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:
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`First published 1971
`Reprinted 1972 (twice), 1973 (twice)
`Second edition 1974, Reprinted 1975
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`
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`
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`
`Lassen — Exhibit 1043, p. 2
`
`Lassen - Exhibit 1043, p. 2
`
`

`

`_ C
`
`ONTENTS
`
`Target cells are told to commit suicide
`Ecslnophils
`SUM MARY
`
`2 - Specific acquired Immunity, 22
`THE NEED FOR SPECIFIC IMMUNE MECHANISMS
`ANTIBODY — THE SPECIFIC ADAPTOR
`Antibody initiates a new complement pathway (‘classical’) .....
`Complexed antibody activates phagocytlc cells ..........
`CELLULAR BASIS OF ANTI BODY PRODUCTION
`Antibodies are made by lymphocytes ...............
`Antigen selects the lymphocytes which make antibody
`The need for clonal expansion means humeral Immunity must
`be acquired
`ACCUIRED MEMORY
`Secondary antibody responses are better
`ACQUIRED IMMUNITY HAS ANTIGEN SPECIFICITY . ..
`Discrimination between different antigens
`Discrimination between self and noneeli
`VACCINATION DE PENDS 0N ACDUI RED MEMORY
`CELL-MEDIATED IM MUNITY PROTECTS AGAINST
`INTRACELLULAR ORGANISMS ...............
`Cytokine-produclng T—cells help macrophages to kill Intracellular
`parasites ............................
`Virally Infected cells can be killed by cytotoxic T-cells and
`ADCC
`IMMUNOPATHOLOGY .....................
`SUM MARY
`FURTHER READING ....................
`General re'adlng
`Reierence work
`.
`Historical
`In-depth series for the advanced reader .............
`Current Information .....................
`Multiple choice questions ...................
`Electronic publications (linked to ‘Roltt‘s Essential
`Immunology)
`Major journals ......................
`
`22
`22
`23
`25
`25
`25
`26
`
`26
`28
`28
`30
`30
`32
`32
`
`33
`
`33
`
`33
`35
`35
`37
`37
`37
`3B
`38
`38
`38
`
`39
`39
`
`xiv
`
`xix
`
`8 9
`
`10
`II
`11
`11
`11
`11
`12
`12
`12
`12
`14
`
`16
`16
`18
`18
`18
`
`PREFACE ..............
`
`ACKNOWLEDGEMENTS ...................
`
`ABBREVIATIONS ...........
`
`USER GUIDE ............... . .........
`
`PART 1
`
`- THE BASIS OF IMMUNOLOGY
`
`Innate immunity, 3
`-
`I
`EXTERNAL BARRIERS AGAINST INFECTION
`PHAGOCYTIC CELLS KILL MICROORGANISMS
`Poiymarphs and macrophages are dedicated ‘professional’
`phagocytes ..........................
`The poiymorphonuclear neutrcphll ...............
`The macrophage .......................
`Microbes are engulfed by phagocytosis ............ .
`.
`.
`There Is an array of killing mechanisms ..............
`Killing by reactive oxygen Intermediates ............
`Killing by reactive nitrogen intermediates ............
`Killing by preformed antlmlcroblals ...............
`......
`COMPLEMENT FACI LITATES PHAGOCYTOSIS
`Complement and Its activation ..................
`CB undergoes slow spontaneous cleavage ...........
`03b levels are normally tightly controlled ............
`03 convertase is stabilized on microbial surtaces ........
`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
`COMPLEMENT 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 .
`.
`.
`.
`.
`.
`.
`lnterterons Inhibit viral replication ................
`EXTRACELLULAR KILLING .................
`Natural killer (NK) cells ....................
`
`Lassen — Exhibit 1043, p. 3
`
`Lassen - Exhibit 1043, p. 3
`
`

`

`VI
`
`CONTENTS
`
`PART 2
`
`THE RECOGNITION OF ANTIGEN
`
`Complement genes contribute to the remaining class III region
`ofthe MHC ..........
`
`3 - Antibodies, 43
`
`43
`
`.
`
`.
`
`THE BASIC sreucrune Is A FOUR-PEPTIDE UNIT .
