Download basic immune response

Basic Immunology
I
Ratanavadee Nanagara, M.D.
Allergy-Immunology-Rheumatology Unit
Department of Medicine
KhonKaen University
Nature of Immunity
Model of Host Immune Response
Self Tolerance
Abnormal immune response
Immunopathogenesis of Autoimmune Dis.
Therapeutic implication
The Nature of Immunity
• Cardinal features of immune response
• Recognition and Defense
Cardinal Features
• specificity
• memory
• discrimination
Recognition & Defense
 Innate (non-specific)
 Adaptive (specific)
Recognition & Defense
 Innate (non-specific)
 Adaptive (specific)
barriers : skin, mucosa
cells: macrophages, neutrophils
cytokines
complements
Fatty acids
Normal bacterial
skin flora
barriers: skin & mucosa
cilia
mucus
lysozyme
in saliva
lysozyme
washing
action
mucus
acid
washing
action of
urine
Cells : professional phagocytes
• macrophage
• monocyte
• NK cells
• neutrophil
attack and eat
kill
adhearance, chemotaxis, phagocytosis, oxidative burst, degranulation, IC killing
complement
bacteria
phagocyte
bacteria
1. lysis
2. chemotaxis
3. opsonization
C5b
C9
C5a
C3b
phagocyte
Y Y
opsonin
binding
_
+
C3b
++
Ab
+
Ab + C3b
++++
Cell receptor and cell differentiation
• Innate
Mannose binding protein
(MBP)
• Adaptive
Protein binding receptor
Recognition & Defense
 Innate (non-specific)
 Adaptive (specific)
Cardinal features
Specific
memory
discrimination
T-cell
CMIR
HIR
B-cell
Part II
Integrated Model
of
Host Immune Response
Innate Immune
Response
effective
IC killing
Professional phagocytes
no disease
adhearance
chemotaxis
phagocytosis
occult (persistent)
infection
IC killing
oxidative burst
defect
degranulation
IC killing
overt infection
? Clinical outcome
Adaptive Immune
Response
Antigen
endogenous
Antigen
exogenous
Antigen processing
Antigen Presenting Cell
Vb
TcR
HLA-DR
Ag
Tyrosine
CD3
kinase
Va
CD4
auxillary
CD2
molecules
LFA-1
CD28
CTL-4
LFA-3
ICAM-1
CD80/86(B7)
Trimolecular complex
IL-1
TNF-a
IFN-g
IL-2
GM-CSF
IL-4
IL-6
IL-6
chemokines
MIF
Fibroblast
Synoviocyte
IL-1
TNF-a
IFN-g
IL-2
GM-CSF
IL-4
IL-6
IL-6
IL-1
TNF-a
GM-CSF
IL-6
Th1
IFN-g
IL-2
IL-4
IL-6
Effector
T-cells
CMI
R
K
Tc
N
HIR
CD40
IL-1
TNF-a
IFN-g
IL-2
GM-CSF
IL-4
IL-6
IL-5
IL-6
Th2
IgG
B-lymphocyte
IgG
IL-1
TNF-a
IFN-g
IL-2
GM-CSF
IL-4
IL-6
IL-6
effector
T-cells
Activated
macrophage
CD25
IF-g
IL-2
®
autocrine
paracrine
Blood vessel
IgG
IL-1
TNF-a
IFN-g
IL-2
GM-CSF
IL-4
IL-6
IL-6
effector
T-cells
L. integrin (CD11/18)
VCAM-1(CD106) ICAM-1 (CD54)
VLA
integrin(CD49/29)
Selectin (CD62)
Adhesion molecules
IgG
IL-1
TNF-a
IFN-g
IL-2
GM-CSF
IL-4
IL-6
IL-6
effector
T-cells
Stop inflammatory cells
IgG
IL-1
TNF-a
IFN-g
IL-2
GM-CSF
IL-4
IL-6
IL-6
effector
T-cells
Facilitate extravasation
TGF-b
ETR
IL-1
TNF-a
IFN-g
IL-2
GM-CSF
IL-4
IL-6
IL-6
IgG
effector
T-cells
Recognition & Defense
