. 186
`T-CELL EFFEGTORS IN CELL-MEDIATED IMMUNITY ,
`Cytoklnes mediate chronic inflammatory responses ........ 186
`Early events ........................
`186
`Chemotaxls ........................
`187
`Macrophage activation .................... 187
`Combatingvirai infection ................. . 187
`KillerT—cells .......................... 188
`Thegenerationofcytotoxichcells
`.
`.
`,
`,
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`. 188
`The lethal process ............. .
`.
`.
`.
`.
`.
`.
`188
`Inflammation mustberegulatea ..............
`.
`. 189
`PROLIFERATION AND MATURATION OF B-CELL
`RESPONSES ARE MEDIATED BY CYTOKINES ...... 189
`WHAT IS GOING ON IN THE GERMINAL CENTER?
`.
`.
`. 190
`THE SYNTHESIS OF ANTIBODY .............. 191
`IMMUNOGLOBULIN CLASS SWITCHING OCCURS
`IN INDIVIDUAL I-CELLS .................
`Class-switched B-ceils are subject to high mutation rates after
`the initial response ....................... 193
`FACTORS AFFECTING ANTIBODY AFFINITY
`IN THE IMMUNE RESPONSE ................ 194
`The effect otantigen dose .................
`194
`Maturation ofaftiniiy ................... .
`. 195
`MEMORY CELLS ......................
`195
`The memory population Is not simply an expansion of
`corresponding naive cells .................... 196
`SUMMARY ....................... .
`198
`FURTHER READING .................. .
`. 199
`
`192
`
`- Control mechanisms, 201
`'II
`ANTIGEN IS.A MAJOR FACTOR IN CONTROL ...... 201
`Antigens can Interfere with each other .............. 202
`ANTIBODY EXERTS FEEDBACK CONTROL ........ 202
`T-CELL REGULATION .................... 203
`T—helper cells ........ ~,‘ ................. 203
`T-cell suppression
`_
`.
`,
`. .................. 204
`Suppressor and helper epitopes can be discrete ........ 204
`Characteristics of suppression ................. 204
`Suppression due to T—Tinteraction an antigen-presenting cells .
`. 206
`Etiector T-cells are guided to the appropriate target by MHG
`. 207
`.
`surface molecules ................. .
`. 207
`.
`IDIOTYPE NETWORKS .............
`.
`.
`Jeme’s networkhypothesis ................. . 207
`Evidence for ldlotypic networks ................. 208
`Anti-Idlotype can be Induced by dutologous idlotypes ...... 208
`A network ls evident in early life
`.
`.
`.
`.
`.......
`.
`.
`. 208
`T-ceils can also do it ....................
`209
`Preoccupation of networks with salt ............... 209
`ldlotypic regulation of Immune responses ............. 210
`Manipulation of the immune response through ldlotypes ...... 21 1
`THE INFLUENCE OF GENETIC FACTORS ......... 213
`Some genes atfect general responsiveness ............ 213
`immune response linked to Immunoglabulln genes ........ 213
`Immune response can be influenced bythe MHC ......... 213
`The Ir genes map to the H-2I region and control T—B
`cooperation ......................... 214
`ARE THERE REGULATORY IMMUNONEUROE NDOCRINE
`N ETWORKS? ......................... 216
`A neuroendocrine feedback loop affecting immune responses
`,
`. 216
`Sex hormones come into the picture
`.
`.
`.
`. -........... 217
`
`Lassen — Exhibit 1045, p. 6
`
`Lassen - Exhibit 1045, p. 6
`
`

`

`CONTENTS
`
`Ix
`
`PART 5 '
`
`I M M U N I TY TO IN F E CT I 0 N
`
`Inching towards ‘psycholmmunology’ ------------- 2‘ 7
`EFFECTS OF DIET. EXERCISE, TRAUMA AND AGE
`an IM MUNITV
`--------------------
`Malnutrition diminishes the effectiveness of the Immune
`response ____________________________ m INFLAMMATION REVISITED ................ 254
`otherfociors
`I
`I
`I
`I
`I
`I
`I
`I
`.