`MIN ACID sequences REVEAL VARIATIONS IN
`IMMUNOGLOBULIN STRUCTURE .............. 45
`IMMUNOILOBULIN IENES ................. 45
`lmmunogloballns are encoded by multiple gens segments ..... 45
`A special mechanism effects VDJ recombination ......... 4B
`STRUCTURAL VARIANTS OF THE sAsIc
`IMMUNOGLOBULIN MOLECULE ,,,,,,,,,,,,,, 47
`lsotypes ............................ 47
`Allolypes ............................ 47
`ldlotypee ............................ 50
`IMMUNOGLOBULINS ARE FOLDED INTO GLOBULAR
`DOMAINS WHICH SUBSERVE DIFFERENT
`FU N CTIC N S .......................... 50
`lmmunoglcbulln domains have a characteristic structure ..... 50
`The variable domain binds antigen ................ 51
`Constant region domains determine secondary biological function .
`5T
`IMMUNOGLOBULIN CLASSES AND SUBCLASSES
`.
`.
`.
`51
`lmmunoglobulln G has major but varied roles in extracellular
`defenses ............................ 53
`Activation of the classical complement pathway ........ 53
`The diversity of FC'y receptors ................. 54
`Nonprecipltaling ‘univalent‘ antibodies ............. 57
`lmmunoglobulin A guards the mucosal surtaces ......... 57
`lmmunogiobuiln M provides a defense against bacteremla ..... 58
`Immunoglobulln D Is a cell surface receptor ,,,,,,,,,,,, 59
`Immunoglabulln E triggers inflammatory reactions ........ 59
`lmmunaglcbulins are further subdivided into subclasses
`.
`.
`.
`.
`.
`60
`SU MMARY .......................... 61
`FURTHER READING ..................... 92
`
`63
`
`.
`
`.
`
`.
`
`4 - Membrane receptors for antigen, 63
`THE B-CELL SURFACE RECEPTOR FOR ANTIGEN ,
`The B-cell inserts a Iransmembrane Immunoglobulln into
`Its surface ........................... 63
`The surface immunoglobulin ls complexes with associated
`membrane proteins ....................... 64
`THE T-CELL SURFACE RECEPTOR FOR ANTIGEN .
`.
`.
`.
`65
`The reaeptorfor antigen Is a trcnsmembrane heterodlmer .....
`65
`There are two classes of T-cell receptors ............. 65
`The encoding of T-oell receptors Is slmllarto that of
`66
`lmmunoglobullns ....................... .
`The CDS complex is an integral part of the T-cell receptor ...... 67
`THE GENERATION OF DIVERSITY FOR ANTIGEN
`RECOGNITION
`....................... 68
`Infrachaln amplification of diversity .............
`.
`.
`69
`Random VDJ combination Increases diversity geometrically .
`.
`.
`69
`Playing with the junctions .................. 89
`Interchain amplification ..................... 70
`Somatic hypermulatlon ..................... 70
`THE MAJOR HISTOCOMPATIBILITY COMPLEX
`(MHC) ............................ 71
`Glass | and class II molecules are membrane-bound
`heterodlmers .......................... 7i
`MHC class I ......................... 71
`MHC class It ......................... 71
`
`72
`.
`Gene map ofthe MHC ....................
`The genes at the MHC display remarkable polymorphism ..... 75
`Nomenclature ........................ 75
`Inheritance of the MHC ................... .
`77
`The tissue distribution of MHC molecules
`............ 77
`MHC Iuncflons ........................ 77
`SUMMARY .......................... 78
`FURTHER READING ....................
`79
`
`.
`.
`
`.
`.
`
`83
`83
`
`5 - The primary Interaction with antigen, 80
`WHAT Is AN ANTIGEN? ................... so
`Ofepitopes and antigen determinants .............. 81
`identification of B-cell epitopes ................. 81
`ANTIGENS AND ANTIBODIES INTERACT BY SPATIAL
`COMPLEMENTARITY NOT BY COVALENT BONDING .
`Variation In hapten structure shows importance of shape
`.
`.
`,
`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
`BECOME SMALL ....................... 86
`i Electrostatic
`....................... 86
`2 Hydrogen bonding ..................... 87
`3 Hydrophobic
`....................... 87
`4 Van derWaals ...................... 87
`AFFINITY MEASURES STRENGTH 0F BINDING OF
`ANTIGEN AND ANTIBODY ................. 88
`The avidity of antiserum for antigen — the bonus effect
`of multivalency ........................ 88
`THE SPECIFICITY OF ANTIGEN RECOGNITION
`BY ANTIBODY IS NOT ABSOLUTE ............. 90
`WHAT THE T-CELL SEES .................. 9T
`Haploiype restriction revealsthe need forMHc participation
`.
