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

`

`==
`
`© 1971, 1974, 1977, 1980, 1984, 1988,
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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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`are available fromthe British Library
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`ISBN 0-86542-729-1
`
`Lassen - Exhibit 1044, p. 2
`
`Lassen - Exhibit 1044, p. 2
`
`

`

`(=
`
`'
`
`CONTENTS
`
`PREFACE ......5--5 5855558
`
`ene
`
`ae aia Ke xili
`
`ACKNOWLEDGEMENTS ...-....e0.5205 see XV
`
`Target cells aretoldtocommitsuicide 2... 1. ee ee ee 19
`Eosinophils 2.2... 1 ee eee aus
`§=20
`SUMMARY ... 0.0... 0p wee
`ee ee eae
`ure
`20
`
`ABBREVIATIONS . ..--.-. ++ Ee ROW OG Se 5 xv
`USER GUIDE ©... ee ee vee
`KK
`
`.
`
`3
`6
`
`33
`
`2 + Specific acquired Immunity, 22
`22
`...
`THE NEED FOR SPECIFIC IMMUNE MECHANISMS
`ANTIBODY—THE SPECIFIC ADAPTOR .......... 22
`Antibody initiates a new complement pathway Cclassical).... .
`23
`Complexed antibodyacflvates phagocyticcells ........4.
`25
`THE BASIS OF IMMUNOLOGY
`PART 1
`CELLULAR BASIS OF ANTIBODY PRODUCTION ..... 25
`Antibodies are made by lymphocyles ...........00 0.
`25
`T
`+
`Innate immunity, 3
`Antigen selects the lymphocytes which make antibody ...... 26
`EXTERNAL BARRIERS AGAINST INFECTION ........
`The need for clonal expansion means humoralImmunity must
`PHAGOCYTIC CELLS KILL MICROORGANISMS .....
`beacquired 2... ee ee - 2
`Polymorphs and macrophages are dedicated ‘professional’
`ACQUIRED MEMORY ...............--0505 28
`phagocytes2. 6
`Secondary antibody responses arebetier =... 1... we 28
`The polymerphonuclear neutrophil .. 2. 2-2. 6
`ACQUIRED IMMUNITY HAS ANTIGEN SPEGIFIGITY ...
`30
`Themacrophage 2... ee ee 6
`Discrimination betwesn differentantigens
`.........004 30
`Microbes are engulfed by phagocytosis... ........,. tea)
`6
`Discrimination betwesnsalfandnonself .... 2... ee ee
`32
`There Is on array of Killing mechanisms . 2. 2. ee ee 8
`VACCINATION DEPENDS ON ACQUIRED MEMORY ...
`32
`Killing by reactive oxygen Intermediotes 2... 1-1 eves
`8
`CELL-MEDIATED IMMUNITY PROTECTS AGAINST
`Killing by reactive nitrogen Intermediates...
`1
`1 ewe ee 9
`INTRACELLULAR ORGANISMS ........,.,..,.-.
`Killing by preformed ontimicroblais.
`. 2... 0...
`4 eee ee
`10
`Cytokine-producing T-cells help macrophagesfokill intracellular
`COMPLEMENT FAGILITATES PHAGOCYTOSIS ...... W
`porasitasee 33
`Complement anditsaciivation. .. 0... 0.0.8 ee eee WV
`Virally intacted cells can be killed by cytotoxic T-cells and
`C3 undergoes slow spontaneous cleavage ..........--.
`VW
`C3blevels are normally fighilycontrolled..,........6- W ADCOee 33
`C3 convertase is stabilized on microblai surfaces... ... 4. 1
`IMMUNOPATHOLOGY... ............ 0000005 35
`The post-C3 pathway generates a membrane attackcomplex ,.
`12
`SUMMARY .. 2.0.0.0... ee 35
`Complement has a range of defensive biological functions .....
`12
`FURTHER READING ..,... 0.0... 0.05 vue
`37
`1 G3b adheres to complement receptors... 6... ee 12
`Generalréading 6. 37
`2 Biologically activa fragments arereleased .......-.4,
`12
`Referencawork «ww 37
`3 The terminal complex can induce membranelesions .....
`14
`Historical2 38
`COMPLEMENT CAN MEDIATE AN ACUTE
`In-depth serles forthe advancedreader... 2. ...,....4,
`38
`14
`eer eee =
`INFLAMMATORY REACTION ........ ms
`Current Information 2... ee 38
`The mast cell playsacentralrole. 2... 14
`Multiple choice questions... 1 ee ee 38
`Mocrophages conaisodoit .... 0.0... 00005
`cae
`15
`Electronic publications (linked to ‘Roltt's Essential
`HUMORAL MECHANISMS PROVIDE A SECOND
`Immunology} 2... ee 39
`18
`DEFENSIVE STRATEGY .........-000 cnn uee
`Mojorjourndls
`.. 2... ee ee oo ae
`39
`16
`Acute phase proteins increase in responseto infection... ... .
`Interferons inhibit viral replication 2... ee 18
`EXTRACELLULAR KILLING ...,...-..-0s 000s
`18
`Natural killer(NK)cells
`. 0... ee ee 18
`
`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
`[MMUNOGLOBULIN STRUCTURE.............,
`IMMUNOGLOBULIN GENES......-..,....,.5,
`Immunoglobulins are encoded by muttiple gene segments .... .
