`
`ROITT’S |
`
`ESSENTIAL
`IMMUNOLOGY
`
`Ivan Roitt
`
`
`
`Lassen - Exhibit 1043, p. 1
`
`

`

`© 1971, 1974, 1977, 1980, 1984, 1988,
`1991, 1994, 1997 by Blackwell Science Ltd
`Editorial Offices:
`Osney Mead, Oxford OX2 0EL
`25Jolin Street, London WC1N 2BL
`23 Ainslie Place, Edinburgh EH3 6AJ
`350 MainStreet, Malden
`MA 021485018, USA
`54 University Street, Carlton
`Victoria 3053, Australia
`
`Other Editorial Offices:
`
`Blackwell Wissenschafts-Verlag GmbH
`Kurfiirstendamm 57
`10707Berlin, Germany
`Zehetnergasse 6
`A-1140 Wien
`Austria
`
`All rights reserved. No part of
`this publication may be reproduced,
`stored in a retrieval system, or
`transmitted, in any form or by any
`means, electronic, mechanical,
`photocopying,recordingor 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., Hong Kong
`Printed and boundinItaly
`by Rotolito Lombarda S.p.A., Milan
`
`The Blackwell Sciencelogoisa
`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
`Fourthedition 1980, Reprinted 1982, 1983
`Fifth edition 1984
`Sixth edition 1988, Reprinted 1988
`Reprinted with corrections 1989
`Seventh edition 1991
`Fighth edition 1994, Reprinted 1996
`Ninthedition 1997
`
`Spanisheditions 1972, 1975, 1978, 1982,
`1988, 1989, 1993
`Italian editions 1973, 1975, 1979, 1986,
`1988, 1990, 1993, 1995
`Portuguese editions 1973, 1979, 1983
`Frencheditions 1975, 1979, 1990
`Dutcheditions 1975, 1978, 1982
`Japanese editions 1976, 1978, 1982, 1986, 1988
`Germaneditions 1977, 1984, 1988, 1993
`Polish edition 1977
`Greek editions 1978, 1989, 1992
`Turkishedition 1979
`Slovak edition 1981
`Indonesian editions 1985, 1991
`Russian edition 1988
`Korean edition 1991
`ELBSeditions 1977, 1982, 1988, Reprinted 1991
`Chinese (Taiwan) edilions 1991, 1994
`
`DISTRIBUTORS
`Marston BookServices Ltd
`PO Box 269
`Abingdon
`Oxon OX14 4YN
`(Orders: Tel: 01235 465500
`Fan: 01235 465555)
`
`USA
`Blackwell Science, Inc,
`Commerce Place
`350 MainStreet
`Malden, MA 02148 5018
`(Orders: Tel: 800 759 6102
`617 388 8250
`Fan: 617 388 8255)
`
`Canada
`Copp Clark Professional
`200 Adelaide St West, 3rd Floor
`Toronto, Ontario M5H 1W7
`(Orders: Tel: 416 597-1616
`800 815-9417
`Fan: 416 597-1617)
`
`Australia
`Blackwell Science Pty Ltd
`54 University Street
`Carlton, Victoria 3053
`(Orders: Tel: 3 9347 0300
`Fax: 3 9347 5001)
`
`Catalogue recordsforthis title
`are available from the British Library
`and the Library of Congress
`ISBN 0-86542-729-1
`
`Lassen - Exhibit 1043, p. 2
`
`Lassen - Exhibit 1043, p. 2
`
`

`

`iTne
`CONTENTS
`
`Target calls are told to commit suicide
`Eosinophils
`SUMMARY
`
`2 + Specific acquired immunity, 22
`THE NEED FOR SPECIFIC IMMUNE MECHANISMS
`ANTIBODY — THE SPECIFIC ADAPTOR
`.
`.
`Antibody initiates a new complement pathway (classical)...
`Complexed antibody acilvates phagooyticcalls .. 2...
`CELLULAR BASIS OF ANTIBODY PRODUCTION
