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basic immune response - eye 98

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Title: basic immune response - eye 98 Subject: lecture for eye resident Author: Medicine Created Date: 2/12/1998 11:24:36 PM Document presentation format – PowerPoint PPT presentation

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Title: basic immune response - eye 98


1
Basic Immunology I
Ratanavadee Nanagara, M.D. Allergy-Immunology-Rh
eumatology Unit Department of Medicine KhonKaen
University
2
Nature of Immunity
Model of Host Immune Response
Self Tolerance
Abnormal immune response
Immunopathogenesis of Autoimmune Dis.
Therapeutic implication
3
Part INature of Immunity
4
The Nature of Immunity
  • Cardinal features of immune response
  • Recognition and Defense

5
Cardinal Features
  • specificity
  • memory
  • discrimination

6
Recognition Defense
  • Innate (non-specific)
  • Adaptive (specific)

7
Recognition Defense
  • Innate (non-specific)
  • Adaptive (specific)

barriers skin, mucosa cells macrophages,
neutrophils cytokines complements
8
barriers skin mucosa
lysozyme in saliva
lysozyme washing action
acid
washing action of urine
normal gut flora
9
Cells professional phagocytes
  • macrophage
  • monocyte
  • NK cells
  • neutrophil

adhearance, chemotaxis, phagocytosis, oxidative
burst, degranulation, IC killing
10
C5a
C3b
11
phagocyte opsonin binding
_
C3b
Ab
Ab C3b
12
Cell receptor and cell differentiation
  • Innate
  • Adaptive

Mannose binding protein (MBP)
Protein binding receptor
13
Recognition Defense
  • Innate (non-specific)
  • Adaptive (specific)

Specific memory discrimination
14
Antibody
  • Neutralized Ag
  • Complement fixed
  • (chemotaxis, permeability lysis)
  • Opsonization

15
Part II Integrated Model of Host Immune Response
16
Innate Immune Response
17
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
18
Adaptive Immune Response
19
Antigen
20
endogenous
Antigen
exogenous
Antigen processing
21
Trimolecular complex
22
(No Transcript)
23
IL-1 TNF-a GM-CSF IL-6
IFN-g IL-2 IL-4 IL-6
24
Th1
IL-1 TNF-a GM-CSF IL-6
IFN-g IL-2 IL-4 IL-6
Effector T-cells
K Tc NK
CMIR
25
HIR
IgG
CD40
IL-1 TNF-a GM-CSF IL-6
IFN-g IL-2 IL-4 IL-6 IL-5
Th2
26
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
27
Blood vessel
IgG
IL-1 TNF-a GM-CSF IL-6
IFN-g IL-2 IL-4 IL-6
effector T-cells
28
Adhesion molecules
IgG
IL-1 TNF-a GM-CSF IL-6
IFN-g IL-2 IL-4 IL-6
effector T-cells
29
Stop inflammatory cells
IgG
IL-1 TNF-a GM-CSF IL-6
IFN-g IL-2 IL-4 IL-6
effector T-cells
30
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
31
Recognition Defense
  • Innate (non-specific)
  • Adaptive (specific)

specific memory discrimination
32
Self Tolerance
Clonal ignorance Central tolerance Peripheral
tolerance
33
autoreactive T-cells
Clonal ignorance
Normal tissue
34
educated T-cell
autoreactive cell
Central Tolerance
35
Peripheral Tolerance
host cell
program cell death or anergy
autoreactive cell
36
Autoreactive T-cell
fas
1. lack of co-stimulator molecules anergy
2. stimulate fas ligand - program cell death
apoptosis
37
Abnormal Immune Response
38
Gel Coombs Classification of Immune
Response (Hypersensitivity)
  • Type I - IgE mediated
  • Type II - Ab mediated
  • Type III - Immune complex
  • Type IV - Delayed-type

