ROITT’S .
`
`ESSENTIAL
`
`IMMUNOLOGY
`
`Ivan Roitt
`
`
`
`Lassen - Exhibit 1044, p. 1
`
`

`

`qjfi
`
`© 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)
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`
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`
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`Catalogue records for this title
`are available from the British Library
`and the Library ofCongress
`ISBN 0-86542-729-1
`
`Lassen — Exhibit 1044, p. 2
`
`Lassen - Exhibit 1044, p. 2
`
`

`

`_
`
`v
`
`CONTENTS
`
`PREFACE .............. .
`
`.
`
`I ....... xiii
`
`ACKNOWLEDGEMENTS .
`
`...........
`
`.
`
`.
`
`.
`
`.
`
`xiv
`
`Target cells are told to commit suicide .............. 19
`Eoslncphils ...................... .
`.
`20
`SUMMARY ................... .
`.
`.
`20
`
`.
`
`A““““’.‘"' ”5 """""" '
`
`'
`
`' """" X"
`
`2 - Specific acquired Immunity, 22
`
`USER GUIDE ..................... .
`
`.
`
`.
`
`xix
`
`22
`.
`.
`.
`THE NEED FOR SPECIFIC IMMUNE MECHANISMS
`ANTIBODY—THE SPECIFIC ADAPTOR .......... 22
`
`T H E BAS I S OF I M M U N 0 I'OGY
`
`3
`6
`
`PA RT 1
`
`.
`
`.
`Innate Immunity, 3
`'
`1
`EXTERNAL BARRIERS AGAINST INFECTION .......
`PHAGOCYTIC CELLS KILL MICROORGANISMS .....
`Polymorphs and macrophages are dedicated ‘professional'
`6
`phagocytes ..........................
`6
`The polymorphonuclear neutrophil ...............
`6
`Themacrophage .......................
`6
`Microbes are engulfed by phagocytosis ........... ,
`.
`.
`.
`8
`There Is an array of killing mechanisms ..............
`8
`Killing byreacllve oxygenlntermediates ............
`9
`Killing by reactive nitrogen Intermediates ............
`Killing by preformed antlmlcroblals ............... 10
`COMFLEMENT FACILITATES PHAGOCYTOSIS ...... 11
`Complement and Its activation .................. 11
`03 undergoes elow spontaneous cleavage ........... 1 1
`03!) levels are normally tightly controlled ............ 1 1
`03 convertase is stabilized on microbial surfaces ........ 1 1
`The post-03 pathway generates a membrane attack complex
`.
`.
`12
`.
`Complement hasa range of defensive biologicalfunclicns .
`.
`.
`.
`12
`I 03b adheres to complement receptors ............ 12
`2 Biologicallvcctlve fragments are released .......... 12
`3 The terminal complex can induce membrane lesions .....
`14
`COMPLEMENT CAN MEDIATE AN ACUTE
`INFLAMMATORY REACTION ........ . ....... 14
`The mast cell plays a central role ................. 14
`Macrophages can also do It ...............
`.
`.
`.
`15
`HUMORAL MECHANISMS PROVIDE A SECOND
`DEFENSIVE STRATEGY ................... 18
`Acute phase proteins Incrmse in response to infection ....... 16
`Interfercns Inhibit viral replication ................ 18
`EXTRACELLULAR KILLING ................. 18
`Natural killer (NK) cells .....................
`18
`
`Antibody Initiates a new complement pathway Cclassical’) ..... 23
`Complexed antibody activates phagocytic cells .......... 25
`CELLULAR BASIS OF ANTIBODY PRODUCTION .
`.
`I
`I
`.
`25
`Antibodies are made by lymphocytes ............... 25
`Antigen selects the lymphocytes which make antibody ...... 26
`The needforclonclexpansion means humeral Immunity must
`26
`be acquired ........................ .
`ACQUIRED MEMORY .................... 28
`Secondary antibody responses are better
`............ 28
`ACQUIRED IMMUNITY HAS ANTIGEN SPECIFICITY . ..
`30
`Discrimination between different antigens ............ 30
`Discrimination between self and nonself ............. 32
`VACCINATION DEPENDS ON ACQUIRED MEMORY .
`.
`.
