INDEX

Activated antigen-presenting cells (APC); see Antigen-presenting cells (APC)

Activation-induced cell death (AlCD), T cell tolerance, 86-87

Altered peptide ligands (APLs), T cell tolerance, 81, 84

Amyloid P component, serum (SAP), systemic lupus erythematosus, 3

Anergic B cells; see B cells Anergy

B cell tolerance, 91-92 T cell tolerance, 85-86

Anti-apoptic molecules, B cell activation through Fas, 34-35; see also Apoptosis

Anti-CD40 activating antibody, autoimmune disease, 8~ 10

Antigen-presenting cells (APC) activated, autoimmune disease, 8-10 ART cell mode of action, 71 autoimmune disease, 8-10, 113 B cell tolerance, 91

immune system function, 79-80 regulatory T cells, 27, 28 T cell tolerance, 81, 85, 88 TMEV, virus and myelin epitopes

presentation in, 104 Anti-inflammatory cytokines, autoimmune

disease, 8; see also Cytokines Anti-TNFu therapy, rheumatoid arthritis,

rationale for, 119-121 Apoptosis

anti-apoptic molecules, B cell activation through Fas, 34-35

autoimmune disease, 11-12, 13 autoimmune lymphoproliferative syndrome

(ALPS),52 Fas-Fas L mediated, recessive tolerance,

42 homeostasis and, 49

Apoptosis (cont.) T cell tolerance, 86-87, 89

negative selection, 84 APT], autoimmune lymphoproliferative

syndrome (ALPS), 50, 51 Aspartic acid, 61 Autoantigen mimicry, autoimmune disease

mechanisms, 68 Autoantigen modification, autoimmune

disease mechanisms, 68 Autoantigen specificity, regulatory T cells,

70-71 Autoimmune disease, 7-19; see also specific

diseases antigen presenting cells (APC) role in, 8-

10 epitope spreading, 99-107; see also

Epitope spreading generally, 7-8 human leukocyte antigen (HLA) and, 59 immune tolerance and, 92-93; see also

Immune tolerance mechanisms of, 68 peripheral T cell tolerance, death

receptors, CD95 and TNFRI role in, 11-12

survival molecule role, 13-14 T cell costimulation inhibition treatment,

113-117; see also T cell costimulation inhibition

Autoimmune gastritis, as model, 22-25 Autoimmune Iymphoproliferative syndrome

(ALPS), 7,49-57 clinical findings, 50 generally, 49 type la, 50-51 type lb, 51 type II, 52-53 type III, 53-54

Autoimmune polyendocrine syndrome (APECED), 72

129

130

Autoimmune related T (ART) cells, 67-77 differentiation and genetic control of, 71-

72 environmental factors, 72 generally, 67 mechanisms of spontaneous autoimmune

disease, 68 mode of action, 71 regulatory T cell autoantigen specificity,

70-71 regulatory T cells prevent or delay disease,

69 regulatory T cell types, 69-70 restoration or induction of, 72-73

Autoimmunity; see also Organ-specific autoimmunity

central tolerance and, T cell tolerance, 84-85

control of, regulatory T cells, 21-32; see also Regulatory T cells; T cells

harmless forms of, 67 molecular pathways, 33-40; see also

Molecular pathways Autoreactive T cells; see also T cells

autoimmune disease, 7-8, 11, 13 autoimmune related T (ART) cell control

of, 67-77; see also Autoimmune related T (ART) cells

B cells acquired tolerance in, 34 activation through Fas, 34-35 gene responses, 35-36, 37 harmless autoimmunity, 67 immune system function, 79 recessive tolerance in, 42 systemic lupus erythematosus, 2 tolerance of, 90-92; see also Immune

tolerance Bel-2

autoimmune disease, 13, 14 B cell ac,ivation through Fas, 35

Bel-XL' autoimmune disease, 13 B7

CD28 interaction, inhibition of, 113-114, 116

T cell tolerance, 85 B7-1, 104 B7-2

B cell activation through Fas, 34-35 TMEV, 104

B7-CD28/CTLA4 pathway, diabetes acceleration, 69

Calciumlca1cineurimlNFAT pathway, molecular pathways, 36

Index

Caspase, autoimmune lymphoproliferative syndrome (ALPS), 49-54

CD4 autoimmune related T (ART) cells, 72, 73 Fas gene, 34 systemic lupus erythematosus, 2

CD4+ autoimmune lymphoproliferative syndrome

(ALPS),50 autoimmunity induction, 22, 23, 24, 25 B cell tolerance, 91 demyelinating disease, 109 diabetes, 44 EAE and, 93 infectious tolerance, 43 recessive tolerance, 42-43 T cell tolerance, 87 TMEV-IDD, 102