`I
`.
`I
`I
`I
`I
`I
`I
`I
`.
`I
`I IIIII 2,9
`Mediators otlnflammation ................... 254
`SUM MARY IIIIIIIIIIIIIIIIIIIIIIIII 22°
`Leukocytes bind to endothelial cells through paired adhesion
`fuRTHER READING ..................... 221
`"WWW“ --------------------------- 255
`Initiation of the acute inflammatory response ........... 255
`The ongoing Inflammatory process ............... . 256
`Regulation and resolution of Inflammation ............ 257
`°h'°"'°'"“°mm°"°n -------------------- 253
`EXTRAOELLULAR sAcTERIA SUSGEPTIBLE To KILLING
`BY PHAGOGYTOSIS AND coNIPLENENT ......... 258
`BOCISIIUISUIVIVCIISII’OIOQIGS ................... 258
`Mum PhagflcviOS'S -------------------- 258
`Challengtng the complement “3'9” -------------- 259
`Antigenic variation ..................... t 260
`The IIOSI GOIJnter-attack ..................... ZGQ
`Toxin neutralization ---------------------- 25‘
`Opsonlzallon °I ”00'9”“ ------------------- 26‘
`Some turther effects of complement .............. 263
`The secretory immune system protects the external mucosal
`surfaces ------------------------- 263
`Some specific bacterial infections.
`.
`.
`. ............. 265
`““5“" WHICH GROW I" A" '"TnAcELI-ULAR
`HABITAT --------------------- 267
`Bacterlal gamblts ---------------------- 267
`Defense '5 ”V T‘cell-mediated Immunity (CMI) ----------- 268
`Activated macrophages klII Intracellular parasites ......... 268
`Examples of Intracellular bacterial infections ........... 269
`”5'9”“ -------------------- *
`-
`. 269
`T”°°'°”'°5'5 ------------------------ 269
`LBWOSV -
`-
`-
`.
`. ----------, ----------- 271
`IMMUNITY T0 VIRAL INFECTION .
`.‘ ........... 271
`Immunity can beevaded by antigen CIIOIIQBB ........... 271
`Changing antigens by drift and shift .............. 271
`MUIOIIOI'I can produce antagonistic T-CGII GDIIODBS ...... 272
`5°” viruses 9“" affect antigen processing ----------- 272
`Viruses can interfere with immune effector mechanisms ...... 272
`”05""?! games with the complement system --------- 272
`Suboiaalna cell-mediated Immunity .............. 272
`Protection by serum antibody .................. 273
`Localtactors """"""""""""""""" 273
`Cell-mediated immunity gets to the Intracellular virus ....... 273
`NK cells can Kill vitally imacled targets ............. 273
`‘CYIOIOXIGT-CSIISCICJ arecruclaleiements in immunityto
`infection bV budding viruses -------------- 275
`Cyteklnes rscrult effectors and provide a ‘ccrdon sanitalre‘
`.
`.
`. 275
`A"”bOdV has a part '00 ------------------- 275
`'M M" N ”Y 1'0 FUNG' ---------------- .
`‘
`-
`- 275
`IMMUNITY To PARASITIO INEEcTIONs ......... 276
`The “”8? “WWW ---------------------- 276
`””mml'mmunlw
`--------------------- 277
`09”'m°d'0*9f“mmun"v -------------------- 275
`EVOSIvIe strategies bylhe parasite ................ 279
`Resfsfmm WWI-Ir mecmnlsms -------------- 279
`AVOIdIIIg antigen [SCOQIIIIIOII byihe IIOSI .......... I
`. 280
`Deviation of the host immune response ............ 281
`'mmunopfllhmgv ----------------------- 23‘
`
`-
`
`. 2‘ 8
`
`13 - Adversarial strategies during infection. 253
`
`12 ' omoge'W 0M phylogeny, 223
`TIIE MULTIPOTENTIAL HEMATOPOIETIG STEM cELL
`GIVES me To THE roRNEo ELEMENTS
`or THE BLOOD IIIIIIIIIIIIIIIIII 223
`THE THYMUS PROVIDES THE ENVIRONMENT
`FOR ME LL DIFFERENTIATION ........... 225
`Bone marrow stem cells become immunocompetent T-ceils
`in thethymus IIIIIIIIIIIIIIIIIIIIIIIII 226
`T- c E I. I. 0“ TOG E N y IIIIIIIIIIIIIIIII 227
`Differentiation is accompanied by changes in surface markers
`.