`Antibodies aremade bylymphocyles........,.+0, 006
`Antigen selects tha lymphocytes which make antibody
`The need for clonal expansion means humoral Immunity must
`be acquired
`ACQUIRED MEMORY
`Secondary entlbody responsesare better
`ACQUIRED IMMUNITY HAS ANTIGEN SPECIFICITY .. .
`Discrimination between different antigens
`Discrimination betweenself ond nonself
`VACCINATION DEPENDS ON ACQUIRED MEMORY
`CELL-MEDIATED IMMUNITY PROTECTS AGAINST
`INTRACELLULAR ORGANISMS ......,..,.,.4.4
`Cytokine-producing T-cells help macrophagesto kill intracellujar
`parasites 6 ee
`Virally Infected cells can be killed by cytotoxic T-cells and
`ADCC
`(MMUNOPATHOLOGY...................5.
`SUMMARY
`FURTHER READING ...,.,.,......-.....005%
`Generalreading
`Reference work
`.
`Historical
`In-depth serles forthe advanced reader... ... 2...
`Current Information 2. ee
`Mulliplecholce questions»... ee ee
`Electronic publications (linked fo ‘Roitt’s Essanilal
`Immunology)
`Mojorjourndls 2... 02. eee ee ee
`
`xiv
`
`xix
`
`8 8
`
`10
`
`1 V
`
`W
`VW
`VW
`
`W1
`
`2
`12
`12
`12
`14
`
`16
`16
`18
`18
`18
`
`PREFACE... 2... 05. eet
`
`ACKNOWLEDGEMENTS ............-2.2505
`
`ABBREVIATIONS ..........4.5
`
`USER GUIDE .. 0... oe ee He Ma ADS AE
`
`PART 1
`
`- THE BASIS OF IMMUNOLOGY
`
`Innate immunity, 3
`-
`Tt
`EXTERNAL BARRIERS AGAINST INFECTION
`PHAGOCYTIC GELLS KILL MICROORGANISMS
`Polymorphs and macrophages are dadicated ‘professional’
`phagocyles 2 ee es
`The polymorphonuclear neutrophll .. 22... ee ee
`Themacrophage «6et
`Microbes are engulfed by phagocytosis. .......,04 ene
`There ls an array ofkilingmechonisms.........,....
`Killing by reactive oxygen Intermediates .....,..,.6%
`Killing by reactive nitrogen intermedidies ...........5
`Killing by preformed antimicrobials... .....,..0005
`tte ae
`COMPLEMENT FACILITATES PHAGOCYTOSIS
`Complement andttsacilvation. .. 1... 1. eee ee
`C3 undergoas slow spontaneous cleavage...
`. 2... we
`C3b levels are normallytightly controlled... ...,..00%
`G3 convertase is stabilized on microblat surfaces... .....
`The post-C3 pathway genarates a membrane affock complex
`.
`Complement has a range of defensive biological functions .... .
`1 G3b adheres to complement recepfors .........00.
`2 Biologically active fragments arereleased «ww. ww,
`3 The ferminal complex can induce membranelesions
`COMPLEMENT CAN MEDIATE AN ACUTE
`INFLAMMATORY REACTION
`. 6. ee te
`The most cell playsacentralrole.
`Macrophages canaleodoit ... 0.0.0.0 eee eee es
`HUMORAL MECHANISMS PROVIDE A SECOND
`DEFENSIVE STRATEGY .......,. 000004 vues
`Acuts phase profeins Increase In response tointection.......
`Interferons Inhibit viral replication 2... ee
`EXTRACELLULAR KILLING ,....,..,. 0.00045
`Natural killer (NK)calls
`. ok ee ee
`
`Lassen - Exhibit 1043, p. 3
`
`Lassen - Exhibit 1043, p. 3
`
`