CD4+CD25+ T cells, 25-29, 30 in vitro studies, 27-29 in vivo studies, 26

CD4+CD45RB T cells, autoimmunity induction, 22

CD8+ autoimmunity induction, 22 diabetes, 44 LCMV-specific, autoimmune disease, 8,

10, 11 peripheral T cell tolerance, autoimmune

disease, 11 recessive tolerance, 42-43 TMEV-IDD, 102

CD25, transfer experiments, 70 CD28

autoimmune disease, 9, 13 B interaction, inhibition of, 113-114, 116 T cell tolerance, 85, 87

CD38, transfer experiments, 70 CD40

autoimmune disease, 9 GP39 interaction, inhibition of, 114-115,

116 T cell tolerance, 86

CD40 L, Fas gene, 34 CD45, transfer experiments, 70 CD62 +, autoimmune related T (ART) cells, 73

Index

CD62L, transfer experiments, 70 CD69+ Tg+, 23-24 CD72, molecular pathways, 35 CD95, autoimmune disease, 11-12, 14 Central nervous system

EAE, epitope spreading in mediating relapses in peptide-induced, 100-102

immune tolerance, 79-98; see also Immune tolerance

inflammation of, virus induced models of, 93

TMEV, epitope spreading in mediation of, 102-104

Central tolerance, autoimmunity and, T cell tolerance, 84-85

Chromatin, murine mouse models, 2, 3 C-myc, B cell response, 36 Colitis, 69 Collagin arthritis, organ-specific

autoimmunity,24 CTLA-4

diabetes acceleration, 69 T cell costimulation inhibition, 113-114,

116 T cell tolerance, 85, 86

CTL response, peripheral T cell tolerance, autoimmune disease, 11

Cyclophosphamide, diabetes onset, 69 Cyclosporine A, autoimmunity induction, 22 Cytokine blockade (rheumatoid arthritis),

119-127 adenovirusIKBo:, TNFo: inhibited by, 121-

123 rationale for anti-TNFo: therapy, 119-121 T cell role, 123-124 TNFo: production in rheumatoid synovium,

121 Cytokines

autoimmune disease, 8 demyelinating disease, 109 infectious tolerance, 41 T cell tolerance, 87-89 TMEV-IDD, 102 TNFo:,l24

Cytotoxic T lymphocyte (CTL) response, 80

Demyelinating disease: see also Multiple sclerosis

gene expression profiling, 109-111 virus-induced, epitope spreading, 99-107;

see also Epitope spreading

Dendritic cell homeostasis, autoimmune lymphoproliferative syndrome (ALPS), 52-53

Diabetes, 88; see also Type I diabetes ART cell mode of action, 71 autoimmune disease, 9 organ-specific autoimmunity, 24 preclinical autoimmune phase, 67

131

Dominant tolerance; see Infectious tolerance Double transgenic mice, 8-15

ECDI treatment, T cell tolerance, 85 End-organ targeting, murine mouse models,

3,4 Environmental factors

autoimmune disease, 7-8 autoimmune related T (ART) cells, 72

Epistatic interaction, among susceptibility genes, 2-4

Epitope,23 Epitope spreading, 99-107

chronic TMEV-induced demyelinating disease, mediating role, 102-104

generally, 99-100 modelof,104-105 peptide-induced R-EAE, mediating role,

100-102 Epstein-Barr virus, 54 Ethyllnitrosourea (ENU), 36, 37 Experimental allergic encephalomyelitis (EAE)

epitope spreading in mediating relapses in peptide-induced, 100-102

gene expression profiling, 110-111 immune tolerance and, 93 multiple sclerosis model, 99-100 organ-specific autoimmunity, 24 regulatory cells, 70 T cell tolerance, 88-89 virus and myelin epitopP.s presentation in,

104

FADD, autoimmune lymphoproliferative syndrome (ALPS), 52

Fas apoptosis, 49 autoimmune lymphoproliferative syndrome

(ALPS), 49-54 B cell activation through, 34-35 molecular pathways, 34

Fas-Fas L recessive tolerance, 42

132

Fas-Fas L (cont.)