`A special mechanism effects VDJ recombination
`STRUCTURAL VARIANTS OF THE BASIC
`IMMUNOGLOBULIN MOLECULE .........,...,
`ISOLYPBSee
`AllotypeS © ee
`IdlotypeBwe
`IMMUNOGLOBULINS ARE FOLDED INTO GLOBULAR
`DOMAINS WHICH SUBSERVE DIFFERENT
`FUNCTIONS... 2. ee ee ee
`Immunoglobulin domains have a chorocterlsilc structure... .
`Tha variobledomainbindsantigean ........,,..0006
`Constant region domains determine sacondary biological tunciion .
`IMMUNOGLOBULIN CLASSES AND SUBCLASSES
`Immunoglobulin G has major bul variedroles in extracellular
`defenseS 2 ee ee
`Activation of the classical complement pathway ..,.....
`The diversity of Feyrecepfots 6... . eee
`Nonprecipltating ‘univalent antibodies... ..........,
`Immunogtobulin A guards fhe mucosalsurfaces 2... .. 7.
`Immunoglobulin M provides a defense against bacteremia... .
`.
`Immunoglobulin Dis.acell surfacerecepior... 2.
`Immunoglobulin E triggers inflammotoryreactions ..,.....
`immunoglobulins are further subdividedinto subclasses
`SUMMARY 0... ee ee
`FURTHER READING ........-...,....0.005
`
`4 » Membranereceptors for antigen, 63
`THE B-CELL SURFACE RECEPTOR FOR ANTIGEN ....
`The B-cell inserts a transmembrane Immunoglobulin into
`ISSUIPOCE eee
`The surface immunoglobulin Is complexed with associated
`membraneproteinswe
`THE T-CELL SURFACE RECEPTOR FOR ANTIGEN
`.
`The receptorfor antigen Is a transmembrane heterodimer... .
`.
`There are two olasses of T-cellrecepiogs 2... le
`The encoding of T-cell receptors !s similar to that of
`Immunoglobulins
`. 2. ee ee :
`The CD3 complexis an integral part ofthe T-cell receptor...
`.
`.
`,
`THE GENERATION OF DIVERSITY FOR ANTIGEN
`RECOGNITION
`....,--- 0... cee eee
`Intrachain amplification of diversiy........,.00, =
`Random VDJ combination Increases diversity geometrically .
`.
`.
`Playing withthe junctions 6 ee
`Interchainamplification . 5. - ee
`Somatlehyparmutation 6... ee
`THE MAJOR HISTOCOMPATIBILITY COMPLEX
`CMHC) 2 ee
`Class | and class Il molecules are membrane-bound
`heterodimers
`5 we ee es ;
`MHCcloss] 6. ee
`MHGclassi] oe ee ee 1 Ma
`
`43
`
`45
`45
`45
`46
`
`47
`47
`4]
`50
`
`50
`50
`5]
`51
`51
`
`58
`58
`
`63
`
`83
`
`64
`65
`65
`65
`
`66
`67
`
`68
`69
`69
`69
`70
`70
`
`7\
`
`71
`71
`7
`
`Complement genes contribute to the remaining classIll region
`ofiheMHG 2.0. 72
`GenemapoftheMHG .. 2... ee es Saajeta
`72
`The genes of the MHCdisplay remarkable polymorphism 5 we ws
`75
`Nomenclature 2... 0-0 er ees tee eee
`18
`Inherltancecfthe MHC 2... 1 ee .
`77
`The tissue distributlon of MHC molecules
`6.
`6 et es 77
`MHCtunctions 2... ee 77
`SUMMARY ......0 00000 ee 78
`FURTHER READING ......---- 22 pee a
`79
`
`83
`83
`
`5 + The primaryInteraction with antigen, 80
`WHAT IS AN ANTIGEN? .. 0.000000. pe eee 80
`Of epitopes and antigen determinants... 6.) - see ree 81
`(dentification of B-cellepifopes we 81
`ANTIGENS AND ANTIBODIES INTERACT BY SPATIAL
`COMPLEMENTARITY NOT BY COVALENT BONDING ...
`Variation in haptenstructure shows imporlance of shape... .
`.
`Spatial complementarity of epitope and paratope can be
`demonstrated og 83
`Antigen-antlbody bonds ore readily reversible 6... .
`B4
`THE FORCES BINDING ANTIGEN TO ANTIBODY
`BECOME LARGE AS INTERMOLECULAR DISTANCES
`86
`BECOME SMALL ... 1... 0-0: peeve err ee
`lElectrosiatic 6g 86
`2Hydrogenbonding 6. 87
`BHydrophobic 6 87
`AVonderWadls 2... ee ..
`87
`AFFINITY MEASURES STRENGTH OF BINDING OF
`ANTIGEN AND ANTIBODY-......-.----: 00% .
`The ovidity of antiserum for antigen — the bonus effect
`ofmultivalency 2... 00. ee ee et
`THE SPECIFICITY OF ANTIGEN RECOGNITION.
`BY ANTIBODY ISNOTABSOLUTE .....-- sere 90
`WHAT THE T-CELL SEES ........-0 2+ +r eee 91
`Haplotyperastriction reveals the need for MHC participalion ....