`.
`.
`.
`91
`T-celis tecogntzea linear peptide sequence from the antigen .
`.
`.
`.
`91
`PROCESSING OF iNTRACELLULAR ANTIGEN
`FOR PRESENTATION BY CLASS I MHC
`......... 92
`PROCESSING OF ANTIGEN FOR CLASS II MHC
`93
`.
`.
`PRESENTATION FOLLOWS A DIFFERENT PATHWAY .
`THE NATURE OF THE ‘GROOVY’ PEPTIDE ........ 96
`Binding to MHC class I ..................... 96
`Binding to MHC class II ..................... 97
`THE up T-CELL RECEPTOR FORMS A TERNARY
`98
`.
`.
`.
`COMPLEX WITH MHC 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 of CDI non-MHC class l-like molecules can
`present exotic antigens ..................... 99
`yrs TCRs have some features 01' antibody ............. 100
`SUPERANTIGENS STIMULATE WHOLE FAMILIES
`OF LYMPHOCYTE RECEPTORS ............... IOO
`Bacterial toxins represent one major group of T-cell
`superontigens ......................... i 00
`Endogenous mouse mammary tumor viruses (MMTV) act
`as superantigens .................. I
`Microbes can also provide B-cellsuperantlgens
`.
`.
`.
`.
`
`.
`.
`
`.
`I
`
`.
`
`,
`.
`
`.
`.
`
`too
`IOI
`
`Lassen — Exhibit 1043, p. 4
`
`Lassen - Exhibit 1043, p. 4
`
`

`

`CONTENTS
`
`VI!
`
`THE RECOGNITION OF DIFFERENT FORMS OF ANTIGEN
`BY
`B- AND T-OELLS IS ADVANTAGEOUS TO THE
`HOST ............................. 101
`SUMMARY .......................... 102
`FURTHER READING ..................... 103
`
`TECHNOLOGY
`PART 3
`6 -
`lmmunochemlcaltechnlques, 107
`ESTIMATION OF ANTIBODY ................ 107
`,
`.
`.
`.
`Ancaggfggerggxlmgggzgz30:13:11,101;ch """" ’
`'
`'
`:2;
`.
`.
`_
`"""""
`The classical preolpltin reaction ................ 109
`Nonpreclpltating antibodies can be detected by nephelometry .
`. 109
`32:1:'21:;12:1de by nonpreclpltatlng antiboaiucan
`110
`""""""""""""
`fl:::;rr:3::ggflsm"°n ”V °°"”'e'°”"em
`1 10
`.
`Measurementofantibooyaftlnlty ............ .
`. 11o
`Agglutlnatlon ot antigen-cooled particles ............. 111
`“Effigy “"me ”5m” 3°"d'pmse ”"96" """" 11:
`Awtde variety oI labels is available .............. 113
`ELISA (enzyme-linked immunosorbent assay) """"
`113
`'
`'
`Other labels
`' 113
`Surface plasmon'resanan-ce """""""""""""" 1 1 4
`IDENTIFICATION AND MEASUREMENT or ANTIGEN.
`.
`. 114
`Precipitation reactianoan becarriedoutlngels
`......... 114
`mmmm‘o? °' “mans by°'°°"°ph°'es's and
`1 1 4
`.
`.'
`'
`'
`'
`.‘ """""""""
`1113::gxgngfigmz‘r‘ggiérzyu'mmusw”(SAND).
`:1:
`'_
`j
`:
`'
`'
`Sodium aoaecyl sultcte-polvccrytcmlde gel electrophoresis
`(SDS-PAGE) foranalysls 01 Immunoprecipitates and
`immunoblotting ........................ 1 18
`Thelmmunoassayotantlgens
`................. 117
`Immunoassay on multiple microspots
`............ 118
`Epilopemapplng ........................ 118
`T—aell epitopes ........................ 118
`B-aell epitopes ........................ 1 19
`DETECTION or IMMUNE cOMPLEX FORMATION .
`.
`.
`. 120
`figgggcmmlmfiewuggffl """""" 1::
`""""""""
`2:3":“11115 d: """""""""""" 1:?