T cell tolerance, 87, 89 FGK45, autoimmune disease, 8

Gastritis, autoimmune, as model, 22-25 Gene expression profiling (multiple

sclerosis), 109-112; see also Multiple sclerosis

EAE and, 110-111 pathophysiology and lessons of, 109-110

Genetic linkage analysis, systemic lupus erythematosus, 1-2

Genome side screens, molecular pathways, 36-38

Gld mutation, autoimmune lymphoproliferative syndrome (ALPS), 50, 51

Glomerulonephritis, systemic lupus erythematosus, 2

Glutamic acid decarboxylase (GAD) diabetes, 60 MHC peptide binding affinity of GAD 65

peptide epitopes, 62 MHC restriction of GAD 65 specific T

cells, 60-61 T-cell response to, I-Ag7 restricted, 60-61

Glycoprotein, diabetes, 44 GP39, CD40 interaction, inhibition of, 114-

115, 116 Graft-versus-host disease, induced, 81

HEL protein B cell response, 36 B cell tolerance, 92 T cell tolerance, 89

Hemagglutenin (HA), T cell response, 44 Hen Egg Lysozyme; see HEL protein HlK ATPase, organ-specific autoimmunity,

22-23 Homeostasis; see also Immune homeostasis

apoposis and, 49 autoimmune lymphoproliferative syndrome

(ALPS), 50; see also Autoimmune lymphoproliferative syndrome (ALPS)

molecular pathways, 33-40; see also Molecular pathways

HTLV-l associated myelopathy, 93 Human leukocyte antigen (HLA),

autoimmune disease and, 59 Huntington's disease, 109

I-Ag7 13 chain, T-cell response to GAD restricted by, 60-61

IFNl' release

Index

autoimmune related T (ART) cells, 72 interleukin-12, autoimmune disease, 9 regulatory T cells, 26 T cell tolerance, 88 TMEV and, 104

IgG anti-nuclear antibody (ANA), murine mouse models, 2

IgG2a antivirus antibody, TMEV-IDD, 102 Immune homeostasis; see also Homeostasis

apoptosis and, 49 molecular pathways, 33-40

Immune privileged sites, T cell tolerance, 89-90

Immune system dysregulation of, murine mouse models,

3-4 function of, 79-80

Immune tolerance, 79-98 autoimmune disease and, 92-93 B cell tolerance, 90-92

affinity maturation, 91 clonal deletion versus anergy, 91-92 clonal versus receptor selection, 91

immune system function, 79-80 to nuclear autoantigens, murine mouse

models, 3 T cell tolerance imposed by thymic

selection, 80-85 anatomy and location, 81 apoptosis in negative selection, 84 central tolerance and autoimmunity, 84-85 cross-reactive basis of, 81-82 models of selection, 82-84 positive and negative selection, 80

T cell tolerance peripheral mechanisms, 85-90

activation-induced cell death, 86-87 anergy, 85-86 cytokine suppression, 87-89 immune privileged sites, 89-90

Infection autoimmune related T (ART) cells, 72 immune system function, 79-80

Infectious tolerance concept of, 41-42 mechanisms of, 43

Influenza hemagglutenin (HA), T cell response, 44

Index

Insulin-dependent diabetes mellitus, preclinical autoimmune phase, 67; see also Diabetes

Insulitis, autoimmune disease, 9 Interferon 13, multiple sclerosis, 111 Interleukin-l, anti-TNFa therapy, 120 Interieukin-1Ra, adenovirusIKBa, 123 Interleukin-2

B cell activation through Fas, 35 regulatory T cells, 28 T cell tolerance, 85, 86-87

Interleukin-4 ART cell mode of action, 71 autoimmune related T (ART) cells, 72 B cell activation through Fas, 34-35 diabetes, 44 infectious tolerance, 41, 43 regulatory T cells, 26 T cell tolerance, 88, 89 Type I diabetes, 64

Interleukin-5, T cell tolerance, 88 Interleukin-IO

adenovirusIKBua, 123 ART cell mode of action, 71 autoimmune lymphoproliferative syndrome

(ALPS),50 autoimmune related T (ART) cells, 72 diabetes, 44 infectious tolerance, 41, 43 regulatory T cells, 26 TNFa,124 Type I diabetes, 64

Interleukin-11, adenovirusIKBa, 123 Interleukin-12, IFN')' release, autoimmune

disease, 9 Interleukin-13, T cell tolerance, 88 Interleukin-15, T cell tolerance, 86-87 l3-islet cells, diabetes, 44-45, 60