`32
`CELL-MEDIATED IM MUNITY PROTECTS AGAINST
`INTRACELLULAR ORGANISMS ............... 33
`Cytokine-prcducing T-cells help macrophagesto kill intracellular
`parasites ............................ 33
`Vlrally infected cells can be killed by cytotoxic T-cells and
`ADCC ............................. 33
`I MM UNO PAT H0 LO GY ..................... 35
`SU M MARY .........................
`35
`FURTHER READING ....................
`37
`General re'ading ......................
`37
`Reference work ......................
`37
`Historical .........................
`38
`In-depth series forthe advanced reader ............ 38
`Current Information .....................
`38
`Multiple choice questions ..................
`38
`Electronic publications (linked to ‘Rol‘rl‘s Essential
`Immunology) .......................
`Majorjournals ................... .
`.
`.
`
`39
`39
`
`.
`
`Lassen — Exhibit 1044, p. 3
`
`Lassen - Exhibit 1044, p. 3
`
`

`

`vi
`
`CONTENTS
`
`PART 2 - THE RECOGNITION OF ANTIGEN
`
`3 - Antibodies, 43
`
`.
`
`.
`
`THE BASIC STRUCTURE Is A FOUR-PEPTIDE UNIT .
`AMINO ACID sequences REVEAL VARIATIONS IN
`IMMUNOGLOBULIN STRUCTURE ..............
`IMMUNOGLOBULIN GENES .................
`lmmunoglobulins are encoded by multiple gene segments .....
`A special mechanism eliects VDJ recombination
`STRUCTURAL VARIANTS OF THE BASIC
`IMMUNOGLOBULIN MOLECULE ..............
`lsotypes ............................
`Ailotypes ............................
`Idiotypee ............................
`IMMUNOGLOBULINS ARE FOLDED INTO GLOBULAR
`DOMAINS WHICH SUBSERVE DIFFERENT
`FU N CTIO N S ..........................
`Immunoglobulin domains have a characteristic structure .....
`The variable domain binds antigen ................
`Constant region domains determine secondary biological function .
`IMMUNOGLOBULIN CLASSES AND SUBCLASSES
`Immunoglobulin G has major but varied roles in extracellular
`defenses ............................
`Activation of the classical complement pathway
`The diversity of Fay receptors ,,,,,,,,,,,,,,,,,
`Nonprecipltaling 'univalent’ antibodies .............
`Immunoglobulin A guards the mucosal surfaces .........
`Immunoglobulin M provides a defense against bacteremla .....
`immunoglabulin D is a cell surface receptor ............
`Immunoglobulin E triggers inflammatory reactions ........
`immunoglabulins are further subdivided into subclasses
`SU MMARY .........................
`FURTHER READING .....................
`
`.
`
`.
`
`.
`
`4 - Membrane receptors for antigen, 63
`THE B-CELL SURFACE RECEPTOR FOR ANTIGEN .
`The B-cell inserts a transmembranc immunoglabulin info
`Its surface ...........................
`The surface Immunoglobulin is complexed with associated
`membrane proteins .......................
`THE T-CELL SURFACE RECEPTOR FOR ANTIGEN
`.
`The receptor for antigen Is a transmembrane heterodimer .....
`There are two classes of T-ceii receptors .............
`The encoding of T-oeil receptors is similar to that of
`lmmunogiobuiins ...................... .
`The CD3 complex is an integral panel the T-cell receptor ......
`THE GENERATION OF DIVERSITY FOR ANTIGEN
`RECOGNITION
`.......................
`Inlrochain amplification of diversity .............
`.
`.
`Random VDJ combination increases diversity geometrically .
`.
`.
`Playing with the junctions ..................
`Interchain amplification .....................
`Somatic hypermulutian .....................
`THE MAJOR HISTOCOMPATIBILITY COMPLEX
`(M NO) ............................
`Glass | and class II molecules are membrane-bound
`heterodimers ........................ .
`MHC classi ........................
`MHC ciassil ...................... .
`.
`
`.
`
`43
`
`45
`45
`45
`46
`
`47
`47
`47
`50
`
`50
`50
`51
`51
`51
`
`59
`59
`
`63
`
`63
`
`64
`65
`65
`65
`
`66
`67
`
`68
`69
`69
`69
`70
`70
`
`71
`
`71
`71
`71
`
`Complement genes contribute to the remaining class ill region
`72
`otthe MHC .........................
`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 functions ......................... 77
`SUMMARY ......................... 78
`FURTHER READING ................. ,
`.
`79
`
`83
`83
`
`88
`
`88
`
`.
