basic immune response eye 98

1
Basic Immunology for internist
Ratanavadee Nanagara, M.D. Allergy-Immunology-Rh
eumatology Unit Department of Medicine KhonKaen
University
2
Nature of Immunity
Self Tolerance
Model of Host Immune Response
Abnormal immune response
Immunopathogenesis of Autoimmune Dis.
Therapeutic implication
3
The Nature of Immunity
4
Type of Recognition Defense
5
Non-specific immune response
6
Physical chemical barriers skin mucosa
lysozyme in saliva
lysozyme washing action
acid
washing action of urine
normal gut flora
7
Cells professional phagocytes

• macrophage
• monocyte
• NK cells

• neutrophil

adhearance, chemotaxis, phagocytosis, oxidative
burst, degranulation, IC killing
8
C5a
C3b
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?
Clonal selection
11
Specific T-cells response to Ag
primary IR
activation proliferation
12
Specific T-cells response to Ag
secondary IR
13
?
14
Nature of Immunity
?
Self Tolerance
Model of Host Immune Response
Abnormal immune response
Immunopathogenesis of Autoimmune Dis.
Therapeutic implication
15
?
Discrimination
immune cell
self Ag
Self tolerance
16
Self tolerance
Clonal ignorance Central tolerance Peripheral
tolerance
17
autoreactive T-cells
Clonal ignorance
Normal tissue
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educated T-cell
autoreactive cell
Central Tolerance
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Peripheral Tolerance
host cell
program cell death or anergy
autoreactive cell
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Autoreactive T-cell
fas
1. lack of co-stimulator molecules anergy
2. stimulate fas ligand - program cell death
apoptosis
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Nature of Immunity
Self Tolerance
?
Model of Host Immune Response
Abnormal immune response
Immunopathogenesis of Autoimmune Dis.
Therapeutic implication
23
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Professional phagocytes
effective IC killing
adhearance chemotaxis phagocytosis oxidative
burst degranulation IC killing
no disease
occult (persistent) infection
IC killing defect
overt infection
? Clinical outcome
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endogenous
Antigen
exogenous
Antigen processing
27
Trimolecular complex
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IL-1 TNF-a GM-CSF IL-6
IFN-g IL-2 IL-4 IL-6
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Th1
IL-1 TNF-a GM-CSF IL-6
IFN-g IL-2 IL-4 IL-6
Effector T-cells
K Tc NK
CMIR
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HIR
IgG
CD40
IL-1 TNF-a GM-CSF IL-6
IFN-g IL-2 IL-4 IL-6 IL-5
Th2
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IgG
IL-1 TNF-a GM-CSF IL-6
IFN-g IL-2 IL-4 IL-6
effector T-cells
Activated macrophage
CD25
autocrine paracrine
33
Blood vessel
IgG
IL-1 TNF-a GM-CSF IL-6
IFN-g IL-2 IL-4 IL-6
effector T-cells
34
Adhesion molecules
IgG
IL-1 TNF-a GM-CSF IL-6
IFN-g IL-2 IL-4 IL-6
effector T-cells
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Stop inflammatory cells
IgG
IL-1 TNF-a GM-CSF IL-6
IFN-g IL-2 IL-4 IL-6
effector T-cells
36
Facilitate extravasation
IgG
IL-1 TNF-a GM-CSF IL-6
IFN-g IL-2 IL-4 IL-6
TGF-b ETR
effector T-cells
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Antibody

• Neutralized Ag
• Complement fixed
• (chemotaxis, permeability lysis)
• Opsonization

38
Nature of Immunity
Self Tolerance
Model of Host Immune Response
?
Abnormal immune response
Immunopathogenesis of Autoimmune Dis.
Therapeutic implication
39
Abnormal Immune Response
?
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Immune deficiency
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Abnormal Immune Response
?
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Gel Coombs Classification of Immune
Response (Hypersensitivity)

• Type I - IgE mediated
• Type II - Ab mediated
• Type III - Immune complex
• Type IV - Delayed-type