`

`vl
`
`CONTENTS
`
`Complementgenescontribute to the remaining classIll region
`oftheMHG ........5.
`72
`GenemapofthaMHG . 6-6. es .
`75
`The genes of the MHC display remarkable polymorphism . ws
`Nomenclature 6.ee 75
`InherllanceoftheMHG 2. ee .
`77
`The tissue distribution of MHC molecules
`6 we 77
`MHGiunctlons 2... 77
`SUMMARY 0.6... ee 78
`FURTHER READING ... 2.0... ere tees
`70
`
`PART 2
`
`THE RECOGNITION OF ANTIGEN
`
`3: Antibodies, 43
`
`43
`
`THE BASIC STRUCTURE IS AFOUR-PEPTIDE UNIT ...
`AMINO ACID SEQUENCES REVEAL VARIATIONS IN
`45
`IMMUNOGLOBULIN STRUCTURE.............,
`45
`IMMUNOGLOBULIN GENES...........,.,,..
`45
`Immunoglobulins ara encoded by muttiple gena segments...
`.
`.
`Aspeclal mechanism effects VDJrecombingflon
`........., 46
`STRUCTURAL VARIANTS OF THE BASIC
`IMMUNOGLOBULIN MOLECULE ........,,..., 47
`ISOWPBS ee ee 47
`AllotypeS© ee 47
`IdlofypeBee 50
`IMMUNOGLOBULINS ARE FOLDED INTO GLOBULAR
`DOMAINS WHICH SUBSERVE DIFFERENT
`FUNCTIONS... 0... ee ee eee 50
`Immunoglobulin domalns have a characteristic structure»... .
`50
`The variabledomain bindsantigen........,...,.0.-
`5]
`Constant region domains determine secondarybiological funciion .
`51
`IMMUNOGLOBULIN CLASSES AND SUBCLASSES
`...
`51
`Immunoglobulin G has major bul varied roles in extracellular
`defenses 2ee 53
`Activation of the classical complement pathway ........ 53
`The diversity of Feyrecepfors 6. ey 54
`Nonprecipltating ‘univolent antibodies ..,..,.....,.. 57
`\mmunoglobulin A guards the mucosal surfaces 6... 57
`Immunoglobulln M provides o defense against bacteremia...
`.
`.
`58
`Immunoglobulin D Isacellsurfacerecepfor......
`59
`Immunoglabulln E triggers inflammatory reactions ........ 58
`immunoglobulins are further subdividedinto subeiasses
`» as
`60
`SUMMARY 0.0. 61
`FURTHER READING .........,.,..,.....04 62
`
`4 - Membrane receptors for antigen, 63
`THE B-GELL SURFACE RECEPTOR FOR ANTIGEN .... 63
`The B-cell inserts o transmembrane Immunoglobulin into
`IWSSUIMDCRwe 83
`The surface immunoglobulin is complexed with associated
`Membrane proteins... ee ee 64
`THE T-CELL SURFACE RECEPTOR FOR ANTIGEN ....
`65
`The receptorfor antigen Is o transmembrane heterodimer...
`.
`.
`65
`There ore two classes of T-cellrecaptors 5... wl kk 65
`The encoding of T-cell receptorsIs similar to that of
`immunoglobulins 2. ee .
`The CD3 complexis an integral part of the T-cell receptor...
`.
`.
`.
`THE GENERATION OF DIVERSITY FOR ANTIGEN
`RECOGNITION ©... , ee eee ee 68
`Intrachain amplification of diversity... .....,.,.,
`..
`69
`Random VDJ combination Increases diversity geometrically...
`89
`Ployingwiththe junctions
`6 ee 69
`Intarchainamplification .. 60... ae ee ee 70
`Somatichypermutation 2... ee ee 70
`THE MAJOR HISTOCOMPATIBILITY COMPLEX
`(MHG) 2 ees 7
`Glass | and clase Il molscules are membrane-bound
`hetercdimeré 2. ee ee ee 7)
`MHCclass}] «0 ee et ee 71
`MHGclossIt 0... ee ee 71
`
`66
`67
`
`83
`83
`
`88
`
`5 - The primaryInteraction with antigen, 80
`WHAT IS AN ANTIGEN? 2... 0.0.00. - 00000 80
`Ofepitopes and antigen determinants «6.
`1 eee ee es
`81
`(dentiflcation of B-cellepifopes 6 ee 81
`ANTIGENS AND ANTIBODIES INTERACT BY SPATIAL
`COMPLEMENTARITY NOT BY GOVALENT BONDING ...
`Variation in hapten structure shows importance of shape
`.....,
`Spatial complementarity of apliope and paratope can be
`demonstrated we ee 83
`Antigen-antibady bonds ore readily reversible
`6 6. es 84
`THE FORCES BINDING ANTIGEN TO ANTIBODY
`BECOME LARGE AS INTERMOLECULAR DISTANCES
`BECOME SMALL ...... 0.0.00 eeu eee reece 86
`TElectrostatic 86
`2Hydrogenbonding
`.. 6. ee ee 87
`BHydrophobic ws 87
`AVondarWadle
`. 1. es 87
`AFFINITY MEASURES STRENGTH OF BINDING OF
`ANTIGEN AND ANTIBODY .......,.--- 0000-5 88
`The avidity of antiserum for antigan — the bonuseffect
`ofmultivalency 6. ee ee
`THE SPECIFICITY OF ANTIGEN RECOGNITION
`BY ANTIBODY IS NOTABSOLUTE .......-.-55.
`WHAT THE T-CELL SEES .......-.. 5-60 pees
`Haplotyperestriction reveals the need for MHC participation ....
`T-cells recognizea IInearpeptide sequence fromthe antigen... ,
`PROCESSING OF INTRACELLULAR ANTIGEN
`FOR PRESENTATION BYCLASSIMHC.........
`PROCESSING OF ANTIGEN FOR CLASS II MHG
`93
`PRESENTATION FOLLOWS A DIFFERENT PATHWAY ., .
`THE NATURE OF THE'GROOVY’ PEPTIDE ........ 96
`BindingtoMHCclasst 2 ee 96
`BindingtoMHCclassi. 97
`THE of T-CELL RECEPTOR FORMS A TERNARY
`98
`COMPLEX WITH MHC AND ANTIGENIC PEPTIDE ....
`Topology of the ternarycomplex 2. es 99
`T-CELLS WITH A DIFFERENT OUTLOOK ......... 99
`Non-classical class | molecules can also presentantigan. ... .
`.
`99
`MHC classI-likKamolecules. © ee ee 99
`The family of CD1 non-MHCclassI-like molecules can
`prasentexoiicantigens 2.6... eee ee 99
`ySTCRs have somefeatures ofantibody «1... 2. ere uae 100
`SUPERANTIGENS STIMULATE WHOLE FAMILIES
`OF LYMPHOCYTE RECEPTORS .........+,5045% 100
`Bacterlal toxins represent one major groupofT-cell
`superontigens 6. ee eb 100
`Endogenous mause mammary tumorviruses (MMTV) act
`assuperantigens .. 6... ee ee ee ee ee 100
`Microbes con algo provide B-call superanfigens
`..,,..... 101
`
`90
`91
`91
`91
`
`92
`
`Lassen - Exhibit 1043, p. 4
`
`Lassen - Exhibit 1043, p. 4
`
`