`
`.
`
`.
`
`5 - The primary Interaction with antigen, 80
`WHAT IS AN ANTIGEN? ................... 80
`0f epifopes and antigen determinants .............. Bi
`identification of B-ceii 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 paralope can be
`demonstrated ......................... 83
`Antigen-antibody bonds are readily reversible ......... .
`84
`THE FORCES BINDING ANTIGEN T0 ANTIBODY
`BECOME LARGE AS INTERMOLEGULAR DISTANCES
`86
`BECOME SMALL .....................
`86
`i Electrostatic
`.....................
`2 Hydrogen bonding ..................... 87
`3 Hydrophobic
`....................... 87
`4Van derWaals .................... ,
`.
`87
`AFFINITY MEASURES STRENGTH 0F BINDING OF
`ANTIGEN AND ANTIBODY < ............... .
`The avidity of antiserum for antigen — the bonus effect
`ofmultivalencv .................
`THE SPECIFICITY 0F ANTIGEN RECOGNITION
`BY ANTIBODY IS NOT ABSOLUTE ............. 90
`WHAT THE T-CELL SEES .................. 9i
`Haplotype restriction revealsthe need forMHC participation
`.
`.
`.
`.
`91
`T-cellsrecognizealinearpeptidesequencefromfhe 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 classl .................... 96
`Binding to MHC class Ii ...................
`.
`97
`THE up T-CELL RECEPTOR FORMS A TERNARY
`98
`.
`.
`COMPLEX WITH MHC AND ANTIGENIC PEPTIDE .
`99
`.
`.
`Topology ofthelernary complex ..............
`T-CELLS WITH A DIFFERENT OUTLOOK ......... 99
`Non-classical class i molecules can also present antigen ...... 99
`MHC class I-Iike molecules .................... 99
`The family of CD1 non--MHG classl-like molecules can
`99
`.
`.
`.
`presentexotic antigens ................. .
`ya TCRs have some features at antibody ............. 100
`SUPERANTIGENS STIMULATE WHOLE FAMILIES
`OF LYMPHOCYTE RECEPTORS ............... 100
`Bacterial toxins represent one major group of T-celi
`superahtigens .................... -.
`Endogenous mouse mammary tumor viruses (MMTV) act
`as superontigens ........................ 100
`Microbescanalso provide B-cclisuperantigens
`.
`.
`.
`.
`.
`.
`.
`.
`.
`lOi
`
`.
`
`.
`
`.
`
`.
`
`. 100
`
`Lassen — Exhibit 1044, p. 4
`
`Lassen - Exhibit 1044, p. 4
`
`

`

`CONTENTS
`
`vil
`
`THE RECOGNITION OF DIFFERENT FORMS OF ANTIGEN
`By B- AND T-CELLS IS ADVANTAGEOUS TO THE
`HOST ............................ 101
`suMMARY .......................... 102
`FURTHER READING ..................... 103
`
`TECHNOLOGY
`PART 3
`6 -
`lmmunochemical techniques, 107
`ESTIMATION OF ANTIBODY IIIIIIIIIIIIIIII 107
`_
`.
`.
`Antigen—OMIDOOV Interactions m solution """""" 107
`What does serum‘anftbody content’ mean? ........ .
`. 107
`.
`.
`The classical preclpltin reaction ................ 109
`lfotln antibodiescanbedetectedb ne helomet
`N
`reci
`109
`p
`°”p
`g
`..
`.
`.
`V.
`p
`Campiexesformed by nonprecipitating antibodiescan
`feet
`ltaIed
`13
`""" . """"""""""
`p
`‘39
`Enhancement of precipitation by countercurrent
`Immunoelectrophoresis .................... 1 10
`.
`.
`.
`Measurement oiantibodyaffinity ............... 110
`_
`_
`Agglutination of antigen-coated particles ............. 111
`.
`.
`lmmunaassayfar antibody usmg solid-phase antigen ....... 112
`_
`The principle ......................... 1 12
`.
`.
`.
`A wide variety of labels is available .............. 1 13
`.
`.
`ELISA (enzyme-linked immunosorbeni assay) ........ 113
`Other labels ........................ 113
`
`W “
`
`110
`
`surface memo" ”mun“ """"""""" 1 14
`IDENTIFICATION AND MEASUREMENT OF ANTIGEN,
`.
`. 114
`,
`_
`.