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Type I Anaphylaxis
Ag
Mast cell
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Target organ
Type II Ab-mediated
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Type III Immune complex
IgG
IFN-g IL-2 IL-4 IL-6 IL-5
B-lymphocyte
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Type IV Cell mediated
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Abnormal Immune Response
?
48
Autoimmunity
How ?
49
Nature of Immunity
Self Tolerance
Model of Host Immune Response
Abnormal immune response
?
Immunopathogenesis of Autoimmune Dis.
Therapeutic implication
50
Triggering Infection
Bacteria Chlamydia Yersinia
Salmonella Shigella Campylobactor
H. Pyroli Virus
Genetic predisposition
HLA Class I - B27 Class II- DR - DW Non
HLA
Abnormal Immune Response
Disease
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How infectious agents induce chronic
inflammatory or autoimmune diseases?
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How infectious agents induce chronic
inflammatory or autoimmune diseases?
T-cells are central to most model of
autoimmunity
53
self reactive T-cell
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Hypersensitivity to persistent organism
or their antigens
Presentation of cryptic cell
Immune activation by superantigen
Molecular mimicry
Antigen activation or disruption by
retroviruses
self reactive T-cell
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Hypersensitivity to persistent organism
or their antigens
Presentation of cryptic cell
Immune activation by superantigen
Molecular mimicry
Antigen activation or disruption by
retroviruses
self reactive T-cell
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cross reactivity (molecular mimicry)
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Hypersensitivity to persistent organism
or their antigens
Presentation of cryptic cell
Immune activation by superantigen
Molecular mimicry
Antigen activation or disruption by
retroviruses
self reactive T-cell
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autoreactive T-cells
Normal tissue
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Hypersensitivity to persistent organism
or their antigens
Presentation of cryptic cell
Immune activation by superantigen
Molecular mimicry
Antigen activation or disruption by
retroviruses
self reactive T-cell
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adhearance, chemotaxis, phagocytosis,
oxidative burst, degranulation, IC killing
effective IC killing
inapparent (persistent) infection
overt infection
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Ineffective intracellular killing
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Mechanism
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H. pylori C. trachomatis C. pneumoniae Salmonella
inf. M. tuberculosis
Viral hepatitis B, C Retrovirus inf. Herpes
zoster Prion
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C. trachomatis persistent infection in
chronic arthritis
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M. Tuberculosis infection that caused
intractable autoimmune disease
68
Hypersensitivity to persistent organism
or their antigens
Presentation of cryptic cell
Immune activation by superantigen
Molecular mimicry
Antigen activation or disruption by
retroviruses
self reactive T-cell
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IgG
IL-1 TNF-a GM-CSF IL-6
IFN-g IL-2 IL-4 IL-6
antigen
effector T-cells
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HLA-DR