`

`CONTENTS
`
`vil
`
`THE RECOGNITION OF DIFFERENT FORMS OF ANTIGEN
`BY B- AND T-CELLS IS ADVANTAGEOUS TO THE
`HOST .. 0. ee 101
`SUMMARY ........ 00.000... eee 102
`FURTHER READING ..................08, 103
`
`TECHNOLOGY
`PART 3
`6 «
`Immunochemical techniques, 107
`ESTIMATION OF ANTIBODY ...........,.... 107
`'
`—-
`:
`
`Bulktechniques .. 1... we ee ee 130
`Separation based on physical parameters ........... 130
`Seporation exploiting biological parameters ........ .. 13)
`Selection byantibodycocting ......... 00050500 e 131
`CeilselectionbytheFACS 5.2... ee ee ee 131
`Enrichment of antigen-specific populations ............ 7131
`IMMUNOHISTOCHEMISTRY — LOCALIZATION
`OF ANTIGENS INCELLS AND TISSUES
`......... 133
`Immunofluosescence techniques 2... eee ee 133
`Direct test with labeled antibody
`=. ww. ee ee 134
`;
`.
`Indirect testforantisody
`6 ww ee es 134
`
`— eee eee ee lmllUm
`
`ASSESSMENT OF FUNCTIONAL ACTIVITY ........ 140
`
`High resolution with the confocal microscope... ..+.5- 135
`lnfare sees a toy
`The classical precipitinreaction ........,....,4. 109 Rees ofrarecells SESS i
`Nonpreclpltating antibodies can be detected by nephelometry .
`. 109
`Other tabeled antibody methods
`........... sees 139
`sdsweramed by nonprecipitating antibodiescan
`10
`Localization intissues ofa gene product
`....... .
`138
`ae. igypounvereuurreth
`119
`__‘Theactivtyof phagooyliccelS ev eee eee 140
`Measurementofantibodyaffinity ........0... 1. 110
`ieneni rere eee eee Gd SH a i
`Agglutination of antigen-cooledpariices ............. 1 sieeea we
`Immunoassayfor antibody using solld-phase antigen ....... 12
`.
`V
`OMS
`se es meme wee
`Theprinciple oe ee ee eevee en 112
`The immunofluorescence sondwichtest 1... ee ee 140
`Awlde variety of labelsisavailable ........,...... 13 es eg BE Py ass Lill
`ELISA (enzyme-linked immunosorbent assay)... .
`.
`13
`Analysis offunctional activity by cellular reconstilution ..... . 142
`Other labels
`i 113
`Radistionchimeras ... 0.0.0... 0.00 ee ee ee 142
`Surface plasmonresonance ee 114
`Mice with severe combined immunodeficiency (SCID)... ... 142
`IDENTIFICATION AND MEASUREMENT OF ANTIGEN, .. 114
`Sacteeaoerr ee ee es ai ic
`‘ i
`Precipitation reactioncan be carried outingels
`........, 114
`GRRE ENGINEERING OFCELLSSTE ENE 144
`ik ofantigens byelectrophoresisand
`114
`Insertion and modification ofgenesin mammaliancells... .
`« 144
`.
`. il cuecisanimee |”;
`Infroducing new genesintognimdls .........,.6605 144
`Stoneeteee aan a
`Establishing ‘designermice’ bearing newgenes ........ 144
`Sodium dodecyl sulfate-polyacrylamidegel electrophoresis ee@MbryonleSOM CBE «+ ge vein» i
`(SDS-PAGE)for analysis of Immunoprecipitates and
`SUMMARY
`Pyinmumans
`vse pe | |
`| Be RE 147
`immunoblotting 6... ee ee V6enpeampn I es ,
`Thelmmunoossay ofantigens
`...,,,..-. 0,0 e WW7
`FURTHER READING ©...) 061s um in
`n M46
`Immuncassay on multiplemicrospots
`.. 1... ee 118
`Epiiopemapping 2... ee eee 118
`Toellepopes oe ee eee 118
`B-cellepliopes 6 ee es 119
`8 - The anafomyof the immune response, 151
`DETECTION OF IMMUNE COMPLEX FORMATION .... 120
`THE SURFACE MARKERS OF CELLS IN THE IMMUNE
`Fomaedinalctyatete pene sents 100
`aeee i THE NEED FOR ORGANIZED LYMPHOID TISSUE... .. 151
`rm snonbolonotefaciefide 123
`~—=CLYMPHOCYTES TRAFFIC BETWEEN LYMPHOID
`grblla a ie a a i Lymphocytes home tothelrspecifictissues ...........,4 153
`Drugs can be based onthe CDRsofminibodies......... 125 wafidigegarinaiSages eee ee i33
`
`PURIFICATION OF ANTIGENS AND ANTIBODIES phymeningandromng ee Pe 154
`BY AFFINITY CHROMATOGRAPHY ............ 126
`Step 2: By Integrin activation andcellfiattening
`....,..,
`NEUTRALIZATION OF BIOLOGICAL ACTIVITY
`127
`Step 3: Transmigration into the tissue (diapedesis) ....... 154
`To detact antibody
`cae 127
`A closerlook atthe Interacting receptors and thelr ligands ,.... 156
`Using antibodyasoninhibitor .. 1... ee 127
`EneAESOESTEDIEVMED WEDESea «B+ - 0+ os -
`SUMMARY
`128
`B-oellareos.. ee ey
`re Tecelloregs 2. es
`FURTHER READING ......,...... 0.02045 129
`SPLEEN.................. 0-0 eee. 158
`MUCOSAL-ASSOCIATED LYMPHOID TISSUE (MALT)... 161
`Intastina) lymphocytes... ee ee 162
`BONE MARROW CAN BE A MAJOR SITE OF ANTIBODY
`SYNTHESIS. ............0 ccc ceceeuee 162
`
`PART 4 - THE ACQUIRED IMMUNE
`RESPONSE
`
`pp ene srs
`
`SYSTEM 2. ee ee ee 151
`
`Shops srs sss
`
`TISSUES 2... ee ee ee 153
`
`7 + Cellular techniques, 130
`IsOLATION OF LEUKOCYTE SUBPOPULATIONS ..... 130
`
`Lassen - Exhibit 1043, p. 5
`
`Lassen - Exhibit 1043, p. 5
`
`