`91
`T-cells recognize a linear paptide sequencefrom the antigen ..,. 1
`PROCESSING OF INTRACELLULAR ANTIGEN
`FOR PRESENTATION BY CLASSI MHG
`... se eeee
`PROCESSING OF ANTIGEN FOR CLASS II MHC
`93
`PRESENTATION FOLLOWS A DIFFERENT PATHWAY...
`THE NATURE OF THE ‘GROOVY’ PEPTIDE .......-- 96
`BindingtoMHCclassless 96
`BindingioMHGclass. es .
`97
`THE of T-CELL RECEPTOR FORMS A TERNARY
`98
`COMPLEX WITH MHC AND ANTIGENIC PEPTIDE ....
`98
`Topology of tha fesnarycomplex .. 1... -- 2 vee ..
`T-CELLS WITH A DIFFERENT OUTLOOK ........- 99
`Non-classical class | molecules can also presentantigen. ..... 99
`MHC class l-like molecules... 0. ep ee ee 99
`The family of CD1 non-MHCclass I-like molecules can
`99
`iwie
`presantexoticantigens «6. ee ee i
`8 TCRs have somefeatures of antibody 2.0... ee es 100
`SUPERANTIGENS STIMULATE WHOLE FAMILIES
`OF LYMPHOCYTE RECEPTORS ....... 02+ seus 100
`Bacteria! toxins represent one major group ofT-cell
`guperontigens 6. ee ty... 100
`Endogenous mouse mammary tumor viruses (MMTV) act
`assuperaniigens 5... 100
`Microbescon also provide B-cell superantigens
`...., 44+ 101
`
`33
`
`88
`
`88
`
`92
`
`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 2-6 ee 101
`SUMMARY 2.00.0... 00 eee ee 102
`FURTHER READING ......-. 0.2.00. ee eee 103
`
`Bulktechniques . 2. 0 ee 130
`Separation based on physical porameters 2... 6. eee eee 130
`Separation exploiting biological parameters .......-.. 13)
`Selection by antibody cocting . 2... ee ee 131
`CellselectionbytheFACS 5.000. ee 131
`Enrichmentof antigen-specific populations ©... ee re ee 131
`IMMUNOHISTOCHEMISTRY — LOCALIZATION
`OF ANTIGENS IN CELLS AND TISSUES
`......4.- 133
`TECHNOLOGY
`PART 3
`Immunofluorescence techniques... 1... ee ee 133
`6 -
`Immunochemicaltechniques, 107
`Direct testwith labeled antibody 2... eee eee 134
`ESTIMATION OF ANTIBODY ............ 2.6. 107
`Indirecttesiforantibody
`.............0.54.4 184
`:
`a?
`High resolution wih the confocal microscope
`135
`Antigen--antibody Interactions in solution =... sss sy os ”
`8
`-
`PRs tail Mito
`Whal does serum ‘antibody content mean? ........ »
`+ 107
`Flowcytofluorimetty
`60 oe ee ee 135
`.
`:
`-
`;
`.
`The classical precipitinreaction ». 1... eee 109
`The detection and isolation otrarecalls
`= =.
`.
`-
`-
`saa mtr a 17
`Nonprecipttating antibodies can be detected by nephelomet
`109
`Other labeled antibody methods 2... es 189
`ool eee
`n
`be
`detected
`DyREPREOMENY eit
`a
`Complexes formed by nonprecipitating antibodies can
`Localization in tissues ofageneproduct
`.. 1... ee eee » 139
`be
`precipitated
`10
`Se
`ee eessl ASSESSMENT OF FUNCTIONAL ACTIVITY ........ 140
`Enhancementof precipitation by countercurrent
`j
`The activity of phagocyticcelis .. 1. ee ee 140
`|Immunoslectrophoresis 2... 110
`.
`Lymphocyie responsiveness ©... 0. ee 140
`:
`a
`Measurement of onfibody affinity
`.......0.-.+.00 4s 110
`eee
`.
`.
`.
`Limiting dilutionanolysis 2. ee ee -.. 140
`Agglutination of antigen-cooled parficies ..........5 +s 111
`.
`.
`:
`:
`:
`Enumeration of anlibody-formingcells .. 0... 0. eee eee 140
`Immunoassayfor antibody using solid-phase antigen ....... 112
`:
`The immunoftuorescance sandwichtes} .. 2... 0.254 140
`Theprinciple2. 112
`:
`:
`:
`:
`Plaquetechniques 2.0... ee es 141
`Awide variety of labelsisavoilable «0... 1 we 113
`-
`:
`.
`a
`;
`:
`Analysis of functional activity by cellular reconstitution ...... 142
`ELISA (enzyme-linked immunosorbentassay) ........ 113
`a :
`Radiotionchimergs .. 0... ee 142
`Otherlabels 2... 1. ee 113
`.
`.
`Mice with severe combined immuncdeficiency (SCID)...
`.
`.
`- 142
`puracslaICU eSDIONS 5 ae a a se _
`Cellular interactions in vitro
`142
`IDENTIFICATION AND MEASUREMENT OF ANTIGEN, .. 114
`;
`:
`FO vere sss cam sit sett
`_—-
`.