KLH protein, EAE, 88

Linkage analysis; see Genetic linkage analysis

LKLF, B cell response, 36 Lpr mutation

autoimmune lymphoproliferative syndrome (ALPS), 50

molecular pathways, 34, 36 LSIRF, B cell response, 36 Lymphocytic choriomeningitis virus (LCMV)­

specific CD8+ T cells, 8, 10, 11

133

Lymphocytopenia-associated autoimmunity, 69-70

Lymphotoxin (LT), T cell tolerance, 88 Lyt-l (CD5) antigen, regulatory T cells,

25

Major histocompatibility complex (MHC) autoimmune disease, 7 demyelinating disease, 109 immune system function, 79 T cell tolerance, 80, 81-82, 84, 85, 89 Type I diabetes and, 59-66; see also Type

I diabetes MEK-ERK pathway, molecular pathways,

36; see also Molecular pathways Membrane-bound immunoglobulin, 79 Metalloproteases, adenovirusIKBa, 123 Molecular pathways, 33-40

B cell activation through Fas, 34-35 Fas gene, 34 generally, 33-34 gene response coordination, 35-36 genome wide screens, 36-38

Monoclonal antibody therapy, Type I diabetes, 64

MP4 protein, TMEV and, 103-104 Multiple sclerosis, 84, 88, 93, 99; see also

Demyelinating disease EAE compared, III epitope spreading, 99-107; see also

Epitope spreading gene expression profiling, 109-112; see

also Gene expression profiling (multiple sclerosis)

Murine insulin, diabetes, 60 Murine mouse model, systemic lupus

erythematosus (SLE), 1-6; see also Systemic lupus erythematosus (SLE)

Mycobacterium avium, 70 Myelin basic protein (MBP)

demyelinating disease, 109 EAE,93 multiple sclerosis, 99, 100, 101 TMEV, 103, 104

Myelin oligodendrocyte glycoprotein (MOG)

demyelinating disease, 109 EAE,93 multiple sclerosis, 99, 100 TMEV,103

Myelopathy, HTLV-l associated, 93

134

NAB-2, molecular pathways, 35 Nephritis, systemic lupus erythematosus, 2 Nervous system, immune tolerance, 79-98;

see also Central nervous system; Immune tolerance

NK cells ART cell differentiation, 71-72 immune system function, 79

NOD mouse ART cell differentiation, 71-73 Type I diabetes, 59-65

Oral tolerance, T cells, 88 Organ-specific autoimmunity; see also

Autoimmunity autoimmune gastritis as model, 22-25 peripheral tolerance and, 41-48; see also

Peripheral tolerance OX40, B cell activation through Fas, 35

Pancreas, 89 autoimmune disease, 9 diabetes, 44

Parkinson's disease, 109 PeptideIMHC complexes

T cell tolerance, 85 thymocytes and, 83-84

Peripheral tolerance, 41-48 death receptors, CD95 and TNFR I role in,

autoimmune disease, 1I-12 diabetes, 43-45 generally, 41-42 infectious tolerance, 43 mechanisms of T cell tolerance, 85-90;

see also Immune tolerance recessive tolerance, 42-43

Phosphatidylinositol 3-kinase (PI3K), autoimmune disease, 13- 14

Picornavirus, demyelinating disease, 93, 100 Poly autoimmune syndrome, 69 Polyclonal B or T cell activation,

autoimmune disease mechanisms, 68 Pro-inflammatory cytokines, autoimmune

disease, 8 Proline, 61 Protein kinase BJ3 (PKB/Akt), autoimmune

disease, 13-14 Proteolipid protein (PLP)

EAE and, 93 multiple myelin epitopes, 104 multiple sclerosis, 99, 100, 101, 102

Proteolipid protein (PLP) (cont.)

T cell tolerance, 89 TMEV and, 103

Index

PTEN deficiency, autoimmune disease, 14

Recessive tolerance, peripheral tolerance, 42-43

Regulatory T cells, 21-32; see also Autoimmune disease; T cells

autoantigen specificity of, 70-71 autoimmune disease, 8 autoimmune disease prevented or delayed

by, 69 autoimmune gastritis as model, 22-25 autoimmunity induced by depletion of, 21-

22 CD4+CD25+ T cells, 25-29

in vitro studies, 27-29 in vivo studies, 26

generally, 21 speculations on, 29-30 types of, evidenced by transfer

experiments, 69-70 Relapsing experimental allergic

encephalomyelitis (R-EAE); see Experimental allergic encephalomyelitis (EAE)

Reverse-transcriptase based PCR expression studies (RT-PCR)

demyelinating disease, 1I0 organ-specific autoimmunity, 24

Rheumatoid arthritis cytokine blockade in, 1I9-127; see also

Cytokine blockade (rheumatoid arthritis)

oral tolerance, 88 T cell role in, 123-124

scm mice, autoimmunity induction, 22 Self-reactive B cells, acquired tolerance in,