`

`vill
`
`CONTENTS
`
`THE ENJOYMENT OF PRIVILEGED SITES..,......, 163
`THE HANDLING OF ANTIGEN .............4. 163
`Macrophagesare general antigen-presentingcells ........ 163
`Interdigitailng dendritic cells present antigen io T-lymphocytes
`.
`.
`. 164
`Follicular dendritic cells stimulate B-cells in germinal centers
`... 165
`M-calls provide the gateway to the mucosal lymphold system ... 166
`SUMMARY ......0.000 0.0.0. . 0c eee een 168
`FURTHER READING ....,....,..,.,.....44
`167
`
`9 - Lymphocyte activation, 168
`IMMUNOCOMPETENT T- AND B-CELLS DIFFER IN
`MANYRESPECTS........,....,,, 00 pueee 168
`T-LYMPHOCYTES AND ANTIGEN-PRESENTING CELLS
`INTERACT THROUGH SEVERAL PAIRS OF ACCESSORY
`MOLECULES ©... 1... ee ee 169
`THE ACTIVATION OF T-CELLS REQUIRES
`TWOSIGNALS 2.0... ee 169
`PROTEIN TYROSINE PHOSPHORYLATION IS AN EARLY
`EVENTINT-CELLSIGNALING .............., 170
`DOWNSTREAM EVENTS FOLLOWING TCR
`SIGNALING 2... WI
`The phosphatidylinosito| pathway... 2... ee ee 7
`p2lrasfunction 2... ep ee 171
`Control of IL-2 gene transcription.
`. 2.2... -, 0.03 00 5
`171
`Further thoughts on the control of T-ceil triggering... ....., 71
`Aserlal TCR engagement modelfor T-cell activation
`...... 171
`Damping T-cellenthusiasm 2... ...........008. 173
`B-CELLS RESPOND TO THREE DIFFERENT TYPES
`OF ANTIGEN... 0... ee es 173
`1 Type 1 thymus-independentantignns .......-...00% 173
`2 Type 2 thymus-independent antigens .... , be eee 173
`SThymus-dependentantigens 6.2... 00.0.2 0200, . 174
`The needfor collaboration with T-helpercellg 2.2... cu 174
`Antigen processing byB-calls
`.. 2... et ee 174
`THE NATURE OF B-CELL ACTIVATION, ....,......% 176
`B-cells are stimulated by cross-linking surface lg... . sy ae 176
`T-halper cells activate restingB-cells
`. 6... ee 77
`SUMMARY 1.0.0.0... 0.0.02 cee ees 177
`FURTHER READING ......,.....,....
`-....
`178
`
`10 - The production of effectors, 179
`A SUCCESSION OF GENES ARE UPREGULATED
`BY T-CELL ACTIVATION ©... eee ee 179
`CYTOKINES ACT AS INTERCELLULAR MESSENGERS ,
`. 179
`Cytakine action fs trangfent and usually shortrange ... 1... 180
`Cytokines act through cell surface receptors»... 2... a, 180
`Thegp 130 subfamily
`2 2 ee 182
`The Bc and yo receptor subfamilies
`2. ..,...,7. eee 182
`Signal transduction through cyfokine receptors ....,,,.., 182
`Cytokines often have muliipleeffects ... 0.0.0... 0. ua 182
`Network interactions
`. 2... ee ee 183
`DIFFERENT CD4 1-CELL SUBSETS CAN MAKE
`DIFFERENT CYTOKINE PATTERNS ...,........, 184
`The bipolar THi/TH2concepf .........,.,-0000 25 184
`Interactions with ceils of the Innate immune system may bias
`the THI/TH2fesponse we ee ee 185
`ACTIVATED T-CELLS PROLIFERATE IN RESPONSE
`TOCYTOKINES ...,.,,..,,.. 0.00 ean, 186
`
`T-CELL EFFECTORS IN CELL-MEDIATED IMMUNITY ., 186
`Cytokines mediate chronic inflammatory responses ....... 186
`Earlyevants 2.2... . ee ee ee »
`186
`Chemotaxls 2...ee 187
`Macrophage activation 2... ee 187
`Combating viralinfectlon 2... ee ee . 187
`KillerT-cells we ee 188
`The generation of cytotoxic T-cells 6... ......0.0,
`.. 188
`Thelethalprocass 6 ee ee 188
`Inflammationmustbereguidfed 6... ee ee 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
`INEINDIVIDUAL B-CELLS............,...04.
`Class-switched B-cells are subject to high mutation rates after
`theinitialresponse 6. . ee ee 193
`FACTORS AFFECTING ANTIBODY AFFINITY
`IN THE IMMUNE RESPONSE ................ 194
`Theeffectofantigandose ...,..,,,,.....0..
`..
`194
`Maturation ofaffinity 2... ee ee .. 195
`MEMORY CELLS ...,...........,-0-0005- 195
`The memory population Is not simply an expansion of
`.. 196
`correspondingnalveceligé ........,......04.,
`SUMMARY 2.0... eee _. 198
`FURTHER READING .,...,...........4,
`..
`199
`
`192
`
`11 + Control mechanisms, 201
`ANTIGEN IS.A MAJOR FACTOR INGONTROL ....., 201
`Antigens can interfere witheachother ... 0.2.0... 4
`6 202
`ANTIBODY EXERTS FEEDBACK CONTROL ....., »
`«+ 202
`JT-CELL REGULATION 3 .........,,. 0.40, 0050.4 203
`Thelparcelis ......., Pe HE 203
`T-callsuppression
`....,ee eye 204
`Suppressor and helper epitopes canbediscrete ........ 204
`Characteristics of suppression, 2.2... 0.004,
`.. 204
`Suppression due to T-T interaction on antigen-presenting cells .
`. 206
`Effector T-cells are guided fo the appropriate target by MHC
`207
`surfacemolaculas ... 2...
`0. ...., 0 eee aey
`207
`IDIOTYPE NETWORKS ..,.......,.....
`.,
`dJerne’snetworkhypothesis 2, ...0....,., 000005 207
`Evidence forldiotypicnetworks 2.6... eee ee 208
`Anti-Idiotype can be Induced by autologous Idlotypes ... 2.
`. 208
`Anetwork isevidentinearlylifa
`.....,,......,0, 208
`Toollscanalsodoit ©. ee ee eg 209
`Preoccupation of networks withself 6... ..,. ee 209
`Idlotypic regulation of lmmune responses. ........,,., 210
`Manipulation of the immune response through idiotypes...
`.
`.
`, 211
`THE INFLUENCE OF GENETIC FACTORS ........., 213
`Some genes affeci general responsiveness ...,.,...,, . 213
`Immuneresponse I[nked to !mmunoglobulingenes ........ 213
`Immune response can be Influenced bytheMHC ....,..~.. 213
`The fr genes mapto the H-2I region and control T-B
`cooperation .ee 214
`ARE THERE REGULATORY IMMUNONEUROENDOCRINE
`NETWORKS? ©... . eee ee 216
`A neuroendocrine feedback loop offecting immune responses
`.. ; 216
`Sex hormones comeintothapicture 2. ....,,..,.0..4 217
`
`Lassen - Exhibit 1043, p. 6
`
`Lassen - Exhibit 1043, p. 6
`
`