`Precipitation reactionean be carried out In gels
`......... 114
`.
`.
`.
`Characterization of antigens by electrophoresis and
`I
`.
`imm”"°fi"°"°" """""""""""" ”4
`Quantification by single radial lmmunodiffusion (SRID) ..... 115
`.
`The nephelomeiric assay for antigen """""""" 1 15
`Sodium dodecyi sulfate-polyacryiamide gel electrophoresis
`(SDS—PAGE)foranalysis oflmmunopreclpiiates and
`lmmunobloiting ........................ 116
`The Immunoassay ofantlgens
`................. 117
`Immunoassay on multiple microspofs
`............ 118
`Epiiopemapplng ........................ 118
`T-celiepitopes ........................ 118
`B-cell epitopes ........................ 1 19
`DETECTION OF IMMUNE COMPLEX FORMATION .
`.
`.
`. 120
`MAKING ANTIBODIES 1.09““ """""" 120
`The monoclonal antibody revolution ............... 120
`ggizmggmfodies """"""""""" 1:?
`"""""""""""
`Human monoclonals can be made ............... 123
`Engineering antibodies ..................... 124
`.
`.
`.
`Fields 0' antibodies """"""""""" ‘25
`Drugs conbebased on me CDRsofminibodles ......... 125
`PURIFICATION or ANTIGENS AND ANTIBODIES
`BY AFFINITY CHROMATOGMPHY """""" 126
`NEUTRALIZATION or eiaLoeicAL ACTIVITY ...... 127
`To detectantlbody
`127
`', """""""""
`'
`'
`Using antibody as an Inhibitor ................. 127
`SUM MARY .......................... 128
`F
`URTHER READING ..................... 129
`
`7 - Cellular techniques, 130
`ISO
`
`LATION OF LEUKOCYTE SUBPOPULATIONS ..... 130
`
`Buikiechniques ........................ 130
`Separation based on physical parameters
`. .......... 130
`Separation exploiting biological parameters
`.
`.
`.
`.
`.
`.
`.
`.
`.
`. 131
`Selection by antibody cooling ................. 131
`Cell selection bytne FACS .................... 131
`Enrichmentof antigen-specific populations ............ 131
`IMMUNOHISTOCHEMISTRY — LOCALIZATION
`i ..... 133
`.
`0F ANTIGENS IN CELLS AND TISSUES
`.
`.
`lmmunofluorescence techniques ................ 133
`Direct testw1th labeled antibody ............... 134
`Indirectfesfforanfibody
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`,
`.
`.
`.
`.
`.
`. 134
`Hi h resolution with the confocal microsco e
`135
`g
`_
`p """""
`Flow cytafluorimeiiy ..................... 135
`.
`.
`.
`Thede'em" “"d'm'“t'°”°”"m°e"5 """""" ‘37
`Otherlabeledaniibodymeihods ..........,... 139
`.
`.
`.
`.
`Localization intissues ofa gene product
`........... . 139
`ASSESSMENT or FUNCTIONAL ACTIVITY ........ 1411
`,
`The activity of phagocytic cells .................. 140
`.
`Lymphocyte responsiveness ................... 140
`.
`..
`,
`.
`.
`Umiiing dilution analySis ................
`.
`.
`. 140
`_
`,
`,
`Enumeration of antibody-fanning cells .............. 140
`.
`The immunotluorescence sandwich test ............ 140
`.
`Plaque techniques ..................... 141
`.
`.
`.
`A
`.
`AnaIVSis of functional activity by cellular reconstitution ...... 142
`.
`.
`.
`Radiation chimeras ...................... 142
`.
`.
`.
`Mice With severe combined Immunodeficiency (SCID) ...... 142
`Cellular interactions In vlf o
`142
`.
`.
`r """""""""
`Probing function with antibodies ................. 143
`GENETIC ENGINEERING 0F CELLS ............ 144
`.
`.
`.
`Insertion and modification of genes in mammalian cells ...... 144
`Introducin new enesintoanlmals
`144
`g.
`, g
`.