`Probing function with antibodies... 01. ee 143
`Precipitation reaction‘can be carried outingels
`........5 114
`Fs
`;
`GENETIC ENGINEERING OF GELLS ......,.4065 144
`Characterization of antigens by electrophoresis and
`.
`:
`.
`;
`Insertion and modification of genes in mammalianeells ...... 144
`Te eee 114
`Introducing new genes into animals
`144
`Quantification by single radial Immunodiffusion (SRID) .... . 115
`9 \ g
`_ fe
`.
`Estoblishing ‘designer mice’ bearingnew genes. ow ee es 144
`The nephelomelric assay foraniigen «+ sve ew ns pe
`Transgenes introduced Into embryonic stem cells
`144
`
`
`
`
`Sodium dodecyl sulfate-polyacrylamidegel elecfrophoresis VORICSTBCBNBie:ths therapy in humans ie Hum aeiit 145
`(SDS-PAGE)for analysis of Immunoprecipitates and
`SUMMARY
`PYINMUMONS re "see 147
`Immunoblotting oe ee es 160
`eran CeeT™
`Thelmmunoossay ofantigens 6... ee te ee ee 17
`FURTHER READING «1.1. +s say os Boke 148
`Immuncassay on mulliple microspots
`6
`1 ww ee et 118
`Epllopemapping «0. ee ee 118
`PART 4 - THE ACQUIRED IMMUNE
`Toallepitopes 6 ee 118
`RESPONSE
`B-cellepitopes 6. ee 119
`DETECTION OF IMMUNE COMPLEX FORMATION .... 120
`8 - The anatomyof the immune response, 151
`Beka Adnipopire te ORDER Ss He
`THE SURFACE MARKERS OF CELLS IN THE IMMUNE
`The monoctonai antibody revolution 2... 1... ee 120
`SYSTEM
`151
`Seoniys ees a+ oh i THE NEED FOR ORGANIZED LYMPHOID TISSUE... .. 151
`
`See LYMPHOCYTES TRAFFIC BETWEEN LYMPHOID
`Human monoclonaiscanbemadé.........-5 +268 123
`TISSUES 2.0.0. ee . 153
`EngineeringantIbodies 2... 0... ee ee 124
`Lymphocytes home to thelr specific tissues... 1.1... se 153
`.
`—,
`Fields ofdnfibodies ow. ee ee i Transmigration occurs In three stages
`153
`Drugs can be based on the CDRsof minibodles ......... 126
`ste 7 ier BS ees =
`PURIFICATION OF ANTIGENS AND ANTIBODIES
`pi
`8 Oe
`Step 2; By Integrin activation and call flattening «1... +. 154
`BY AFFINITY CHROMATOGRAPHY... ss ws Leia
`Step 3: Transmigration into the tlssue (dlapedesis)
`154
`pe
`9
`ara a
`NEUTRALIZATION OF BIOLOGICAL ACTIVITY ...... 127
`To detact antibody
`127
`Acloser ookatthe Interacting receptors ond thelr ligands ..... 156
`ee ees ENCAPSULATED LYMPH NODES............054 158
`Using antibody asan{nhibitor .. 0... ee 127
`B-cell areas
`158
`SUMMARY 2.00.00... 0 ce ee 128
`imine. c#a......u.....Geee+gs on 187
`
`
`F SLEWUIGUB«oo. 6 ew ew eet
`
`
`URTHER READING ....,..,. 0.0, +e per ueeue 129
`SPLEEN ........... ccc cee cee eens 158
`MUCOSAL-ASSOCIATED LYMPHOID TISSUE (MALT)... 161
`Intestinal lymphocytes. 00. ee 162
`BONE MARROW CAN BE A MAJOR SITE OF ANTIBODY
`SYNTHESIS. .....,-0..ccceeuueeuceees 162
`
`7 + Cellular techniques, 130
`Iso LATION OF LEUKOCYTE SUBPOPULATIONS ..... 130
`
`Lassen - Exhibit 1044, p. 5
`
`Lassen - Exhibit 1044, p. 5
`
`

`

`vill
`
`CONTENTS
`
`THE ENJOYMENT OF PRIVILEGED SITES........ » 163
`THE HANDLING OF ANTIGEN ...........04 4s 163
`Macrophagesare general antigen-presenting cells 2... 1. ee 163
`Interdigitating dendritic cells present antigen to T-lymphocytes ... 164
`Follicular dendritic cells stimulate B-cells in germinal centers
`... 165
`M-calls provide the gateway to the mucosal lymphold system ... 186
`SUMMARY ... 000.0000 0.00 ec eee ee 166
`FURTHER READING ........ 0.0, 00 eee euue 167
`
`9 - Lymphocyte activation, 168
`IMMUNOCOMPETENT T- AND B-CELLS DIFFER IN
`MANY RESPECTS. ..... 0.0... pee eee 16B
`T-LYMPHOCYTES AND ANTIGEN-PRESENTING CELLS
`INTERACT THROUGH SEVERAL PAIRS OF ACCESSORY
`MOLECULES ... 0... cee ee ee 169
`THE ACTIVATION OF T-CELLS REQUIRES
`TWOSIGNALS 2.0... .... ee ee 169
`PROTEIN TYROSINE PHOSPHORYLATION IS AN EARLY
`EVENTIN T-CELLSIGNALING..........,.... 170
`DOWNSTREAM EVENTS FOLLOWING TCR
`SIGNALING .. 0.0... 0... 0 ee ee WW
`
`T-CELL EFFECTORS IN CELL-MEDIATED IMMUNITY .. 186
`Cytokines mediate chronic inflammatory responses ....... - 186
`Earlyevents 2. ee ee 186
`Chemotoxis 2... 187
`Macrophoge activation ©... ee 187
`Combating virdlinfection 2... ee . 187
`KillerT-calls 2... ee 188
`The generation of cytotoxic T-cells 6... ......02.,
`..