`

`CONTENTS
`
`PART 5 -
`
`IMMUNITY TO INFECTION
`
`... 1.0... ses 217
`Inching towards ‘psycholmmunology’
`EFFECTS OF DIET, EXERCISE, TRAUMA AND AGE
`ONIMMUNITY «0.12 eee eee reo 218
`Malnutrition diminishesthe effectiveness of the Immune
`FSO eee vice es ven veeaes 218
`OtherfactorSs 6 ee ee ee 219
`SUMMARY .........0,0 0.000 eee eas 220
`FURTHER READING ......,....0 00.000 uee 221
`
`13 - Adversarial strategies during infection, 253
`INFLAMMATION REVISITED ..............., 254
`Mediators of Inflammation 6... ea ee 254
`Leukocytes bind to andothelial cells through palrad adhesion
`MOWCUIES ee ee ee eee 255
`Inittatlon of the acute inflammatoryresponse ,...... 0. » 255
`The ongoing inflammatory procasB.. 5... ee ee . 256
`Regulation and resolution ofinflammation .,........., 257
`12 + Ontogeny and phylogeny, 223
`Chronic inflammation 6. ee 268
`THE MULTIPOTENTIAL HEMATOPOIETIC STEM CELL
`EXTRACELLULAR BACTERIA SUSCEPTIBLE TO KILLING
`GIVES RISE TO THE FORMED ELEMENTS
`BY PHAGOCYTOSIS AND COMPLEMENT ........, 258
`OFTHEBLOOD .....,.,......000-. 223
`Bacterial survival strafegles 6... ee ee 258
`THE THYMUS PROVIDES THE ENVIRONMENT
`Evading phagocytosis... ee 258
`FOR T-CELL DIFFERENTIATION ........2., 225
`Challenging the complement system... .........0. 259
`Bone marrow stem cells become immunocompetentT-cells
`Antigenicvoriation «6... ee 260
`inthathyMUS 6 ee 226
`Thehostcounter-atack 6... ee 260.
`T-CELLONTOGENY.........,.,...4004 207
`Toxin neutralization. es see ee eee tere 261
`Differentiation is accompanied by changes In surface markers.
`.
`. 227
`Opsonizotion of bacteria «1... ee ee . 261
`Receptor rearrangement ......... 0... cece ee 228
`Some furthereffects of complement ............4, 263
`The development oforeceptors ..........0000. 229
`The secrefory immune system protects the external mucosal
`The development of ySreceptors
`2 ow. ek ee 229
`BUTTOCES ow ee 263
`Cells are positively selected for self-MHCrestriction in the thymus.
`. 229
`Somespecific bacterial infectlons..............0. , 266
`T-CELL TOLERANCE ....,... 0,0 v ev euuus 231
`BACTERIA WHICH GROW IN AN INTRACELLULAR
`Theinductionof immunological tolerance is necessary to avoid
`HABITAT© 267
`self-reocivity 6 ee ey 231
`Baclerialgombits eee 267
`Self-tolerance can be induced Inthethymus,........... 231
`DefenseIs by T-cell-mediated immunity(OMI). ee 268
`Intrathymle cional deletion laadsto self-tolerance 2 =... 231
`Activated macrophagesklll Intracellular parasifes ........., 268
`Factors affecting posifive or nagatlve selaction inthe thymus.
`.
`, 233
`Examplesof infracellular bacterial infections ........,,. 268
`T-cell tolerance can be duetoclonalonergy............ 234
`Usted ee eee 260
`Infectousanergy 2 eee 235
`Tuberculosis». ee eee 269
`Lack of communication can couse unresponsiveness 2... 236
`LOPFOSY ee ee eee 271
`B-CELLS DIFFERENTIATE IN THE FETAL LIVER
`IMMUNITY TO VIRAL INFECTION .2...,....... 271
`AND THEN IN BONE MARROW............... 236
`Immunity can be evaded by antiganchanges ......mm . a 27
`B-1 AND B-2 CELLS REPRESENT TWO DISTINCT
`Changing antigens by driftandshiff «. ke ee 271
`POPULATIONS
`..........0ecc0veveuue |. 237
`Mutation can produce antagonistic T-cell epitopes 6... . 272
`DEVELOPMENT OF B-GELL SPECIFICITY......... 238
`Someviruses con affect antigen processing. .......... 272
`The sequence of immunoglobulin gene rearrangements ..... . 238
`Viruses can interfere with immune effector mechanisms ..,.,. 272
`The importance ofallelicexclusion. .....5..0 ee eae 240
`Playing games with the complement system ......,... 272
`Different specific responses can appear sequentially ....... 240
`Sabotaging cell-mediated immunity .. 0... -.., 000, 272
`THE INDUCTION OF TOLERANCE IN
`Protection byserumantibody 2... ... cpp eee 273
`B-LYMPHOCYTES ..........,......0e000- 240
`Localfaciors ©... ee ee ee ee eee 273
`Tolerance can be caused by clonal deletion and clonal anergy
`.
`.
`. 240
`Cell-mediated immunity gets to the intracellularvirus ... 2... 273
`Tolerance may result from helpless B-cell ..,........, 241
`NK ceils cankill virally infectedtargets ©. 2... ee 273
`THE OVERALL RESPONSE IN THE NEONATE
`...... 243
`‘Cytotoxic T-cells (Tc) are crucial elements In Immunity to
`THE EVOLUTION OF THE IMMUNE RESPONSE...... 243
`infection by budding viruses... ee 275
`Recognition ofself is fundamental for multicellular organisms
`.. . 243
`Cytokines recrult effactors and provide a ‘cordon sanitaire’
`=.
`.
`, 275
`Invertebrates have microbial defense mechanisms ........ 244
`Adaptive Immune responses appearwith the vertebrates... . , 245 Antibodyhasaparttoo 275
`Lowervertebrates 5.0. ee ee 245 IMMUNITYTO FUNG! ,. 0... 00.sce reve 275
`
`Toallsappear sss wee 945
`IMMUNITY TO PARASITIC INFECTIONS ........ . 276
`Generation of antibody diversily 6... 0... ee. eee , 247
`The host responses... . Pe eens ris. 278
`THE EVOLUTION OF DISTINCT B- AND T-CELL
`Humoralimmunity 6. 277
`LINEAGES WAS ACCOMPANIED BY THE DEVELOPMENT
`Call-mediated mmunity. ee oo. 278
`OF SEPARATE SITES FOR DIFFERENTIATION .,.... 247
`Evasive strategies bythe parasitg
`.. 1... se eye eee 278
`CELLULAR RECOGNITION MOLECULES EXPLOIT
`Resistance to effector mechanisms ..... 1,1... 279
`THE IMMUNOGLOBULIN GENE SUPERFAMILY ..,.. . 247
`Avoiding antigen recognition bythehost
`. .... 2... 1 +s 280
`SUMMARY ........ 0000 cyueeueeeunvue 248
`Daviation of hehostimmuneresponse
`. 1-1. ee 281
`FURTHER READING............,......2, 250
`Immunopathology «ee ee es 28)
`
`Lassen - Exhibit 1043, p. 7
`
`Lassen - Exhibit 1043, p. 7
`
`