 Innate (non-specific)
 Adaptive (specific)
specific
Cardinal features
memory
discrimination
Self Tolerance
Clonal ignorance
Central tolerance
Peripheral tolerance
autoreactive
T-cells
Clonal ignorance
Normal tissue
blood barrier
Self Ag
educated T-cell
autoreactive cell
Central Tolerance
Peripheral Tolerance
host cell
program cell death
… or anergy…
autoreactive cell
Autoreactive
T-cell
Vb
TcR
HLA-DR
auto Ag
Va
LFA-3
ICAM-1
fas
1. lack of co-stimulator molecules – “anergy”
2. stimulate fas ligand - program cell death “apoptosis”
Abnormal Immune
Response
immunodeficiency
hypersensitivity
autoimmune diseases
Gel & Coombs
Classification of Immune Response
(Hypersensitivity)
 Type I
- IgE mediated
 Type II - Ab mediated
 Type III - Immune complex
 Type IV - Delayed-type
Type I
Anaphylaxis
SRSA
Ag
IgE
Mast cell
Target organ
Y
Y
Y
Type II
Ab-mediated
IgG
IFN-g
IL-2
IL-4
IL-6
IL-5
B-lymphocyte
Type III
Immune complex
IgG
IFN-g
IL-2
LE cell
IL-4
IL-6
IL-5
B-lymphocyte
Type IV
Cell mediated
IgG
IL-1
TNF-a
IFN-g
IL-2
GM-CSF
IL-4
IL-6
IL-6
effector
T-cells
Abnormal Immune
Response
immunodeficiency
hypersensitivity
autoimmune diseases
Part III
Immunopathogenesis
of
Autoimmune Diseases
Triggering
Infection
Bacteria
Genetic
predisposition
HLA
Class I B27
Class IIDR
DW
Non HLA
Chlamydia
Yersinia
Salmonella
Abnormal
Immune Response
Shigella
Campylobactor
H. Pyroli
Virus
Disease
How infectious agents induce
chronic inflammatory or
autoimmune diseases?
How infectious agents induce
chronic inflammatory or
autoimmune diseases?
T-cells are central to most
model of autoimmunity
self reactive
T-cell
proliferation, cytokines,
B-cell activation, cytolysis
Hypersensitivity to
persistent organism
or their antigens
Presentation
of cryptic cell
Molecular
mimicry
Immune activation
by superantigen
self reactive
T-cell
Antigen activation
or disruption by
retroviruses
Hypersensitivity to
persistent organism
or their antigens
Presentation
of cryptic cell
Molecular
mimicry
Immune activation
by superantigen
self reactive
T-cell
Antigen activation
or disruption by
retroviruses
microbe
APC
T-cell
cross reactivity
(molecular mimicry)
self antigen
effector cells
against microbe
Hypersensitivity to
persistent organism
or their antigens
Presentation
of cryptic cell
Molecular
mimicry
Immune activation
by superantigen
self reactive
T-cell
Antigen activation
or disruption by
retroviruses
autoreactive
T-cells
Normal tissue
Self Ag
Hypersensitivity to
persistent organism
or their antigens
Presentation
of cryptic cell
Molecular
mimicry
Immune activation
by superantigen
self reactive
T-cell
Antigen activation
or disruption by
retroviruses
Ineffective intracellular killing
inapparent infection
overt infection
H. pylori
C. trachomatis
C. pneumoniae
Salmonella inf.
M. tuberculosis
Viral hepatitis B, C
Retrovirus inf.