`.
`. 227
`Receptor rearrangement .................... 228
`The development of up receptors IIIIIIIIIIIIIII 229
`The development atyfi receptors IIIIIIIIIIIIIII 229
`Cells are positively selected for self-MHc restriction In the thymus .
`. 229
`T-GELL TOLERANCE IIIIIIIIIIIIIIIIIIII 23]
`The induction of Immunological tolerance is necessaryto ovoid
`self-reactivity ......................... 231
`Self—tolerance can be induced In the thymus ............ 231
`Intrathymlc clonal deletion leads to self-tolerance ......... 23]
`Factors aftectln| positive or negative selection In the thymus I
`I
`I 233
`T-ceII tolerance can be due ,0 clonal energy IIIIIIIIIIII 234
`Infectious anergy ...................... 235
`Look of communication can cause unresponsiveness ....... 235
`s-cELLs DIFFERENTIATE IN THE FETAL LIVER
`AND THEN III BONE MARROW IIIIIIIIIIIIIII 236
`B" AND 3.2 CELLS REPRESENT Two DISTINCT
`[)0 I)“ LATIO N s IIIIIIIIIIIIIIIIIIIIIII 237
`DEVE LOPM E NT 0 F B-GE I.I. sp ECIFICITY IIIIIIIII 233
`The sequence of immunoglobulin gene rearrangements ...... 238
`The Importance of allelic exclusion IIIIIIIIIIIIIIII 240
`Different specific responses can appear sequentially ....... 240
`THE moucno" or mun”; m
`3 . Ly M p H 0 0" Es IIIIIIIIIIIIIIIIIIIIII 240
`Tolerance can be caused by clonal deletion and clonal anergy
`.
`.
`. 240
`Tolerance may result from helpless B-cells IIIIIIIIIIII 241
`THE OVERALL RESPONSE I" THE NEONATE
`IIIIII 243
`THE EVOLUTION OF THE IMMUNE RESPONSE IIIIII 243
`Recognition of self is fundamental for multicellutar organisms
`.
`.
`. 243
`Invertebrates have microbial defense mechanisms IIIIIIII 244
`Adaptive Immune responses appear with the vertebrates ...... 245
`Lower vertebrates ,,,,,,,,,,,,,,,,,,,,,, 245
`Hensappea, IIIIIIIIIIIIIIIIIIIIIIII 245
`Generation or antibody diversity ................ 247
`THE Ev0LuTI0N or elsrlNcT E- AND T-cELL
`LINEAeEs was AccoMPANIEo sv THE DEVELOPMENT
`or SEPARATE srrEs F01! DIFFERENTIATION ...... 247
`CELLULAR ItEcoeNITION MOLECULES EXPLOIT
`THE IMMUNOGLOUULIN GENE SUPERFAMILY IIIIII 247
`Sun MARY IIIIIIIIIIIIIIIIIIIIIIIIII 243
`FURTHER READING ..................... 250
`
`Lassen — Exhibit 1045, p. 7
`
`Lassen - Exhibit 1045, p. 7
`
`

`

`CONTENTS
`
`. ...... 281
`.
`.
`SUMMARY ........ . ....... .