`,
`. """"""""
`Establishing designer mice bearing new genes ........ 144
`cries introduced Into embr onlc stem cells
`Tran
`144
`Gesfie them In humans
`Y
`"""" i 45
`SUMMARY W
`""""""" '
`‘
`'
`'
`'
`14'}
`""""""" ‘ """"""
`FURTHER READING """"""""""" 148
`
`PART 4 - THE ACQUIRED IMMUNE
`RESPONSE
`
`8 - The anatomyofthe immune response, 151
`THE SURFACE MARKERS OF CELLS IN THE IMMUNE
`SYSTEM
`151
`THE NEED r011 ORGANIZED LYMPHOID TISSUE ..... 151
`LYMPHOCYTES TRAFFIC BETWEEN LYMPHOID
`TISSUES ......................... . 153
`Lymphocytes home to their specific tissues ............ 153
`Transml ration occurslnthree sla
`s
`153
`Ste 19mm anmmn
`”‘3 """"""" 153
`p '
`9
`9 """""""""
`Step 2: 132 lntegrln activation and cell flattening
`........ 154
`Ste 3-Transml ratlonlntottietlssue(dla edesls)
`154
`p '
`9
`p
`""""
`Acloser iookatthe interacting receptors and their ligands ..... 156
`ENCAPSULATED LYMPH NODES .............. 156
`5-09“ areas
`156
`T cell areas """""""""""""" 157
`'
`...........................
`SPLEEN lllllllllllllllllllllllll 158
`MUCOSAL-ASSOCIATED LYMPIIOID TISSUE (MALT).
`,
`. 161
`Intestinal lymphocytes ..................... 162
`BONE MARROW CAN BE A MAJOR SITE or ANTIBODY
`SYNTHESIS llllllllllllllllllllllll 162
`
`Lassen — Exhibit 1044, p. 5
`
`Lassen - Exhibit 1044, p. 5
`
`

`

`vlll
`
`CONTENTS
`
`THE ENJOYMENT OF PRIVILEGED SITES ........ . 163
`THE HANDLING OF ANTIGEN ............... 163
`Macrophages are general antigen-presenting cells ........ 163
`Interdlgltating dendrltlc cells present antigento T—Iymphocytes
`.
`.
`. 164
`Follicular dendrltlc cells stimulate B-cells In germinal centers
`.
`.
`. 165
`M-cells provide the gateway to the mucosal lymphoid system .
`.
`.
`1156
`SUMMARY .......................... 166
`FURTHER READING ..................... 167
`
`9 » Lymphocyte activation. 168
`IMMUNOCOMPETENT T- AND B-CELLS DIFFER IN
`MANY RESPECTS ....................... 168
`T-LYMPHOCVTES AND ANTIGEN-PRESENTING CELLS
`INTERACT THROUGH SEVERAL PAIRS 0F ACCESSORY
`MOLECULES ......................... 169
`THE ACTIVATION OF T-CELLS REOUIRES
`TWO SIGNALS
`....................... 189
`PROTEIN TYROSINE PHOSPHORYLATION IS AN EARLY
`EVENT IN T-CELL SIGNALING ............... 170
`DOWNSTREAM EVENTS FOLLOWING TOR
`SIGNALING ......................... 171
`
`The phosphotldylinosltol pathway ................ 171
`p21 rastunction ........................ 171
`Control at IL—2 gene transcription ................ 171
`Further thoughts on the control at T-celi triggering ......... 171
`A serial TCR engagement model tor T-cell activation
`...... 171
`Damping T-cell enthusiasm .................. 1 73
`B-CELLS RESPOND TO THREE DIFFERENT TYPES
`OF ANTIGEN ......................... 173
`1 MM thymus-Independentantigens .............. 173
`2 Type 2 thymus-Independent antigens .............. 173
`3 Thymus-dependentantlgens ................. 174
`The need for collaboration with T—helper cells
`......... 174
`.
`Antigen processing by B-cells .....
`......... 174
`THE NATURE OF B-CELI. ACTIVATION ........... 176
`B-cells are stimulated by cross-linking surface lg ......... 176
`T-helper cells activate resting B-cells ............... 177
`SUMMARY .......................... I77
`FURTHER READING ................. 178
`
`10 - The production of effectors, 179
`A SUCCESSION OF GENES ARE UPREGULATED
`179
`BY T-CELL ACTIVATION ...............
`. 179
`CYTOKINES ACT AS INTERCELLULAR MESSENGERS .
`. 180
`Cytoklne action lstranslent and usually short range
`.
`.
`.
`.
`.
`.
`.