`188
`Theletholprocess
`6 wwwe 188
`inflammation mustbereguidted .. 0... . eee ee 18¢
`PROLIFERATION AND MATURATION OF 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..............04.
`Class-switched B-cells are subject to high mutation rates after
`theinitialresponse 2... ee 193
`FACTORS AFFECTING ANTIBODY AFFINITY
`.. 194
`IN THE IMMUNE RESPONSE .............
`Theeffactofantigandose 6... ....... 0... 0-004
`194
`Maturation of affinity 6... ee ee
`195
`MEMORY CELLS .........,,.. 4-0 c eee
`195
`The memory population Is not simply an expansion of
`corraspondingnalvecelis 2.0... .. ee ee ee 196
`SUMMARY .. 0.0.0.0... eee ee 198
`FURTHER READING .......,......-..04,
`..
`199
`
`... 190
`
`192
`
`The phosphatidylinositol pathway 6... 2. ee 71
`p2lrosfunction 2... ee 71
`Control of ll-2 gene transcription... 2.0.0...
`0.206 oe 171
`Further thoughts on the control of T-cell tiggering ......... 171
`Aserlal TCR engagement model for T-cellactivation
`...... 71
`Damping T-cellenthusiasm ........-2.....0-.0, 173
`B-CELLS RESPOND TO THREE DIFFERENT TYPES
`11 - Control mechanisms, 201
`OF ANTIGEN... 1... ee 173
`ANTIGEN IS.A MAJOR FACTOR INGCONTROL ...... 201
`1 Type | thymus-Independentantigans ..........-004 173
`Antigens oan Interferewitheach other .........0-0 04 202
`2 Type 2thymus-independentantigens ....,...-.,004 173
`ANTIBODY EXERTS FEEDBACK CONTROL ........ 202
`3Thymus-dependentantigens . 0.0. ee ee 174
`J-CELL REGULATION ..........,....405-04 203
`The need for collaboration with T-helpercells
`.. 2... 00 174
`
`Antigan processing by B-calis 2... ee 174 T-helpereelis ... 2.0.0, See ems -.r.203
`THE NATURE OF B-CELL ACTIVATION,i ret SHO ib ecw 176
`T-cell suppression Se ee 204
`Supprassor and helper epitopes canbe discrete ....... . 204
`B-cells are stimulaied by cross-linking surfacelg 2... 2.0% 176
`Characteristics of suppression, ©... ee 204
`T-halper cells activate resting B-cells 2... VW
`SUMMARY ....,.... 0.0... 40.0 beeen 177
`Suppression due to T-T interaction on antigen-presenting cells .
`. 206
`FURTHER READING ...........0006s ev uue 178
`Effector T-cells are guided to the appropriate torget by MHC
`surface molecules ..........-..,004 ....207
`IDIOTYPE NETWORKS ..........,,.......
`207
`derne’snetworkhypothesis
`2. ee 207
`Evidence forldlotyplenetworks 2.2... ee es .
`. 208
`Anti-idlotype can be Induced by autologous Idlofypes ...... 208
`Anetwork Isevidentineorylifa
`.....,.......40, 208
`Tcellscanaisodgit 2. ee ee 209
`Preoccupation of nefworkswithself 2... .....,.,,008 209
`Idiotypic regulation of Immune responses... .,......... 210
`Manipulation of the immune response through idlotypes ..... . 211
`THE INFLUENCE OF GENETIC FACTORS ......... 213
`Some genes affect general responsivenéss ... 1... ee 213
`Immuneresponselinked to Immunoglobulingenes ........ 213
`immune response con be influencedbytheMHGC ......... 213
`The Ir genes map to the H-2I region and control T-B
`cooperation 2 ee 214
`ARE THERE REGULATORY IMMUNONEUROENDOCRINE
`NETWORKS? .. 0.0... 0... . epee een 216
`A neuroendocrine feedbackloop affecting immune responses
`.. . 216
`Sex hormonescomeintothaplctura 2... we 217
`
`10 + The production ofeffectors, 179
`A SUCCESSION OF GENES ARE UPREGULATED
`179
`BY T-CELL ACTIVATION
`......,.,..-,04.
`CYTOKINES ACT AS INTERCELLULAR MESSENGERS ., 170
`Cytokine actionIs frangient and usually shortranga . .. .... . 180
`Cytokines act through cell surface receptors
`2 1, we 180
`Thegp 130subfamily 2.0... 182
`The Be and yo receptor subfamilies 2 1. ee 182
`Signal transduction through cytokine receptors... 1... ee 182
`Cytokines often have multipleeffects . 0... te 182
`Networkinteractions 2... eee 183
`DIFFERENT CD4 T-CELL SUBSETS CAN MAKE
`DIFFERENT CYTOKINE PATTERNS ............, 184
`The bipolar THi/Tu2 concepf.......20..0..