39
Type I Anaphylaxis
Ag
Mast cell
40
Target organ
Type II Ab-mediated
41
Type III Immune complex
IgG
IFN-g IL-2 IL-4 IL-6 IL-5
B-lymphocyte
42
Type IV Cell mediated
43
Abnormal Immune Response
44
HYPERSENSITIVITY
AUTOIMMUNITY
Autoimmune Diseases
45
Inflammatory process
Immune Response
46
h
lymphokine mediated cytotoxicity
Target cell
47
Th
h
activated macrophage
48
Effector T-cells
Th
Ab mediated
h
cytotoxic T
Cytotoxic NK-cell
49
Th
Complement
K
h
Tc
NK
50
B
Th
Y
s
Y
s
K
h
Tc
NK
51
B
Th
Y
s
Y
s
K
h
Tc
NK
52
Part IIIImmunopathogenesis of Autoimmune
Diseases
53
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
54
How infectious agents induce chronic
inflammatory or autoimmune diseases?
55
How infectious agents induce chronic
inflammatory or autoimmune diseases?
T-cells are central to most model of
autoimmunity
56
self reactive T-cell
57
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
58
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
59
cross reactivity (molecular mimicry)
60
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
61
autoreactive T-cells
Normal tissue
62
(No Transcript)
63
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
64
Ineffective intracellular killing
65
Mechanism
66
H. pylori C. trachomatis C. pneumoniae Salmonella
inf. M. tuberculosis
Viral hepatitis B, C Retrovirus inf. Herpes
zoster Prion
67
C. trachomatis persistent infection in
chronic arthritis
68
(No Transcript)
69
M. Tuberculosis infection that caused
intractable autoimmune disease
70
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
71
IgG
IL-1 TNF-a GM-CSF IL-6
IFN-g IL-2 IL-4 IL-6
antigen
effector T-cells
superantigen
72
HLA-DR
LFA-3
ICAM -1
Antigen Presentation
73
HLA-DR
LFA-3
ICAM -1
Trimolecular complex
74
Normal T-cell activation
Vb
TcR
HLA-DR
Trimolecular complex
75
Kawasakis Disease
76
SUPERANTIGEN
HLA-DR
CD4 CD5
ICAM -1
Activate T-cell without Ag processing
77
Vb
TcR
HLA-DR
CD4 CD5
ICAM -1
78
Y
Y
Y
Y
Y
Vb
TcR
HLA-DR
CD4 CD5
Y
ICAM -1
Y
Treatment of Kawasakis disease by giving
intravenous immunoglobulin (IVIG)
79
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
80
(No Transcript)
81
(No Transcript)
82
Signal Transduction
83
Trimolecular complex
84
Model of TNF-a
- receptors - down regulation - signal
transduction
85
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
86
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)
87
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
88
specific receptor
post- transcription
signal transduction
transcription translation
stimulus
Protein kinease pathways
Receptor associating proteins
Translocation of transcription factors
mRNA
HLA-DR
proteins
89
Nature of Immunity
Model of Host Immune Response
Self Tolerance
Abnormal immune response
Immunopathogenesis of Autoimmune Dis.
?????
90
To be continued
Basic Immunology II Targeted Therapy
Biologic response modification
91
(No Transcript)
92
Therapeutic Implication
93
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
94
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
95
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
96
(No Transcript)
97
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
98
? 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
99
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
100
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
101
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
102
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
103
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
104
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
105
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
106
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
107
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
108
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
109
  • 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

110
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
111
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
112
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
113
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
114
(No Transcript)
115
Physiological uptake of apoptotic cells
116
Complement Deficiency in SLE
117
Waste-disposal hypothesis
Complement deficiency caused SLE because of
impairment of the clearance of apoptotic or
necrotic cells and/or immne complexes which
cause inflammation and provide a source of
autoantigens
118
Pathological uptake of dying cells
119
How dose C1q contribute to the clearance of
apoptotic cells?
  • C1q binds to apoptotic cells
  • C1q bound to apoptotic cells in conjuction
    with CD91 this stimulates their uptake by
    pinocytosis
  • C1q bound to apoptotic cells also causes
    activation of the classical pathway
  • C3 bound to apoptotic cells stimunlates their
    uptake through C3 receptors

120
SLE -dying cells as source of autoantigen
121
Effector Activity of Complement
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