34 Self-reactive T cells; see Autoreactive T

cells Self-tolerance, molecular pathways, 33-40;

see also Molecular pathways Serum amyloid P component (SAP),

systemic lupus erythematosus, 3 SHPl, molecular pathways, 35 Skin, importance of, 79 SLEI mediation, SLE, 2, 3, 4 SLE2 mediation, SLE, 2, 3

Index

SLE3 mediation, SLE, 2, 3, 4 Spleen

autoimmune disease, 9 autoimmunity induction, 22, 26

Splenomegaly, murine mouse models, 2 Superantigens, autoimmune disease

mechanisms, 68 Suppressor T cell function, CD4+CD25+ T

cells, in vitro studies, 27-29 Survival molecule, role of, autoimmune

disease, 13-14 Systemic lupus erythematosus (SLE), 1-6;

see also Autoimmune disease defined,l epistatic interaction among susceptibility

genes, 2-4 genetic linkage analysis, 1-2 SLE3 mediation of T cell activity

dysregulation, 4

Target organ inflammation, autoimmune disease mechanisms, 68

T cell costimulation inhibition, 113-117 B7 and CD28 interaction, 113-114 CD40 and GP39 interaction, 114-115 future research, 116 simultaneous blockade, 116

T cells; see also entries under CD; Regulatory T cells

autoimmune disease, 8 autoimmune related T (ART) cell control

of, 67-77; see also Autoimmune related T (ART) cells

autoreactive, autoimmune disease, 7-8 CD8+ T cells, LCMV-specific,

autoimmune disease, 8, 10, 11 demyelinating disease, 109-110 diabetes, 44

I-Ag7 restricted T-cell response to GAD, 60-61

MHC restriction of GAD 65 specific T cells, 60-61

dysregulation, SLE3 mediation of, murine mouse models, 4

endogenous myelin peptides response, 100 Fas gene, 34 harmless autoimmunity, 67 immune system function, 79 infectious tolerance, 41-42, 43 MHC molecules, 59 molecular pathways, 37

135

T cells (cont.) murine mouse models, 2 NK T cells, ART cell differentiation, 71-72 R-EAE, epitope spreading in mediating

peptide-induced, 100-102 recessive tolerance in, 42-43 regulatory; see Regulatory T cells rheumatoid arthritis, 123-124 TMEV, chronic demyelinating disease

induced by, epitope spreading in mediation of, 102-104

tolerance of peripheral mechanisms, 85-90; see also

Immune tolerance thymic selection and, 80-85; see also

Immune tolerance TCR chain

autoimmunity induction, 22, 23, 24, 27, 28,29

T cell tolerance, 82-84, 85 TGFj3

infectious tolerance, 41, 43 T cell tolerance, 88

Tg+ T cells, 23 Theiler's murine encephalomyelitis virus

(TMEV) chronic demyelinating disease induced by,

epitope spreading in mediation of, 102-104

demyelinating disease, 93, 100 Thymectomy

autoimmunity induction, 21-22 diabetes onset, 69

Thymic selection, T cell tolerance imposed by, 80-85; see also Immune tolerance

Thymocytes, peptideIMHC complexes and, 83-84

Thymus ART cell differentiation, 71-72 autoimmunity induction, 22, 23 MHC molecules, 59

Thyroid,89 Thyroiditis, autoimmunity induction, 21-22 T lymphotropic virus, autoimmunity

induction, 22 TNFa

adenovirusIKBa inhibits, 121-123 production of, in rheumatoid synovium, 121 T cells and, 88, 123-124

136

TNFR adenovirusIKBa, 123 apoptosis, 49

TNFRI autoimmune lymphoproliferative syndrome

(ALPS), 50, 52 diabetes, 44, 45 peripheral T cell tolerance, autoimmune

disease, 11-12 recessive tolerance, 43

TNFR2, autoimmune lymphoproliferative syndrome (ALPS), 52

Tolerance, molecular pathways, 33-40; see also Molecular pathways

Tumor necrosis factor; see TNF Type I diabetes, 59-66; see also Diabetes

antigen-specific prevention of,. 64-65

Type I diabetes (cant.)

future research, 63 generally, 59 implications of study, 63-64

Index

MHC peptide binding affinity of GAD 65 peptide epitopes, 62

MHC restriction of GAD 65 specific T cells, 61-62

target autoantigens, 60 T-cell response to GAD, I-Ag7 restricted,

60-61

Virus-induced demyelinating disease, epitope spreading, 99-107; see also Epitope spreading

Wistar rat, autoimmunity induction, 21-22