`

`CONTENTS
`
`SUMMARY 2.0. wee es eye ace wesocenie oe 28)
`FURTHER READING... 2. 2. cee eee 284
`
`14 + Prophylaxis, 285
`PASSIVELY ACQUIRED IMMUNITY.......,...,. 285
`Maternally acquiredantibody ........,,- 2.00 2s eee 287
`Pooledhumany-globulin 2.0... eee ee ee 287
`Cultured antibodies madefoorder .... 11. ee 287
`Adoptive transfer of cytoloxic T-cells 2.0... cu ee ee 288
`VACCINATION ........-... 00,0... 050424 Ge 288
`Herdimmunfy 2... 0 ee ee ee ee ee 288
`Strategic considerations 5. kk te ee 288
`KILLED ORGANISMS AS VACCINES
`..........,. 288
`LIVE ATTENUATED ORGANISMS HAVE MANY
`ADVANTAGES AS VACCINES .........,...005056 289
`Classical methods of atienudtion 5.2... ee ee 290
`Atfenuation by recombinant DNAtechnology...,....... . 290
`Microblal vectors forothergenes.... 0.0... cee ees 290
`Constraints on the use of attenuated vaccines... ...-. 04s 293
`SUBUNIT VACCINES CONTAINING INDIVIDUAL
`PROTECTIVE ANTIGENS ......-.......465 «+ 203
`The use of purified components ...... ee ee 293
`Antigens can be synthesized through genecioning
`.......% 294
`The naked gene itselfacisasavaccine.......... 200s 295
`EPITOPE-SPECIFIC VACCINES MAY BE NEEDED. .... 296
`Epitopes can be mimicked by synthetic peptides ......... 207
`Becallepitopes 6. ee ee 297
`Vcellepitopes6 297
`Making the peptidesimmunogenic........ (ore pe ace 208
`Idfotypes can be exploited as epltops-specific vaccines .,.... 299
`Unwanted epltope-loss mutants can correctly fold destred
`discontinuous B-cellapitopes
`6 www 2209
`CURRENT VACCINES ....,....... 0... 0000 os 299
`EXPERIMENTAL VACCINES IN DEVELOPMENT. ..... 300
`Malgrld. ee ee +. 800
`Schistosomiasis.
`. 2. 0, ke ee ee eae ee 302
`Cholefo 1. ee ee ee 303
`Tuberculosis 2. eee ee 303
`ADJUVANTS 200 ee ee ea 303
`Depoteffects . 0. ee ee ee 303
`Macrophage activation ©... . eee ee ee 304
`Specific effectsonlymphocytes .......... 000080 5 304
`NEW APPROACHES TO THE PRESENTATION
`OF ANTIGEN... 0. eee ee ee 304
`SUMMARY 2. ce ee ee ee ee 305
`FURTHER READING... 2.2... 2. eee eae 307
`
`PART 6
`
`CLINICAL IMMUNOLOGY
`
`Immunodeficlency, 311
`15 -
`PRIMARY IMMUNODEFICIENCY STATES
`INTHE HUMAN ...... 0... cee 311
`DEFICIENCIES OF INNATE IMMUNE MECHANISMS ... 311
`Phagocyticcelidefects 2... ... te ee we 311
`Complement system deficienclés..........,,.0004 312
`Defects Incontrolprotelns.........00.20 2c ae 312
`Daficlancy of components of the complement pathway .... . 313
`PRIMARY B-CELL DEFICIENCY.........,...,.. , 314
`
`PRIMARY T-CELL DEFICIENCY. ....,........4. 315
`COMBINED IMMUNODEFICIENCY ........,.., 317
`Mutation In the commoncytokine receptor y, chain causesSCID ,
`. 317
`SCID can be due fo mutationsIn purine salvage
`pathwoyenzymes
`. 1... ee ee . 317
`OtherSCiDvariants . 1...ke 317
`RECOGNITION OF IMMUNODEFICIENCIES..,...... 317
`SECONDARY IMMUNODEFICIENCY ............ 318
`ACQUIRED |MMUNODEFICIENCY SYNDROME (AIDS). . 319
`AIDSresults from infection by a human immunodeficiency virus
`CHM) Ce ee 319
`The infection ofcellsbyHiV.......0.. 00... 00 cae a1
`The AIDSInfection depletes helperT-calls ©. ......,..4. 321
`Natural history offhediseasa 5... ee 321
`Mechanisms ofdeplefon .. 2... ee ee ee 323
`Diognosisof AIDS 2. ee eee 324
`ThacontrolofAIDS 6. ee eae 324
`Identifying protective Immune rasponses ............ 324
`The development ofanimol models .......,....4. 325
`Other therapautlc strategies 5... ee vo, 325
`SUMMARY .., 0.0. vee ee 326
`FURTHER READING 2... . ic eee eee 327
`
`16 - Hypersensitivity, 328
`INAPPROPRIATE {MMUNE RESPONSES CAN LEAD
`TOTISSHE DAMAGE
`...,,,.,... 000 0evaae 328
`TYPE | —ANAPHYLACTIC HYPERSENSITIVITY... ... 329
`The phenomenon ofanaphyiaxig .... 1 ke, 329
`Human anaphylactic antibodies ore mainly gE. .....,.4, 330
`Anaphylaxis is triggered by clustering of IgE receptors on mast aalis
`througheross-linking 2... cee te te ee ee 330
`Alopicallegy. ee ee ee . 331
`Clinical responses toinhaledgilergens ....,......,. 331
`Foodallagy .,..... P.+.o-op- +). a: 333
`Eflological factors In the developmentof atopic allergy .... . 333
`Clinical testis for allergy 3... ke ee 334
`Therapy oe ee ee ee 334
`Allargenavoldance . ow. ee ee 334
`Modulation of the immunologicalresponse =... 1... 335
`Mastcellstobllization ©... .. 0... eee ee 335
`Medjatoraniagonism 2. 6... ee te a 337
`Atlacking chronic inflammation. .......,.,..44 337
`TYPE |] — ANTIBODY-DEPENDENT CGYTOTOXIG
`HYPERSENSITIVITY .........,.,.060, 337
`TypeIl reactions between members of ihe same species
`(allolmmune) 6. ee 338
`Transfusionreactions 6... ee 338
`Rhesus Incompotibilify
`.. 2... 0... e ee eee 339
`Orgontransplanis 5... ee ee 339
`Autoimmunetype |i hypersensitivity reactions ..........., 340
`Wpelidrugreactiongs .. we ee 340
`TYPE I1t—IMMUNE COMPLEX-MEDIATED
`HYPERSENSITIVITY ©... 0.00... 0.00 y ree 341
`Inflammatory lesions due fo locally formed complexes... .. 342
`TheArthusreaction 6 ee es 342
`Reactions toinhofedaniigens -. 2... ee ee 342
`Reactlonstotnternaianfigens .. 6-1. ee 343
`Diseaseresulting from circulating complexes... 2... , 344
`Serumsickness
`. 0... pe ee ee 344
`
`Lassen - Exhibit 1043, p. 8
`
`Lassen - Exhibit 1043, p. 8
`
`