`Cytoklnes actthrough cell surface receptors ........... 180
`The gp 130 subtamlly .................... 182
`The [to and ye receptor subiamilles .............. 182
`Signal transduction through cytoklne receptors .......... 182
`Cytokines oiten have multiple eftects ............... 182
`Network interactions ...................... 1 83
`DIFFERENT CD4 T-CELL SUBSETS CAN MAKE
`DIFFERENT CYTOKINE PATTERNS ............. 184
`The bipolar THl/THZ concept .............. .
`.
`.
`, 184
`Interactions with cells at the Innate Immune system may bias
`the Tilt/TH2 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
`Chemotoxls ........................
`187
`Macrophage activation ...................
`187
`Combating viral iniection .................. . 187
`Killer T—cells ....................... .
`. 188
`The generation of cytotoxic T-cells ............
`.
`188
`The lethal process .....................
`188
`lntlammatlon must be regulated ................. 189
`PROLIFERATION AND MATURATION 0F 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 II-CELLS .................
`Class-switched B-ceils are subject to high mutation rates alter
`the initial response ....................... 193
`FACTORS AFFECTING ANTIBODY AFFINITY
`.
`IN THE IMMUNE RESPONSE .............
`The ettect of antigen dose ...................
`Maturation ofcttlnity ................... .
`MEMORY CELLS ......................
`The memory population is not simply an expansion oi
`corresponding naive cells .................... 196
`SUMMARY .......................... 198
`FURTHER READING .................. .
`199
`
`. 194
`194
`. 195
`195
`
`192
`
`11 - Control mechanisms, 201
`ANTIGEN IS.A MAJOR FACTOR IN CONTROL ...... 201
`Antigens oan tntertere with each other .............. 202
`ANTIBODY EXERTS FEEDBACK CONTROL ........ 202
`T-CELL REGULATION .................... 203
`T—helper cells ........ -.' ........... .
`.
`.
`.
`203
`Neil suppression
`,
`.
`. .................. 204
`Suppressorand helper epltcpes can be discrete ....... . 204
`CharacIeristlcs ot suppression ................. 204
`Suppression due to T—Tlnteraction on antigen-presenting cells .
`. 206
`Ettector T-cells are guided to the appropriate target by we
`207
`.
`surtoce molecules ................. .
`207
`IDIOTYPE NETWORKS ..................
`. 207
`Jeme’s network hypothesis
`.
`.
`............
`.
`. 208
`Evidence tor ldiotyplc networks .............. .
`Anti-Idlotype can be Induced by outolcgous ldiotypes ...... 208
`A network Is evident in early life
`........... 208
`T-cells can also do it ..................... 209
`Preoccupatlon ot networks with salt ............... 209
`ldiotyplc regulation of Immune responses ............ 210
`Manipulation at the immune response through idlotypes ...... 211
`THE INFLUENCE OF GENETIC FACTORS ......... 213
`Some genes ctfect general responsiveness ............ 213
`Immune response llnked to immunoglobulln genes ........ 213
`Immune response can be intluenced bythe MHC ......... 213
`The Ir genes map to the H—ZI region and control T—B
`cooperation ......................... 214
`ARE THERE REGULATORY IMMUNONEUROENDOCRINE
`N ETWORKS? ......................... 216
`A neuroendocrine feedback loop aftecting immune responses
`.
`,
`. 216
`Sex hormones come into the picture ............... 21 7
`
`Lassen — Exhibit 1044, p. 6
`
`Lassen - Exhibit 1044, p. 6
`
`

`

`CONTENTS
`
`ix
`
`Inching towards ‘psycholmmunalagy' .............. 217
`EFFECTS OF DIET, EXERCISE, TRAUMA AND AGE
`0" IM M "N'"
`----------------------- 2‘ 8
`Malnutrition diminishes the effectiveness of the Immune
`response ____________________________ 218
`ormrfactors __________________________ 219
`SW MARY lllllllllllllllllllll y
`_
`’
`. 220
`FURTHER READING ..................... 221
`
`12 ' Ontogeny and phylogeny, 223
`THE NIuLTIPorENTIAL HEMATOPOIETIG erN cELL
`GIVES RISE TO THE FORMED ELEMENTS
`OF THE Moog ,,,,,,,,,,,,,,,,,, 223
`THE THVMUS PROVIDES THE ENVIRONMENT
`FOR T~GELL DIFFERENTIATION ........... 225
`Bone marrow stem cells become immunocompetent T—cells
`in the thymus _________________________ 226
`T-CELL ONTOGENY _______________ 227
`Differentiation is accompanied by changes In surface markers
`.