Herpes zoster
Prion
C. trachomatis persistent infection
in chronic arthritis
M. Tuberculosis infection that caused
intractable autoimmune disease
Hypersensitivity to
persistent organism
or their antigens
Presentation
of cryptic cell
Molecular
mimicry
Immune activation
by superantigen
self reactive
T-cell
Antigen activation
or disruption by
retroviruses
IgG
antigen
IL-1
TNF-a
IFN-g
IL-2
GM-CSF
IL-4
IL-6
IL-6
effector
T-cells
superantigen
HLA-DR
LFA-3
ICAM -1
Antigen Presentation
Vb
TcR
HLA-DR
CD3
CD4
LFA-3
CD2
ICAM -1
LFA-1
Trimolecular complex
Normal T-cell
activation
Vb
TcR
HLA-DR
Trimolecular complex
SUPERANTIGEN
Vb
TcR
HLA-DR
CD4
CD5
ICAM -1
Activate T-cell without Ag processing
Y
Y
Vb
Y
Y
HLA-DR
TcR
CD4
CD5
ICAM -1
Treatment of Kawasaki’s disease by giving
intravenous immunoglobulin (IVIG)
Hypersensitivity to
persistent organism
or their antigens
Presentation
of cryptic cell
Molecular
mimicry
Immune activation
by superantigen
self reactive
T-cell
Antigen activation
or disruption by
retroviruses
Signal Transduction
Vb
TcR
HLA-DR
Ag
CD3
Tyrosine
kinase
Va
LFA-3
ICAM-1
CD80/86(B7)
CD4
CD2
LFA-1
CD28
Trimolecular complex
auxillary
molecules
Model of
TNF-a
- receptors
- down regulation
- signal transduction
2 types of
TNF receptor
Location of TNFR
in steady state
express
constitutively
Dead signal → apoptosis
Down
regulation
TNFa
mechanism
overproduction
Inducible
LPS
TNFR cleaved into
soluble TNFRs
→ cytokines production
 soluble TNFRs
production
TNF-a-TNFR
complex
endocytosis
FADD: factor asso death domain
TRADD- TNFR I asso death domain
Signal Transduction
• Transcription associated protein
• Protein
kinase cascade
caspase
TNFR I
• Transcription
factors
TNF-a,
IL-1b, IL-6, IL-8, COX2, INOS
NIK
NF-kB
TNFR II
MAPK
Protein transcription
AP-1
IL-1, IL-6, IL-8, IL-10, GM-CSF
Adhesion molecules
PGE2, collagenase
Rx target
TNFR associated factors (TRAF 1-6)
RIP: R. interacting protein
Kinase cascade (MAPK, NIK, caspase)
Transcription factors (AP-1, NF-kB)
TNF family proteins
anti fas mAb
Therapeutic
implication
Lymphocyte
Ig
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
stimulus
specific
receptor
signal transduction
transcription
translation
posttranscription
Protein kinease
pathways
Receptor
Translocation of
associating
transcription factors
proteins
proteins
HLA-DR
mRNA
Nature of Immunity
Model of Host Immune Response
Self Tolerance
Abnormal immune response
Immunopathogenesis of Autoimmune Dis.
?????
To be continued
Basic Immunology II
Targeted Therapy
Biologic response modification
Therapeutic Implication
VCAM-1
7
ICAM-1
Collagenase
MMP
PGs
IgG
8
IL-1
TNF-a
6
GM-CSF
IL-4
IL-6
IL-6
1
3
2
5
IFN-g
IL-2
4
effector
T-cells
VCAM-1
7
ICAM-1