`... 184
`Interactions with cells ofthe Innate immune system may bias.
`theTHi/TH2response
`2 ww ee 186
`ACTIVATED T-CELLS PROLIFERATE IN RESPONSE
`TOGYTOKINES ..,......,. 0.0050 ‘
`
`186
`
`Lassen - Exhibit 1044, p. 6
`
`Lassen - Exhibit 1044, p. 6
`
`

`

`CONTENTS
`
`. 1... 0.1. es 217
`Inching towards ‘psycholmmunology’
`EFFECTS OF DIET, EXERCISE, TRAUMA AND AGE
`ON IMMUNITY | - 2 ee ee 218
`Malnutrition diminishesthe effectiveness of the Immune
`OPOee eee en eee eee lp 218
`OtherfactoS oe eee 219
`SUMMARY ........0-. 000-000 ue 2. 220
`FURTHER READING .........-. 0,00 c eae 22]
`
`12 - Ontogeny and phylogeny, 223
`THE MULTIPOTENTIAL HEMATOPOIETIC STEM CELL
`GIVES RISE TO THE FORMED ELEMENTS
`OFTHEBLOOD ..... eee 293
`THE THYMUS PROVIDES THE ENVIRONMENT
`FOR T-CELL DIFFERENTIATION ........... 225
`Bone marrow stem cells become immunocompetentT-cells
`inthathyMUS 2 eee 226
`T-CELLONTOGENY. 2.2... ,. 2... caus 997
`Differentiation is accompaniedby changes in surface markers
`.
`.
`. 227
`Receptor rearrangement 2... ee 228
`The development ofoBreceptors ......,,....0-- 229
`The development of ySreceptors 6.1... ee 229
`Cells are positively salacted for salf-MHCrestriction In tha thymus.
`. 229
`T-CELL TOLERANCE 2... pee ee ees 231
`The induction of immunological toleranceis necessaryto avoid
`self-recciivity 2. ee ee eee 231
`Selt-tolerance can beinducedinthethymus............ 231
`intrathymicolonaldeletion leadstoself-tolerance ......... 231
`Factorsaffecting positive or negative selection inthe thymus.
`.
`. 233
`T-cell tolerance can be duetoclonolonergy. .... ee ee 234
`InfectlousOnergy 235
`Lack of communication con cause unresponsiveness... .. 235
`B-CELLS DIFFERENTIATE IN THE FETAL LIVER
`AND THEN IN BONE MARROW...............- 236
`B-1 AND B-2 CELLS REPRESENT TWO DISTINCT
`POPULATIONS ........ 5 0c ee euevnevaee 237
`DEVELOPMENT OF B-CELL SPECIFICITY......... 238
`The sequence of Immunoglobulin gene reartangaments ..... 238
`The importance of allelicaxclusion. oe ee ee 240
`Different specific responses can appear sequentially ....... 240
`THE INDUCTION OF TOLERANCE IN
`B-LYMPHOCYTES ..........00cceveeueee 240
`Tolerance can be caused by clonal deletion and clonal anargy
`.
`.
`. 240
`Tolerance mayresult from helpless B-cells»... ee 241
`THE OVERALL RESPONSE INTHE NEONATE
`...... 243
`THE EVOLUTION OF THE IMMUNE RESPONSE...... 243
`Recognition of self is fundamentalfor multicellular organisms
`.
`.
`. 243
`Invertebrates have microbial defense mechanisms ........ 244
`Adaptive Immune responses appearwith the vertebrates...
`.
`.
`, 245
`Lowarvertebrates 6. ee 245
`TOONS OPPO vc ect ee eee eee es 945
`Generation of antibody diversity... 0... 00a ae . 247
`THE EVOLUTION OF DISTINCT B- AND T-CELL
`LINEAGES WAS ACCOMPANIED BY THE DEVELOPMENT
`OF SEPARATE SITES FOR DIFFERENTIATION ...... 247
`CELLULAR RECOGNITION MOLECULES EXPLOIT
`THE IMMUNOGLOBULIN GENE SUPERFAMILY ...... 247
`SUMMARY ... 0c ce eee tates 248
`FURTHER READING ...........00 0000000 250
`
`PART 5 -
`
`IMMUNITY TO INFECTION
`
`13 - Adversarialstrategies during infection, 253
`INFLAMMATION REVISITED .............0-. 254
`Mediators ofinflammation
`2. ........50..000,8 » 254
`Leukocytes bind to endothelialcells through palred adhesion
`molecules 6. ee ee ees 255
`{nitiation of the acute Inflammatory response... 2. eee 255
`The ongoing inflammatory process... 2... ee 256
`Regulation and resolution of Inflammation ....,...... . 257
`Chronicintammation 6. ee ee 258
`EXTRACELLULAR BACTERIA SUSCEPTIBLE T0 KILLING
`+BY PHAGOCYTOSIS AND COMPLEMENT ......... 258
`Bactorial survival strategies 6. we ee 258
`Evading phagocytosis... ee ee ee ee 258
`Challenging ine complement sysiem .- 6... 6s eves 259
`Antigeniovarlation ©. ee 260
`Thehostcounter-atiack ©... te 260
`Toxin neutralization... ee ee ee 261
`Opsonizationof bacteria Pee es 261
`Some furthereffects of complement... . 1 ve ea 263
`The secrelory immune system protects the external mucosal
`SUTOCESoe 263
`Somespecific bacterial infections. ©... ee 265