`

`CONTENTS
`
`xl
`
`. 2. ee ee 344
`Immune complex glomerulonephritis.
`Deposition of Immune complexes at othersites .. 1... 1 es 345
`Jreatment.ee 346
`TYPE IV — CELL-MEDJATED (DELAYED-TYPE)
`HYPERSENSITIVITY ©2002... . 0000002020034 346
`The cellular basis of type IV hypersensifivity ..... 0... ee 346
`Tissue damage produced by type !V reactions... . 1... 0 347
`InfecHlONS we ee 347
`Contact dermatitis 2... ee ee 348
`Tn2-mediated hypersensitivity ©... ee ee ee 348
`Otherexamples 2... ee et eee ea eee 348
`TYPE V —STIMULATORY HYPERSENSITIVITY ...... 348
`‘INNATE’ HYPERSENSITIVITY REACTIONS ........ 349
`SUMMARY acs
`tee ere eae eee eatw BE eee see tae 350
`FURTHER READING
`... 0.2... 0.2 c eee 352
`
`17 « Transplantation, 353
`......., 353
`GRAFT REJECTION IS IMMUNOLOGICAL
`Firstandsacondsetreactions .. 1... ee ee es 354
`Specificity 2. ee ee ee 354
`Roleoffhalymphooyte ........,.0- 0... 0508 354
`Productionofantibodies 2.0... 0,0... 02-0000 e 355
`GENETIC CONTROL OF TRANSPLANTATION
`ANTIGENS 2.0... - ce eee 356
`SOME OTHER CONSEQUENCES OF MHG
`INCOMPATIBILITY «0... 0... eer eee reas 358
`Class |] MHC differances produce a mixed lymphocyte reaction
`(MLR)2 ee 356
`The groft-vs-host(g.v.h. reaction 2... -
`1 ee pp eae 356
`MECHANISMS OF GRAFT REJECTION ...,...... 357
`Lymphocytes con mediaterajaction
`..........~0. 1». 357
`The allograft response is powerful .,..-...... 00050, 358
`Theroleofhumoratantibody 2.0... . ee ee ee 359
`THE PREVENTION OF GRAFT REJECTION ......,. 359
`Mofching tissue types on graff donorandrecipient ......,., 359
`Methodsforfissuetyping 6... pe ee ee ee 360
`The polymorphism of the human HLA-system ....... »
`« 362
`The value of matchingtissue types... 1... 5.000 362
`Agents producing general Immunosuppression ,...,.....,- 363
`Targeting lymphoid populations ..,.........4. ,» 363
`Tofal lymphoid Irra