`111mm maozoc‘iofjscan'be' ”10111; """""""" 123
`""""""""
`Engagflgamgzflf """"""""""" 1::
`Drugs can be based on the own;at mlnlboates ......... 125
`PURIFICATION OF ANTIGENS AND ANTIBODIES
`BY AFFINITY CHROMATOGRAPHY lllllllllll 126
`NEUTRALIZATIOII OF BIOLOGICAL ACTIVITY
`127
`'
`‘
`'
`'
`'
`To datect antibody
`' 127
`Using antibodyas anlnhlbllor ................. 127
`SU M MAIIY
`128
`"""""""""""""
`F
`URTHER READING ..................... 129
`
`7 - Cellulartechnlques, 130
`IS
`
`OLATION 0F LEUKOOYTE SUBPOPULATIONS ..... 130
`
`Bulktechnlquea ......................... 130
`Separation based on physical parameters ........... 130
`Separation exploiting biological parameters ........ .
`. 131
`Selection by antibody cooling ................. 131
`Cell selection bythe FACS .................... 131
`Enrichmentofantigen-specific populations .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`. 131
`IMMUNOHISTOGHEMISTRY —LOGALIZATION
`OF ANTIGENS IN CELLS AND TISSUES
`......... 133
`lmmunofluotescence techniques ................ 133
`DirecI test with labeled antibody ............... 134
`.
`.
`Indirect test tarantlbody ................... 134
`High resolution with the confocal microscope
`.
`.
`.
`. ..... 135
`Flow oytotluorimetry ..................... 135
`.
`.
`.
`o1ng1gzgfisgznggrflmg rarecells """ ‘ """ :2;
`Locallzalionintissues ofagene ptoducl
`....... .
`.
`.
`.
`. 139
`ASSESSMENT OF FUNCTIONAL ACTIVITY .
`.
`.
`.
`.
`.
`.
`. 140
`The activity at phagocytic cells .................. 140
`gflrnggzpfijxgm """""""""" 1:3
`Enumefuflon of ammodv-1011111111; 66113"""""""" 14o
`The immunoiluoreseence sandwich test ............ 14o
`””9"” “"19““ '. """""" .‘
`.‘ """" 141
`Analysts offunclianalactivlly bvcellulorreconstltutlon ..... . 142
`Radiation chimeras ...................... 142
`Mice with severe combined Immunodeficiency (SCID) ...... I42
`P13:1?"1'151'12'11’;:°£1‘;::’n’;1‘1;z:1’es"""""""" ‘ 12:
`GENE‘TIG ENGINEERING OF'GIELLS""""""" 144
`insertion and moaltloation 01 genes in mammalian cells ...... 144
`Introducing newgenesintaanimals ............... 144
`Establishing ‘deslgnermice’ bearing newgenes ........ 144
`T'°$::'1'11‘:1':"°1‘:1"::;::: embw°"'° 5mm “”5 """" 1::
`SUMMARY W
`""""""""" 147
`""""""" " """"" '
`FURTHER READING """""""""" '
`‘48
`
`PART 4 ' THE ACQUIRED IMMUNE
`RE 5 P0 N S E
`
`8 - The anotomyotthe Immune response, 151
`THE SURFACE MARKERS or cats IN THE IMMUNE
`SYSTEM 151
`THE NEED FOR ORGANIZED LYMPHOID TISSUE ..... 151
`LYMPHOOYTES TRAFFIC BETWEEN LYMPHOID
`TISSUES
`153
`Lymphocytes home to their speeltlcllssues ............ 153
`“0:1?"If‘rgggllssglgsér‘rgmzz smges """"""" 1::
`p
`'
`""" ."""""" 4
`Step 2: p2 lntegrln activatIon and cellflattening
`........ 15
`Step 3:Transmlgrollon Into the tissue (dlapedesls) ....... 164
`Aeioserlookatthetnteracllngreceptorsandthelrligands ..... 156
`ENGAPSULATED "MPH MODES """"""" :52
`E-cell areas ........................... 1:7
`T-celloreas.......,....,..............
`SPLEEN IIIIIIIIIIIIIIIIIIIIIIII 158
`MUCOSAL-ASSOGIATED LYMPHOID TISSUE (MALT).
`.