`BACTERIA WHICH GROW IN AN INTRACELLULAR
`HABITAT©. 267
`Bacterialgambils ee 267
`DefenseIs byT-cell-mediated immunity(CMI). ee 268
`Activated macrophagesKill Intracellular parasites ......... 268
`Examplesof intracellular bacterial infections ........... 269
`Listeriq 2... ht ee 269
`Tuberculosis 2. ee 268
`Leprosy ee es 27)
`IMMUNITY TO VIRALINFECTION .:.....,....., 271
`Immunity con be evaded byantigenchanges ......-..... 271
`Changing antigens by driffandshiff
`.. 0... ee ee 271
`Mufatlon can produce antagonistic T-cellepitopes =... .... 272
`Someviruses con affect antigen processing. ........ 5. 272
`Viruses can interfere with immuneeffector mechanisms .,.... 272
`Playing gomes with the complement sysiom ........ +. 272
`Sabotaging cell-mediatedimmunity 2... ee es 272
`Protection by serumantibody 2.0... ee eee es 273
`Localfactors 6 ee ee tes 273
`Cell-mediated immunity gets to the Intracellularvirus ....... 273
`NK calls can kill virally infectedtargets .... 2... 02-0. 273
`‘Cytctoxic T-cells (Tc) are crucial elements In immunity to
`pigeon BDOeS ues se ie Oa aa ae 2
`Cytokines recrult effectors and provide a ‘cordon sanifalre’
`.
`.
`. 275
`Antibodyhasaparttoo . 2... ee ee 275
`IMMUNITY YO FUNG»... eee eee ns 275
`IMMUNITY TO PARASITIC INFECTIONS ......... 276
`The hostresponses eee ee ee 276
`Humoralimmunity
`6. eee eee 277
`Call-mediated immunity... . + eee eee 278
`Evasive strategies bytheparosite 6... ee eee 279
`Resistance to effector mechanisms... ....-.- +++. 279
`Avoiding antigen recognition bythehost .... ++. sess 280
`Deviation of the host Immune response... ee 281
`Immunopathology «ee ee ees » 28)
`
`Lassen - Exhibit 1044, p. 7
`
`Lassen - Exhibit 1044, p. 7
`
`

`

`SUMMARY 2.1 ee ee ee ees 281
`FURTHER READING ... 0... eee eee eee 284
`
`PRIMARY T-CELL DEFICIENCY. ...........045 315
`COMBINED IMMUNODEFIGIENCY
`............ 317
`
`CONTENTS
`
`14 + Prophylaxis, 285
`PASSIVELY ACQUIRED IMMUNITY............. 285
`Maternolly acquired antibody 5... ee ee ee 287
`Pooledhumany-globulin 2... we ee ee 287
`Cullured antibodies madefoorder .. 2... we . 287
`Adoptive transfer of cytofoxic T-celis
`. 6.0... 1
`1 ee ee ee 288
`VACCINATION... 0... 20... 00.
`e ee ees 288
`Herdimmunity .... ee 288
`Sirategic considerations 6. ee 288
`KILLED ORGANISMS AS VACCINES
`........44. 288
`LIVE ATTENUATED ORGANISMS HAVE MANY
`ADVANTAGES AS VACCINES ........-.0 00046 289
`Classical methods ofafienudtion 2... 1 ep ee es 290
`Attenuation by recombinant DNAfechnology........--.. 290
`Microblal vectors for othergenes.. 2... ee 290
`Constraints on the use of aHenuoted vaccines... ..,-...- 293
`SUBUNIT VACCINES CONTAINING INDIVIDUAL
`PROTECTIVE ANTIGENS ©... 20... 0.00 enue 293
`The use ofpurlfledcomponents
`.. 0... 2. ee ee ee 293
`Antigens can be synthesized through genecioning .....4.. 294
`The naked gene itselfactsasavaccine......,... 004 295
`EPITOPE-SPECIFIC VACCINES MAY BE NEEDED..... 296
`Epitopes can be mimicked by synthetic peptides ......... 207
`B-callepitopes 6. ee 297
`Teoollepitopes ow ee ee 297
`Making the peptidesimmunogenic. .......4-, 0005 298
`Idiotypes con be explotted as epltops-specific vaccines =... . 299
`Unwanted epitope-loss mutants can correctly fold desired
`discontinuous B-cellepifopes 2... ee 299
`GURRENT VACCINES ....,..,... 0... e aun 299
`EXPERIMENTAL VACCINES IN DEVELOPMENT...... 300
`Malaga. 2. ee ee 300
`Schistosomiasis. ©... et ee et 302
`Cholera 2. 1 ee 303
`Tuberculosis6. 303
`ADJUVANTS .. 0... ee 303
`Depoteffects 0.ee 303
`Macrophage activation
`.........00% tee eS 304
`Specific effects onlymphocyles .........0..0. 0008 304
`NEW APPROACHES TO THE PRESENTATION
`OFANTIGEN.... 0.2... 0.0... eee 304
`SUMMARY ... 0.0.0 eee eee ee ee 305
`FURTHER READING ......,...,....0.. 00005 307
`
`PART 6
`
`CLINICAL IMMUNOLOGY
`
`15 - Immunodeficiency, 311
`PRIMARY IMMUNODEFICIENCY STATES
`INTHE HUMAN ., 1... ee ee 311
`DEFICIENCIES OF INNATE IMMUNE MECHANISMS ... 311
`Phagocytic celldefects 2... te ee 311
`Complement system deficiencles.