`.
`. 227
`Receptor rearrangement .................... 228
`The development of alt receptors ............... 229
`The development of 75 receptors llllllllllllll 229
`Cells are positively selected for self-MHc restriction In the thymus .
`. 229
`T-CELL TOLERANCE _________________ 23]
`The induction of immunological tolerance is necessaryto avoid
`self-reactivity ......................... 231
`Self-tolerance can be induced in the thymus ............ 231
`lntrathymlc olonai deletion leads to self-tolerance ......... 231
`Factors aflecflng positive or negative selection in the thymus .
`_
`_ 233
`7.09" tolerance can be due to clonol energy lllllllllll 234
`Infectious unergy ______________________ 235
`Lack of communication can cause unresponsiveness ....... 235
`some DIFFERENTIATE IN THE FETAL LIVER
`AND THEN IN BONE MARROW lllllllllllllll 238
`3.1 AND 3,2 CELLS REPRESENT TWO DISTINCT
`popu ”no N s """""""""""""""""" 237
`DEVELOPMENT OF 3-05“ spEcmcn-y lllllllll 233
`The sequence of Immunoglobulln gene rearrangements ...... 238
`The Importance of allelic exclusion lllllllllllllll 240
`Different specific responses can appear sequentially ....... 240
`THE moucnou 0F 10L: RANGE m
`3. mm; H OGYTES ____________________ 240
`Tolerance can be caused by clonal deletion and clonal anergy
`.
`.
`. 240
`Tolerance may result from helpless B-cells IIIIIIIIIII 241
`THE OVERALL RESPONSE IN THE NEONATE
`______ 243
`THE EVOLUTION OF THE IMMUNE RESPONSE _____ 243
`Recognition of self is fundamental for multicellular organisms
`.
`.
`. 243
`Invertebrates hcvs microbial defense mechanisms ........ 244
`Adaptive Immune responses appear with the vertebrates ...... 245
`Lower vertebrates ...................... 245
`Hensappea, llllllllllllllllllllllll 245
`Generation of antibody diversity ............... , 247
`THE EVOLUTION OF DIsTINcT 3- AND T-cELL
`LINEAoEs WAs AccOMPANIED at THE DEVELOPMENT
`or SEPARATE srrEs FOR DIFFERENTIATION ...... 247
`CELLULAR necosNITION NOLEcULEs EXPLOIT
`THE IMNuuosLoeuuN GENE SUPERFAMILY ...... 247
`SUM MARY ________________________ 248
`FURTHER ITEADI No ..................... 250
`
`PART 5 .
`
`I M M u NITY TO IN FE CTION
`
`13 - Adversarial strategies during infection, 253
`
`INFLAMNIATION REVISITED ................ 254
`Mediators of Inflammation .................. . 254
`Leukocytes bind to endothellal cells through pdlred adhesion
`"WINGS --------------------------- 255
`initiation of the acute Inflammatory response ........... 255
`The ongoing inflammatory process ................ 256
`Regulation and resolution oflnilammatlon ........... . 257
`Chmmclnflummafim --------------------- 258
`EXTRACELLULAR BACTERIA SUSCEPTIBLE T0 KILLING
`at PHAsochosIs AND COMPLEMENT ......... 258
`Bacterlaisurvlvalstrategles ................... 258
`Emmi! PMQOW'OS'S -------------------- 258
`Challenging the complement WSW“ -------------- 259
`Antigenic variation ...................... 260
`The host counter-attack ..................... 26Q
`70“” neutralization ---------------------- 251
`Opsonlzaiion otbacterla
`-
`i’ -------------- 261
`Some further effects of complement -------------- 263
`The secretory immune system protects the external mucosal
`surfaces --------------------------- 263
`Some specliic bacterial infections ................. 265
`BACTERIA WHICH GROW ”I A" INTRAcELI-“UR
`"WT“ -
`. -------------------- 267
`Bacterial gamblls
`-
`-l-
`-
`-.
`,
`- -------------- 267
`03'5”“ '5 by T-ceII-medlated ImmunIty (CMI) ----------- 253
`Activated macrophages kill Intracellular parasites ......... 268
`Examples of intracellular bacterial infections ........... 269
`LISIBIICI ........................... 269
`Tuberculosis ------------------------- 269
`“WW -
`'
`I
`-
`.
`-
`-
`.
`-
`.
`.