`. 161
`Intestinal lymphocytes ..................... 162
`BONE MARROW CAN BE A MAJOR SITE OF ANTIBODY
`SYNTHESIS """"""""""""""""""""" 162
`
`Lassen — Exhibit 1043, p. 5
`
`Lassen - Exhibit 1043, p. 5
`
`

`

`VIII
`
`CONTENTS
`
`THE ENJOYMENT OF PRIVILEGED SITES ......... 163
`THE HANDLING OF ANTIGEN ............... 163
`Macrophages are general antigen-presenting cells ........ 163
`Interdlgitatlng dendritic cells presenlantigento T—Iymphacytes
`.
`.
`. 164
`Follicular dendritlc cells stimulate B-ceils in germinal centers
`.
`.
`. 165
`M-cells provide the gateway to the mucosal lymphoid system .
`.
`. 166
`SUMMARY ......................... 168
`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 0F T-CELLS REQUIRES
`TWO SIGNALS
`....................... 169
`PROTEIN TYROSINE PHOSPHORYLATION IS AN EARLY
`EVENT IN T-CELL SIGNALING ............... 170
`DOWNSTREAM EVENTS FOLLOWING TCR
`SIGNALING ......................... 171
`The phosphatidylinosltol pathway ................ 171
`p21 rastunction ........................ 171
`Control of IL-2 gene transcription ................. 171
`Further thoughts on the control 01 T—cell triggering ......... 171
`A serial TOR engagement model tor T-cell activation
`...... 171
`Damping T-cell enthusiasm .................. 1 73
`B-CELLS RESPOND TO THREE DIFFERENT TYPES
`OF ANTIGEN ......................... 173
`I Typei thymus-independent antigens .............. I73
`2 Type 2 thymus-independent antigens ..... r ........ 173
`3Thymue-dependentantlgene ................. . 174
`The need tor collaboration with T—helper cells
`......... 174
`Antigen processing by B—celis ................ 174
`THE NATURE OF B-CELL ACTIVATION ........... 176
`B-celie are stimulated by cross-linking surface lg ......... 176
`T-heiper cells activate resting B—ceiis ............... 177
`SUMMARY .......................... 177
`FURTHER READING ...............
`.
`.
`.
`178
`
`10 - The production oteftectors. 179
`A SUGCESSION OF GENES ARE UPREGULATED
`BY T-CELL ACTIVATION .................. 179
`CYTOKINES ACT AS INTERCELLULAR MESSENGERS .
`. 179
`Cytokine action is transient and usually short range ........ 180
`Cytokines act through cell surface receptors ........... 180
`The gp 130 subfamily .................... 182
`The pc and ye receptor subfamilies .............. 182
`Signal transduction through cytoklne receptors .......... 182
`Cytokines often have multiple efteots ............... 182
`Network Interactions ...................... 1 83
`DIFFERENT CM T-CELL SUBSETS CAN MAKE
`DIFFERENT CYTOKINE PATTERNS ............. 184
`The bipolar THl/THZ concept ................... 184
`Interactions with cells of the innate Immune system may bias
`the THt/THZ response ...................... 185
`ACTIVATED T-CELLS PROLIFERATE IN RESPONSE
`TO CYTOKINES ....................... 186
`
`. 186
`T-CELL EFFECTORS IN CELL-MEDIATED IMMUNITY .
`Cytokines mediate chronic intiammatory responses ........ 186
`Early events ...................... .
`186
`Chemotaxls ........................
`187
`Macrophage activation .................... 1 S7
`Combating viral intectlon .................
`. 187
`Killer T~ceils .......................... 188
`The generation of cytotoxic T-celis ............ .
`. 188
`The lethal process ....................
`188
`inflammation must be regulated ................. 189
`PROLIFERATION AND MATURATION 0F B-CELL
`RESPONSES ARE MEDIATED BY CYTOKINES
`WHAT IS GOING ON IN THE GERMINAL CENTER?
`THE SYNTHESIS OF ANTIBODY
`IMMUNOGLOBULIN CLASS SWITCHING OCCURS
`IN INDIVIDUAL B-CELLS .................
`Class-switched B-ceils are subject to high mutation rates alter
`the initial response ....................... 193
`FACTORS AFFECTING ANTIBODY AFFINITY
`IN THE IMMUNE RESPONSE ................ 194
`The eftectot antigen dose ................. .
`194
`Maturation of affinity ................... .
`. 195
`MEMORY CELLS ....................... 195
`The memory population Is not simply an expansion of
`corresponding naive cells .................
`SUM MARY .......................
`FURTHER READING ..................
`
`.
`
`.