Collagenase
MMP
PGs
IgG
8
IL-1
TNF-a
6
GM-CSF
IL-4
IL-6
IL-6
1
3
avoid Ag exposure
antimicrobial
2
5
IFN-g
IL-2
4
effector
T-cells
VCAM-1
7
ICAM-1
Collagenase
MMP
PGs
IgG
8
IL-1
TNF-a
6
GM-CSF
IL-4
IL-6
IL-6
1
3
2
5
IFN-g
IL-2
4
effector
T-cells
Antimalarial drug
change pH in
phagosome
VCAM-1
7
ICAM-1
Collagenase
MMP
PGs
IgG
8
IL-1
TNF-a
6
GM-CSF
IL-4
IL-6
IL-6
1
3
2
5
IFN-g
IL-2
4
effector
T-cells
? RA refractory to TNF-a
Cytotoxic T lymphcyte-associated
antigen inhibitor
4
CTLA4-Ig
- CTLA4-Fc
- LEA29Y
? RA subset
= immunoregulatory
protein
? SLE mice
TcR b
Ag
TcR
CD3
APC
HLA-DR
CD4
LFA-3
ICAM-1
CD40
CD80/86 (B7)
CD2
LFA-1 (CD11a/CD
CD40L
CD28
CTLA4
(CD154)
TRIMOLECULAR COMPLEX
& COSTIMULATORY PATHWAY
TH
Anti CD40L mAb RA
( IDEC-131, hu5c8, BG9588, Biogen )
B
SLE
CD40
TcR b
Ag
TcR
CD3
APC
HLA-DR
LFA-3
ICAM-1
CD40
CD80/86 (B7)
TT
H
CD4
CD2
LFA-1 (CD11a/CD
CD40L
CD28
CTLA4
(CD154)
TRIMOLECULAR COMPLEX
& COSTIMULATORY PATHWAY
efalizumab
: humanized mAb CD11a
psoriasis
TcR b
Ag
TcR
CD3
APC
HLA-DR
LFA-3
ICAM-1
CD40
CD80/86 (B7)
TH
CD4
CD2
LFA-1 (CD11a/CD
CD40L
CD28
CTLA4
(CD154)
TRIMOLECULAR COMPLEX
& COSTIMULATORY PATHWAY
Anti-CD3 : HuOKT3g1 (Ala-Ala)
TcR b
Ag
TcR
CD3
APC
HLA-DR
LFA-3
ICAM-1
CD40
CD80/86 (B7)
TH
CD4
CD2
LFA-1 (CD11a/CD
CD40L
CD28
CTLA4
(CD154)
TRIMOLECULAR COMPLEX
& COSTIMULATORY PATHWAY
VCAM-1
7
ICAM-1
Collagenase
MMP
PGs
IgG
8
IL-1
TNF-a
6
GM-CSF
IL-4
IL-6
IL-6
1
3
2
IFN-g
IL-2
5
Profound peripheral
4
lymphopenia
effector
T-cells
CAMPATH-1H
VCAM-1
7
ICAM-1
Collagenase
MMP
PGs
IgG
8
IL-1
TNF-a
6
GM-CSF
IL-4
IL-6
IL-6
1
5
IFN-g
IL-2
4
effector
T-cells
3
2
IL-2
DAB IL-
VCAM-1
7
ICAM-1
Collagenase
MMP
PGs
IgG
8
IL-1
TNF-a
6
GM-CSF
IL-4
IL-6
IL-6
1
3
2
5
IFN-g
IL-2
4
Rituximeb
anti-CD20
effector
T-cells
Autoimmune with antibody production
refractory Wegener granulomatosis, SLE with AIHA, ITP
essential mixed cryoglobulinemia,
Plasma cell
P
memory
B
CD20
RA (? RF+ve)
mature
naive
immature
B
B depletion
B-cell
CD20
CD20
Rituximeb
anti-CD20
VCAM-1
7
ICAM-1
Collagenase
MMP
IVIG
PGs
IgG
8
IL-1
TNF-a
6
GM-CSF
IL-4
IL-6
IL-6
1
3
2
5
IFN-g
IL-2
4
effector
T-cells
VCAM-1
Collagenase
MMP
7
ICAM-1
Biologic response modifier
PGs
IgG
8
IL-1
TNF-a
6
GM-CSF
IL-4
IL-6
IL-6
1
3
2
5
IFN-g
IL-2
4
effector
T-cells
VCAM-1
Collagenase
MMP
PGs
7
ICAM-1
ET-1®
TGF-b
IgG
8
IL-1
TNF-a
6
GM-CSF
IL-4
IL-6
IL-6
1
3
2
5
IFN-g
IL-2
4
effector
T-cells
VCAM-1
7
ICAM-1
block adhesion
molecules
Collagenase
MMP
PGs
IgG
8
IL-1
TNF-a
6
GM-CSF
IL-4
IL-6
IL-6
1
3
2
5
IFN-g
IL-2
4
effector
T-cells
VCAM-1
7
ICAM-1
Collagenase
Anti-inflammatory agents
MMP
PGs
IgG
8
IL-1
TNF-a
NO synthetase
Superoxide dismutase
6
GM-CSF
IL-4
IL-6
IL-6
1
3
2
5
IFN-g
IL-2
4
effector
T-cells