`. 2... 1. ee eee 312
`Defects Incontrol proteins. 6... ee ee 312
`Deflclancy of components of the complement pathway ..... 313
`PRIMARY B-CELL DEFICIENCY..........-.065 314
`
`. 317
`
`Mutation in the commoncytokine receptor y, chain causesSCID .
`SCID can be due to mutations In purine salvage
`pathwoyenzymeS 2.6. 317
`OtherSCiD variants... ee 317
`RECOGNITION OF IMMUNODEFICIENCIES........ 317
`SECONDARY IMMUNODEFICIENCY ..........., 318
`ACQUIRED IMMUNODEFICIENCY SYNDROME (AIDS).
`. 319
`AIDS results from infactlon by a human immunodeficiency virus
`CHV 2ee 319
`The infection ofcellsbyHIV. 2.0... ee ee 319
`The AIDS infection depletes helperT-cells ...........4-% 321
`Natural history ofthediseasa 2... we es 321
`Mechanisms of depletion 2... ee et 323
`DiognosisofAIDS 2. ee 324
`ThecontrolofAIDS 2... ee 324
`Identifying protective Immune responses .. 2... eee 324
`The development of animal models ..........,.64 325
`Other therapeutic strategies ©... 325
`SUMMARY .... 0.00.
`,. 0.00.0... eee eee 326
`FURTHER READING
`...,....,... 0.00.00. 0 4 327
`
`16 - Hypersensitivity, 328
`INAPPROPRIATE IMMUNE RESPONSES CAN LEAD
`TO TISSUE DAMAGE ..,.,... 0: ceva nnvaee 328
`TYPE 1 —ANAPHYLACTIC HYPERSENSITIVITY. ..... 329
`The phenomenon ofanaphyloxis 6... ee ee 328
`Human anaphylactic antibodias aremainly|lgE .......04- 330
`Anaphylaxis is triggered by clustering of IgE receptors on mastcells
`through cross-linking 2... ee ee 330
`Alopicallergy6.0 331
`Clinical responses fo Inhaied gilergens . 2... 6 ee 331
`Foodallergy ....... Dee EWE Wg RETA 333
`Etlological factors in the development of atopic allergy ..... 333
`Clinical tasisforaliergy 6... ee ee ee 334
`Therapy 2ee 334
`Allargenavoidonce .. 2. ee ee 334
`Modulation of the Immunologicalresponse ......... 335
`Mastcellstabllization 2... 01. ee 335
`Medioforantagonism . 2... ee 337
`Attacking chronicinflammation .. 2... 0... ee we 337
`TYPE |) —ANTIBODY-DEPENDENT CYTOTOXIC
`HYPERSENSITIVITY ©... 0... 2... eee 337
`Type Il reactions between members of the same species
`(allokmmune) 2... ee 338
`Jronsfusionreactions 6. ee 338
`Rhesus Incompatibility
`. 0... ee ee 339
`Organtransplants 5... ee es 339
`AutoimmunetypeIi hypersensitivity reactions... 6... ae . 340
`Typelidrugreactions 6... ee 340
`TYPE I1I—IMMUNE COMPLEX-MEDIATED
`HYPERSENSITIVITY ........- 0000 eee 341
`Inflammatory lesions dua to locally formed complexes»... . 342
`TheArthusteaction 2 6. ee 342
`Reactions toinhaledantigens .. 2... 2... eee ee es 342
`Reoctlonstointemolanfigens 2... 1. ee 343
`Disease resulilng from clrculatingcomplexes «1 2... ee, 344
`Serumsickness 2... te ee es 344
`
`Lassen - Exhibit 1044, p. 8
`
`Lassen - Exhibit 1044, p. 8
`
`

`

`CONTENTS
`
`xt
`
`SUMMARY .. 1. pee ee eee ee eens S77
`FURTHER READING ........ a BORN BR STA Se Re 378
`
`. 2... te ee es 344
`immune complex glomerufonephritis.
`Deposition of Immune complexesat othersitas .. 1... . + 345
`Treatment. 346
`TYPE JV — CELL-MEDIATED (DELAYED-TYPE)
`"
`
`HYPERSENSITIVITY 20.0000... e eee ee 346 18-Tumorimmunology, 379
`The cellular basis of type IV hypersensitivity. ........ , +» 346
`CHANGES ON THE SURFACE OF TUMOR CELLS ..... 380
`Tissue damage produced by type iVreacilons ... 1... 2.5 347
`Virally controliedanfigens . 6... et er 380
`InfactloONS ee ee 347
`Expression ofnormallysilenfgenes
`6 ww 380
`Contact dermatitis2. 348
`Mutantantigeng 2... ee 380
`Tuo-mediotad hypersensitivily . 6... ee 348
`Changes in carbohydrate structure...) ee ee ee 38]
`Otherexamples 2... eee ee 348
`Change