`
`. 190
`
`192
`
`196
`198
`199
`
`11 ' Controlmechanisms, 201
`. 201
`.
`.
`.
`.
`.
`ANTIGEN IS,A MAJOR FACTOR IN CONTROL
`Antigens can interfere with each other .............. 202
`ANTIBODY EXERTS FEEDBACK CONTROL ...... .
`202
`T-CELL REGULATION .................... 203
`T-helper cells ........ { ................. 203
`T-ceii suppression
`.
`Suppressor and helper epitopes can be discrete ........ 204
`Characteristics of suppression .............
`.
`. 204
`Suppression due to T-Tinteraction on antigen-presenting cells .
`. 206
`Ettector T-ceiis are guided to the appropriate target by MHC
`surface molecules .................... 207
`IDIDTYPE NETWORKS ................
`207
`James network hypothesis ................... 207
`Evidence for ldiotypic networks ................. 208
`Anti-Idiotype can be Induced by autoiagous ldiotypes ...... 208
`A network is evident in early life
`........... 208
`T-ceils can also do it ..................... 209
`Preoccupation ot networks with self ............... 209
`Idlotypic regulation of immune responses .
`,
`.
`......... 210
`Manipulation oi the immune response through ldiotypes ...... 21 1
`THE INFLUENCE OF GENETIC FACTORS ......... 213
`Some genes affect general responsiveness ........... . 213
`immune response linked to Immunoglobulln genes ........ 213
`Immune response can be Influenced by the MHC ......... 213
`The Ir genes map to the H-2| region and control T—B
`cooperation ......................... 214
`ARE THERE REGULATORY IMMUNONEUROENDOCRINE
`NETWORKS? ......................... 216
`A neuroendocrine feedback loop attesting immune responses
`.
`.
`. 216
`Sex hormones come into the picture ............... 217
`
`Lassen — Exhibit 1043, p. 6
`
`Lassen - Exhibit 1043, p. 6
`
`

`

`CONTENTS
`
`IX
`
`Inchlns towards ‘psycholmmunology' ------------ 2‘7
`EFFECTS OF DIET. EXERCISE. TRAUMA AND AGE
`0N IM MUN'TY
`------------------ -
`Malnutrition diminishes the effectiveness at the Immune
`response ____________________________ 218
`otherfactors ________________________ 219
`SUM MARY IIIIIIIIIIIIIIIIIIIIIIII 220
`wan-I ER READING ..................... 221
`
`- 21 3
`
`-
`
`12 ' Ontogeny and phylogeny, 223
`THE MULTIPOTENTIAL HEMATOPOIETIC STEM cELL
`GIVES RISE TO THE FORMED ELEMENTS
`on”; Hoop ,,,,,,,,,,,,,,,,,, 223
`THE THYMUS PROVIDES THE ENVIRONMENT
`FOR ME LL DIFFERENTIATION ........... 225
`Bone marrow stem cells become immunocompetent T-cells
`In the thymus ......................... 226
`1-0 ELL omoce My ,,,,,,,,,,,,,,,,, 227
`Differentiation is accompanied by changes In surface markers
`.
`.
`. 227
`Receptor rearrangement .................... 228
`The development ofoiB receptors ............... 229
`The development of ya receptors ,,,,,,,,,,,,,,, 229
`Cells are positively selected for self-MHc restriction In the thymus .
`. 229
`1.05“ TOLE RANGE __________________ 23]
`The induction of immunological tolerance is necessary to avoid
`self-reactivity ......................... 231
`Self-tolerance can be induced In the thymus ............ 231
`lntrathymlc clonal deletion leads to self-tolerance ......... 231
`Factors affecting positive or negaflve selection In the thymus .
`.
`. 233
`7.09" tolerance can be due to clonal energy ,,,,,,,,,, 234
`Infectious anergy ...................... 235
`Look of communication can cause unresponsiveness ....... 235
`s-cELLs DIFFERENTIATE IN THE FETAL LIVER
`AND THEN I" BONE MARROW lllllllllllll 236
`3.1 AND 3,2 CELLS REPRESENT TWO DISTINCT
`. 237
`popu LATI 0 N s lllllllllllllllll '
`DEVELOPMENT OF 3.95“ spEcmcn-y _________ 233
`The sequence of lmmunoglobulln gene rearrangements ...... 238
`The Importance of allelic excluslon """""""""""" 240
`Different specific responses can appear sequentially ....... 240
`THE INDUCTION 0F TOLERANCE IN
`s-meuocyres ,,,,,,,,,,,,,,,,,,,,,, 240
`Tolerance can be caused by clonal deletion and clonal anergy
`.