LFA-3
ICAM -1
Antigen Presentation
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HLA-DR
LFA-3
ICAM -1
Trimolecular complex
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Normal T-cell activation
Vb
TcR
HLA-DR
Trimolecular complex
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Kawasakis Disease
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SUPERANTIGEN
HLA-DR
CD4 CD5
ICAM -1
Activate T-cell without Ag processing
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Vb
TcR
HLA-DR
CD4 CD5
ICAM -1
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Y
Y
Y
Y
Y
Vb
TcR
CD4 CD5
Y
Y
Treatment of Kawasakis disease by giving
intravenous immunoglobulin (IVIG)
77
Hypersensitivity to persistent organism
or their antigens
Presentation of cryptic cell
Immune activation by superantigen
Molecular mimicry
Antigen activation or disruption by
retroviruses
self reactive T-cell
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Nature of Immunity
Self Tolerance
Model of Host Immune Response
Abnormal immune response
Immunopathogenesis of Autoimmune Dis.
?
Therapeutic implication
80
7
VCAM-1
ICAM-1
Collagenase MMP PGs
IgG
8
5
IL-1 TNF-a GM-CSF IL-6
IFN-g IL-2 IL-4 IL-6
6
4
1
effector T-cells
3
2
81
7
VCAM-1
ICAM-1
Collagenase MMP PGs
IgG
8
5
IL-1 TNF-a GM-CSF IL-6
IFN-g IL-2 IL-4 IL-6
6
4
1
effector T-cells
3
avoid Ag exposure antimicrobial
2
82
7
VCAM-1
ICAM-1
Collagenase MMP PGs
IgG
8
5
IL-1 TNF-a GM-CSF IL-6
IFN-g IL-2 IL-4 IL-6
6
4
1
effector T-cells
3
2
83
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84
7
VCAM-1
ICAM-1
Collagenase MMP PGs
IgG
8
5
IL-1 TNF-a GM-CSF IL-6
IFN-g IL-2 IL-4 IL-6
6
4
1
effector T-cells
3
2
85
? RA refractory to TNF-a inhibitor ? RA subset ?
SLE mice
Cytotoxic T lymphcyte-associated antigen 4
immunoregulatory protein
TcR b
TcR
Ag
CD3
APC
HLA-DR
TH
CD4
LFA-3
CD2
ICAM-1
LFA-1 (CD11a/CD18)
CD40
CD40L
CD28
CD80/86 (B7)
CTLA4 (CD154)
TRIMOLECULAR COMPLEX COSTIMULATORY PATHWAY
86
RA
Anti CD40L mAb ( IDEC-131, hu5c8, BG9588, Biogen )
SLE
TcR b
TcR
Ag
CD3
APC
HLA-DR
TH
CD4
LFA-3
CD2
ICAM-1
LFA-1 (CD11a/CD18)
CD40
CD40L
CD28
CD80/86 (B7)
CTLA4 (CD154)
TRIMOLECULAR COMPLEX COSTIMULATORY PATHWAY
87
efalizumab
humanized mAb CD11a
psoriasis
TcR b
TcR
Ag
CD3
APC
HLA-DR
TH
CD4
LFA-3
CD2
ICAM-1
LFA-1 (CD11a/CD18)
CD40
CD40L
CD28
CD80/86 (B7)
CTLA4 (CD154)
TRIMOLECULAR COMPLEX COSTIMULATORY PATHWAY
88
Anti-CD3 HuOKT3g1 (Ala-Ala)
TcR b
TcR
Ag
CD3
APC
HLA-DR
TH
CD4
LFA-3
CD2
ICAM-1
LFA-1 (CD11a/CD18)
CD40
CD40L
CD28
CD80/86 (B7)
CTLA4 (CD154)
TRIMOLECULAR COMPLEX COSTIMULATORY PATHWAY
89
7
VCAM-1
ICAM-1
Collagenase MMP PGs
IgG
8
5
IL-1 TNF-a GM-CSF IL-6
IFN-g IL-2 IL-4 IL-6
6
4
Profound peripheral lymphopenia
1
effector T-cells
3
2
90
7
VCAM-1
ICAM-1
Collagenase MMP PGs
IgG
8
5
IL-1 TNF-a GM-CSF IL-6
IFN-g IL-2 IL-4 IL-6
6
4
1
effector T-cells
3
2
IL-2
91
7
VCAM-1
ICAM-1
Collagenase MMP PGs
IgG
8
5
IL-1 TNF-a GM-CSF IL-6
IFN-g IL-2 IL-4 IL-6
6
4
1
effector T-cells
3
2
92
Autoimmune with antibody production
refractory Wegener granulomatosis, SLE with
AIHA, ITP essential mixed
cryoglobulinemia, RA (? RFve)
mature naive
Plasma cell
memory
immature
B-cell depletion
93
7
VCAM-1
ICAM-1
Collagenase MMP PGs
IVIG
IgG
8
5
IL-1 TNF-a GM-CSF IL-6
IFN-g IL-2 IL-4 IL-6
6
4
1
effector T-cells
3
2
94
7
VCAM-1
ICAM-1
Collagenase MMP PGs
Biologic response modifier
IgG
8
5
IL-1 TNF-a GM-CSF IL-6
IFN-g IL-2 IL-4 IL-6
6
4
1
effector T-cells
3
2
95
7
VCAM-1
ICAM-1
Collagenase MMP PGs
ET-1 TGF-b
IgG
8
5
IL-1 TNF-a GM-CSF IL-6
IFN-g IL-2 IL-4 IL-6
6
4
1
effector T-cells
3
2
96