`-
`-
`-
`-
`; ----------- 271
`IMMUNITY T0 VIRAL INFECTION .
`.' ........... 271
`Immunity can be evaded by antigen changes ........... 271
`Changing antigens by arm and ShIfI .............. 271
`Mutation can produce antagonistic T-cell epitopes ....... 272
`5°” "”555 “a" ““9” “""99" Prose-“mg ----------- 272
`Viruses can interfere with immune effector mechanisms ...... 272
`Playing games With the complement system .......... 272
`Suboluglng cell-medIated Immunity .............. 272
`Protection by serum antibody .................. 273
`Localtactore """""""""""""" 273
`Cell-mediated immunity gets to the intracellular virus ....... 273
`NK cells can kill viraliy Infected targets ............. 273
`‘cytotoxIcT-cells (Tc) arecruclalelements In Immunityto
`' 275
`-
`-
`I,
`'"Iecfion by budding viruses
`-
`.
`.'
`-
`-‘ ----- .'
`-
`4 275
`-
`-
`Cytoklnes recruit “99‘0“ and Wow“ a cordon WWII”
`”‘1'”de has a parttoo -------------------- 275
`IMMUNITY 1'0 FutIGl ----------------- 275
`IMMUNITY To FAIIAsmc INFEcTIONs ......... 27s
`The "03”680001985 ----------------------- 275
`Humml'mmunlh’
`--------------------- 277
`GEN-medlatefilmmunliv -------------------- 278
`EVUSIveslrulegIesbthe parasite ................ 279
`Refilsfflncmefiwormechunlsms -------------- 279
`AVO'd'ng"fl“gemmgnmon Wham“ ------------ 28°
`Deviation of the host immune response ............ 281
`'mmuml’a'hmgv --------------------- . 281
`
`-
`
`Lassen — Exhibit 1044, p. 7
`
`Lassen - Exhibit 1044, p. 7
`
`

`

`SUMMARY .......................... 281
`FURTHER READING ..................... 284
`
`PRIMARY T-CELL DEFICIENCY ............... 315
`COMBINED IMMUNODEFICIENCY
`............ 317
`
`GONTE NTS
`
`14 - Prophylaxis, 285
`PASSIVELY ACOUIRED IMMUNITY ............. 285
`Maternaity acquired antibody .................. 2B7
`Pooled human y-globulln .................... 287
`Cultured antibodies made to order ............... . 287
`Adoptive transfer of cytotoxic T-ceils ............... 288
`VACCINATION ........................ 238
`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 attenuated vaccines ........... 293
`SUBUNIT VACCINES CONTAINING INDIVIDUAL
`PROTECTIVE ANTIGENS .................. 293
`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
`E-celi epitopes ........................ 297
`T-ceii epitopes ........................ 297
`Making the peptides immunogenic ............... 298
`Ialotypes can be exploited as epliops-spealfic vaccines ...... 299
`Unwanted epitope-Icss mutants can correctly fold desired
`discontinuous B-cell epitopes .................. 299
`CURRENT VACCINES .................... 299
`EXPERIMENTAL VACCINES IN DEVELOPMENT ...... 300
`Malaria ............................. 300
`Schistosomiasis ......................... 302
`Cholera ............................ 303
`Tuberculosis .......................... 303
`ADJUVANTS ......................... 303
`Depot effects .......................... 303
`Macrophage activation ........... . ......... 304
`Specific effects on lymphocytes ................. 304
`NEw APPROACHES TO THE PRESENTATION
`OF ANTIGEN ......................... 304
`SUM MARY .......................... 305
`FURTHER READING ..................... 307
`
`PART 6
`
`CLIH ICAL IMMUNOLOGY
`
`15 - Immunodeficiency. 31 1
`PRIMARY IMMUNODEFICIENCY STATES
`IN THE HUMAN ....................... 311
`DEFICIEHCIES OF INIIATE IMMUNE MECHANISMS .
`.
`. 311
`Phagocytic cell defects ..................... 311
`Complement system dellciencles ................. 312
`Defects In control proteins ................... 312
`Deficiency of components of the complement pathway ..... 31 3
`PRIMARY B-CELL DEFICIENCY ............... 314
`
`. 317
`
`Mutation in the common cytokine receptor yu chain causes SCID .
`SCID can be due to mutations In purine salvage
`pathway enzymes ....................... 31 7
`other SCID variaMs ....................... 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 ..............