`.
`. 240
`Tolerance may result from helpless B—cells ____________ 241
`THE OVERALL RESPONSE IN THE NEONATE
`______ 243
`THE Evolu'nou OF THE IMMUNE RESPONSE IIIII 243
`Recoanltlon of self is fundamental for multicellular organisms
`.
`.
`. 243
`anertebrates have microbial defense mechanisms ....... 244
`Adaptive Immune responses appear with the vertebrates ..... . 245
`Lower vertebrates ...................... 245
`Mausuppea, llllllllllllllllllllllll 245
`Generation of antibody diversity ............... . 247
`THE EVOLUTION OF bIsTINcT e- ANb T-cELL
`Human WAS AGOOMPANIED at THE DEVELOPMENT
`OF SEPARATE sITEs FOR DIFFERENTIATION ...... 247
`CELLULAR necoeNITwN NOLEcIILEs ExPLOIT
`THE IMMUNOGLOBULI N eENE su PERFAMILY ...... 247
`SUM MARY ________________________ 248
`FURTHER READING ,,,,,,,,,,,,,,,,,,,,, 250
`
`PART 5 ~
`
`I M M U N ITY TO IN FE CTION
`
`13 - Adversarial strategies during infection, 253
`
`INFLAMNATION NEVIstrEo ................ 254
`Mediators of Inflammation
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.- ........ 254
`Leukocytes bind to endothetlal cells through paired adhesion
`"'01900193 --------------------------- 255
`Initiation of the acute inflammatory response .......... . 255
`The ongoing inflammatory process ............... . 256
`Regulation and resolution of inflammation ............ 257
`°h'°n'°'""°mm°"°" --------------------- 258
`EXTRACELLULAR BACTERIA SUSCEPTIBLE To KILLING
`at PNAoochOSIs ANo cOMPLEMENT ......... 258
`Bacterial survival strategies ................... 258
`Emmi! PhagOchOSls -------------------- 258
`Challeng'W "'9 complement system -------------- 25'
`An'lflen'cvarlaflm ---------------------- 260
`The host counter-attack ..................... 26g
`TON” neutralization --------------- . ----- 25‘
`Opsonization 0' “9'3”” ------------------ - 261
`Some further effects of complement .............. 263
`The secretory immune system protects the external mucosal
`surfaces --------------------------- 253
`Some specific bacterial infections ................ . 265
`”37"" W" '0" GROW 'N A" '"TMGELL" UR
`HABIT“
`-
`_ -------------------- 2‘57
`Bacterial 90ml)“
`_
`j
`-
`- -------------- 267
`09‘9”“ '5 by T-cell-mediated Immunity (0M1) ----------- 263
`Activated macrophages klll Intracellular parasites ......... 268
`Examples of Intracellular bacterial Infections ........... 269
`”573”“ -------------------------- 259
`Tuberculosis ------------------------ 269
`“WOW IIIII .
`~
`,
`.
`.
`,
`-
`-
`-
`-
`3 ----------- 271
`IMMUNITY T0 VIRA INFECTION .
`.’ ........... 271
`lmmunltycan beevaded byantlgenchanges .......J.
`.
`.
`. 271
`Changing antigens by dim and Shift
`.~ ............. 271
`Mutation can produce antagonistic T-cell epltopes ....... 272
`50m“ “"1595 0°” ““991 0””99” Process” ----------- 272
`VIIuses can InIeneIe WIIh Immune eflecIor mwhunisms ...... 272
`Playing games with "‘9 complement WSW“ ---------- 272
`Sabotaging cell-mediated immunity .............. 272
`Protection by serum antibody .................. 273
`Local factors -------------------------- 273
`Cell-mediated immunity gets to the intracellular virus ....... 273
`NK cells can kill VitOllViflTecIed targets ............. 273
`'cytotoxlcT-cells (Tc) are cruclaielements In lmmunltyto
`infection bV budding viruses ----------------- 275
`Oyloklnes recruit effectors and provide a ‘oordon sanitalre’
`.
`I
`. 275
`”'1‘me has a part '00 ------------------- 275
`'M M" N I" To FUNGI
`' ------- , --------- 275
`IMMUNITY To PARASlTic INFEcTIONs ......... 276
`"'5 “05* "38an vvvv . ------------ -
`.