`FURTHER READING ..................... 284
`
`14 - Prophylaxis, 285
`PASSIVELY ACCUIRED IMMUNITY ............. 285
`Maternaliy acquired antibody .................. 287
`Pooled human ygiobulln .................... 287
`Cultured antibodies made to order ............... . 287
`Adoptive transfer of cytotoxic T-celis ............... 288
`VACCINATION ........................ 288
`Herd immunity ......................... 288
`Strategic considerations .................... 288
`KILLED ORGANISMS AS VACCINES ........... 288
`LIVE ATTENUATED ORGANISMS HAVE MANY
`ADVANTAGES As VACCINES ................ 289
`Classical methods of attenuation ................ 290
`Attenuation by recombinant DNA technology ............ 290
`Microbial vectors for other genes ................. 290
`Constraints on the use of ahenuated vaccines ........... 293
`SUBUNIT VACCINES CONTAINING INDIVIDUAL
`PROTECTIVE ANTIGENS .................. 283
`The use of purified components ................. 293
`Antigens can be synthesized through gene cloning ........ 294
`The naked gene itself acts as a vaccine .............. 295
`EPITOPE-SPECIFIC VACCINES MAY BE NEEDED ..... 298
`Epitopes can be mimicked by synthetic peptides ......... 297
`B-celi epitopes ........................ 297
`T—celi epitopes ........................ 297
`Making the peptides immunogenic ............... 298
`Idiotypes can be exploited as options-specific vaccines ...... 299
`Unwanted epitope-ioss mutants can correctly fold desired
`discontinuous 8-cell epitopes .................. 299
`CURRENT VACCINES .................... 299
`EXPERIMENTAL VACCINES IN DEVELOPMENT ...... 300
`Malaria ............................. 300
`Schlstosomiasis ......................... 302
`Cholera ............................ 303
`Tuberculosis .......................... 303
`ADJ UVANTS ......................... 303
`Depot effects .......................... 303
`Macrophage activation ..................... 304
`Specific effects on lymphocytes ................. 304
`NEW APPROACHES TO THE PRESENTATION
`OF ANTIG E N ......................... 304
`SUM MARY .......................... 305
`FURTHER READING ...... l .............. 307
`
`PART 6
`
`CLINICAL IMMUNOLOGY
`
`15 - Immunodeficiency. 31 l
`PRIMARY IMMUNODEFICIENCY STATES
`IN THE HUMAN ....................... 311
`DEFICIENCIES 0F INNATE IMMUNE MECHANISMS .. . 311
`Phagocyfic cell defects ..................... 311
`Complement system deficiencies ................. 312
`Defects in control proteins ................... 312
`Deficiency of components of the complement pathway ..... 31 3
`PRIMARY B-CELL DEFICIENCY ............... 314
`
`PRIMARY T-CELL DEFICIENCY ............... 315
`COMBINED IMMUNODEFICIENCY ............ 317
`Mutation in the common cytokine receptoryc chain causes SCID .
`. 317
`SCID can be due to mutations In purine salvage
`pathway enzymes ....................... 317
`OtherSClD variants ....................... 317
`RECOGNITION OF IMMUNODEFICIENCIES ........ 317
`SECONDARY IMMUNODEFICIENCY ............ 318
`ACQUIRED IMMUNODEFICIENCY SYNDROME (AIDS).
`. 319
`AIDS results from infection by a human immunodeficiency virus
`(HIV) ............................. 319
`The infection of cells by HIV .................... 319
`The AIDS infection depletes helper T-cells ............. 321
`Natural history of the disease ................. 321
`Mechanisms of depletion ................... 323
`Diagnosis of AIDS ....................... 324
`The control of AIDS ....................... 324
`Identifying protective immune responses ............ 324
`The development of animal models .............. 325
`other therapeutic strategies .................. 325
`5U M MARY .......................... 326
`FURTHER READING .................... 327
`
`18 - Hypersensitivity, 328
`iNAPPROPRiATE IMMUNE Responses CAN LEAD
`TO TISSUE DAMAGE .................... 328
`TYPE I —ANAPHYLACTIC HYPERSENSITIVITY ...... 329
`The phenomenon of anaphyiaxis ................. 329
`Human anaphylactlc an