• TNF-a soluble p75-TNFR type II (etanercept)
• chimeric human mouse mAb (infliximab)
• humanized mAb (adalimumab)
• converting enzyme inhibitors (GW3333)
• IL-1 recombinant IL-1R antagonist
  (anakinra)
• soluble IL-1R type II
• IL-1 Trap (recomb.IL-1R I IgG Fc)
• IL-1 converting enzyme inhibitor
  (caspase-1)
• IFN recombinant IFN-b,
• recombinant IFN-a
• IL-6 IL-6 mAb
• soluble IL-6R

97
Alternative targets of cytokine modifying Rx
Signal vx-745 (inh. p38 MAPK pathway)
transduction c-Jun-N terminal kinase
inhibitor calcineurin inhibition (post R
signaling) CIS3/SOCS3 (signaling
repressor) Chemokines recombinant human IL-18
binding protein humanized CXCL8/IL-8
Ab oral CCR1-antagonist ET-1 ET-1
receptor antagonist TGF-b anti-TGF-b VEGF
soluble VEGFR1-Fc
TNF model
98
7
block adhesion molecules
VCAM-1
ICAM-1
Collagenase MMP PGs
IgG
8
5
IL-1 TNF-a GM-CSF IL-6
IFN-g IL-2 IL-4 IL-6
6
4
1
effector T-cells
3
2
99
Anti-human-ICAM-1 Ab (enlimomab)
anti VCAM-1
ICAM-1
mAb E-selectin
VCAM-1 (CD106)
ICAM-2
P E Slectin (CD62)
CLA
VLA-4 (CD49/29)
humanized antiavb3 (integrin mAb)
LFA-1
CD 44
HLA DR
ADHESION MOLECULES
Humanized 4-1, 4-7 mAb (Natalizumab) 2ME2 (2
methoxyextradiol) antiangiogenesis
100
7
VCAM-1
ICAM-1
Collagenase MMP PGs
Anti-inflammatory agents
IgG
8
5
IL-1 TNF-a GM-CSF IL-6
IFN-g IL-2 IL-4 IL-6
6
NO synthetase Superoxide dismutase
4
1
effector T-cells
3
2
101
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102
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103
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104
Cytokine function TNF model
- receptors - down regulation - signal
transduction
105
2 types of TNF receptor
Location of TNFR in steady state
express constitutively
Dead signal ? apoptosis
TNFR-I (p55, CD120a)
Down regulation mechanism
TNF-a overproduction
TNFR cleaved into soluble TNFRs
Inducible
? cytokines production
LPS
TNFR-II (p75, CD120b)
TNF-a-TNFR complex
106
Signal Transduction

• Transcription associated protein

• Protein kinase cascade

TNFR I
caspase

• Transcription factors

TNF-a, IL-1b, IL-6, IL-8, COX2, INOS
NF-kB
NIK
TNFR II
Protein transcription
AP-1
MAPK
IL-1, IL-6, IL-8, IL-10, GM-CSF Adhesion
molecules PGE2, collagenase
Rx target
Kinase cascade (MAPK, NIK, caspase)
Transcription factors (AP-1, NF-kB)
107
TNF family proteins
Therapeutic implication
Lymphocyte
Belimumab Lymphostat RA, SLE
Humanized mAb
TRAIL TNF related apoptosis-inducing ligand
BAFF-R B-cell activating factor receptor TACI
transmembrane activator and calcium modulator and
cyclophilin ligand-interactor BCMA B-cell
maturation
BLyS B-lymphocyte stimulator (increase serum
level in SLE) differentiation, activation,
survival APRIL a proliferation inducing ligand
108
Signal Transduction
109
specific receptor
post- transcription
signal transduction
transcription translation
stimulus
Protein kinease pathways
Receptor associating proteins
Translocation of transcription factors
HLA-DR
proteins
cell surface
cytoplasm
nucleus
110
specific receptor
post- transcription
signal transduction
transcription translation
stimulus
Protein kinease pathways
Receptor associating proteins
Translocation of transcription factors
mRNA
HLA-DR
proteins
JNK inhibitor
Calcineurin inhibitor
TRAF inhibitor
RANKL
MAPK inhibitor Scio-469 (oral ) phase IIb
siRNA TNF blockade mouse model
AMG162 Humanized Ab
Antiresorptive during bone remodeling
111
Infection and Host defense
112
Implication
113
specific IR
non-specific cells
114
adhearance, chemotaxis, phagocytosis,
oxidative burst, degranulation, IC killing
effective IC killing
inapparent (persistent) infection
overt infection
115
??????????????????
??????????????
116
Efficiency of Immune Response
6. physiology
117
Exercise and Immunity
118
Exercise IR
(NK cells)
119
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120
immune ? infection
acute vs chronic
relaxation exercise