`-
`- 273
`HWOWIWWUHW
`--------------------- 277
`Cell-medlatefllmmunltv ---------------- .
`.
`-
`- 278
`mm “families t’Y ”'9 Parasite ---------------- 279
`WWW” BMW mechanisms -------------- 279
`AVO'd'W 0""99" recognlllon bV "'9 "03' ------------ 28°
`Deviation of the host immune response ............ 281
`lmmunopathology ----------------------- 251
`
`Lassen — Exhibit 1043, p. 7
`
`Lassen - Exhibit 1043, p. 7
`
`

`

`GONTE NTS
`
`SUMMARY .............. . ........... 2B]
`FURTFIER READING ..................... 284
`
`14 - Prophylaxis, 285
`PASSIVELY ACQUIRED IMMUNITY ............. 285
`Maternalty acquired antibody .................. 287
`Pooled human y-globulln .................... 287
`Cultured anttbodies 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 at attenuated vaccines ........... 293
`SUBUNIT VACCINES CONTAINING INDIVIDUAL
`. 293
`PROTECTIVE ANTIGENS ................ .
`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.
`.
`.
`.
`. 296
`Epitopes can be mimicked by synthetic peptides ......... 297
`B-celt epitopes ........................ 297
`T—cell epitopes ........................ 297
`Making the peptides immunogenic ........ . ...... 298
`ldtotypes can be exploited as epitope-speolftc vaccines ...... 299
`Unwanted epltope-Ioss mutants can correctly told desired
`discontinuous B-celt epttopes .................. 299
`CURRENT VACCINES .................... 299
`EXPERIMENTAL VACCINES IN DEVELOPMENT ...... 300
`Malaria ........................... I
`. 300
`Schlstosomtasis .................... .
`.
`.
`.
`. 302
`Cholera ............................ 303
`Tuberculosis .......................... 303
`ADJ UVANTS ......................... 303
`Depot effects .......................... 303
`Macrophage activation ..................... 304
`Specific etfects on lymphocytes ................. 304
`NEW APPROACHES TO THE PRESENTATION
`OF ANTIG EN ......................... 304
`SUMMARY .......................... 305
`FURTHER READING ..................... 307
`
`PART 6
`
`CLINICAL IMMUNOLOGY
`
`Immunodeficiency. 31 I
`15 -
`PRIMARY IMMUNODEFICIENCY STATES
`IN THE HUMAN ....................... 311
`DEFICIENCIES OF INNATE IMMUNE MECHANISMS .
`.
`. 311
`Phagocytlc cell detects ..................... 311
`Complement system deficiencies ................. 312
`Defects In control proteins ................... 312
`Deficiency of components of the complement pathway ..... 313
`PRIMARY B-CELL DEFICIENCY .............. . 314
`
`PRIMARY T—CELL DEFICIENCY ............... 315
`COMBINED IMMUNODEFICIENCY ............ 317
`Mutation In the common oytokine receptory‘1 chain causes SCID .
`. 317
`9010 can be due to mutations In purine salvage
`pathwayenzymes ...................... , 317
`Other SCID variants ....................... 317
`RECOGNITION OF IMMUNODEFICIENCIES ........ 317
`SECONDARY IMMUNODEFICIENCY ............ 318
`ACGUIRED IMMUNODEFICIENCY SYNDROME (AIDS).
`. 319
`AIDS results from Infection by a human immunodeficiency virus
`(HIV) ............................. 319
`The infection of cells by HIV .................... 31
`The AIDS Infection depletes helper T-celts ............. 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
`Othertherapeutlc strategies ............... t
`.
`. 325
`SU 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 anaphylaxie ................. 329
`Human anophylactlc antibodies are mainly IgE .......... 330
`Anaphylaxis is triggered by clustering of IgE receptors on mast cells
`through cross—linking ...................... 330
`Atopic allergy ......................... . 331
`Clinical responses to Inhaled allergens ............. 331
`Food allergy ....... '. ................. 333
`Etlotagical factors In the development of atoplc allergy ..... 333
`Cltnlcat tests for allergy ,
`' ................... 334
`Therapy ........................... 334
`Allergen avoidance ..................... 334
`Modulation of the Immunological response ......... 335
`Most cell stabilization ................... 335
`Mediator antagonism .................... 337
`Attacking chronic infla