Basic Immunology Ratanavadee Nanagara, M.D. Allergy-Immunology-Rheumatology Unit Department of...
-
Upload
aubrey-doyle -
Category
Documents
-
view
225 -
download
0
Transcript of Basic Immunology Ratanavadee Nanagara, M.D. Allergy-Immunology-Rheumatology Unit Department of...
Basic ImmunologyBasic Immunology
Ratanavadee Nanagara, M.D.
Allergy-Immunology-Rheumatology UnitDepartment of MedicineKhonKaen University
Nature of Immunity
Model of Host Immune Response
Immunopathogenesis of Autoimmune Dis.
Self Tolerance
Abnormal immune response
Therapeutic implication
Cardinal features of IRCardinal features of IR
specific
memory
discrimination
The Nature of ImmunityThe Nature of Immunity
Specific (adaptive)
Non-specific (innate)
Type of Recognition & Defense
Type of Recognition & Defense
Non-specific immune responseNon-specific immune response
Cells: professional phagocytes
Physical barriers
Cytokines
Complement
Chemical property
The cell can talk
Immune assistant
Physical & chemical barriers: skin & mucosaPhysical & chemical barriers: skin & mucosa
lysozymein saliva
acid
mucus
cilia mucus
no
rmal
gu
t fl
ora
lysozymewashingaction
Fat
ty a
cid
sN
orm
al b
acte
rial
skin
flo
ra
washingaction ofurine
Cells : professional phagocytes Cells : professional phagocytes
• neutrophil
• macrophage• monocyte• NK cells
adhearance, chemotaxis, phagocytosis, oxidative burst, degranulation, IC killing
attack and eat kill
complement
bacteriaphagocytebacteria
2. chemotaxis
C5a
3. opsonization
C3b
1. lysis
C9C5b
phagocyte opsonin binding
_ +
C3b ++
Ab +
Ab + C3b ++++Y
Y
Specific (adaptive)
Non-specific (innate)
Type of Recognition & Defense
Type of Recognition & Defense
specific
memory
discrimination
specific
memory
discrimination
Cardinal featuresCardinal features
1o vs. 2o IR
clonal selection
self/non-self
SpecificSpecific
antigen
activation
primary IRClonal selection
& proliferation
secondary IR
antigen
MemoryMemory
Nature of Immunity
Model of Host Immune Response
Immunopathogenesis of Autoimmune Dis.
Self Tolerance
Abnormal immune response
Therapeutic implication
Discrimination
Self tolerance
??immune cell
self Ag
Clonal ignorance
Central tolerance
Peripheral tolerance
Self tolerance
autoreactive T-cells
blood barrier
Clonal ignorance
Normal tissue Self AgSelf Ag
educated T-cellautoreactive cell
Central Tolerance
autoreactive cell
host cell
Peripheral Tolerance
program cell death … or anergy…
HLA-DRHLA-DRauto Agauto Ag
TcR
V
V
ICAM-1LFA-3
1. lack of co-stimulator molecules – “anergy”
2. stimulate fas ligand - program cell death “apoptosis”
Autoreactive T-cell
fas
Specific (adaptive)
Non-specific (innate)
Type of Recognition & Defense
Type of Recognition & Defense
specific
memory
discrimination
specific
memory
discrimination
Cardinal featuresCardinal features
1o vs. 2o IR
clonal selection
self-nonselfCMIR2 types &
The cells can talk via CYTOKINES
HIR
Nature of Immunity
Model of Host Immune Response
Immunopathogenesis of Autoimmune Dis.
Self Tolerance
Abnormal immune response
Therapeutic implication
Non-specific (innate) IR
effectiveIC killing
occult (persistent) infection
overt infection
adhearance
chemotaxis
phagocytosis
oxidative burst
degranulation
IC killing
Professional phagocytes
no disease
IC killing defect
? Clinical outcome
PMN, monocytes/ macrophage
Specific (adaptive) IR
Antigen Presenting CellAntigen processingAntigen processing
exogenousexogenous
endogenousendogenous
Antigen
CD28LFA-1
CD2CD4
CD3
HLA-DRHLA-DRAgAg
TcR
V
V
ICAM-1LFA-3
CD80/86(B7)
auxillarymolecules
CTL-4
Tyrosine kinase
Trimolecular complex
IL-1TNF-GM-CSFIL-6
IFN-IL-2IL-4IL-6
IL-1TNF-GM-CSFIL-6
IFN-IL-2IL-4IL-6
chemokinesMIF
FibroblastSynoviocyte
IL-1TNF-GM-CSFIL-6
IFN-IL-2IL-4IL-6
Effector T-cells
CMIR
Th1
KTcNK
IL-1TNF-GM-CSFIL-6
IFN-IL-2IL-4IL-6IL-5
B-lymphocyte
IgG
HIR
Th2
CD40
IL-1TNF-GM-CSFIL-6
IFN-IL-2IL-4IL-6
IgG
Activatedmacrophage
effectorT-cells
IF-IL-2
CD25 ®autocrineparacrine
IL-1TNF-GM-CSFIL-6
IFN-IL-2IL-4IL-6
IgG
Blood vessel
effectorT-cells
IL-1TNF-GM-CSFIL-6
IFN-IL-2IL-4IL-6
IgG
VCAM-1(CD106) ICAM-1 (CD54)
effectorT-cells
L. integrin (CD11/18)
VLA integrin(CD49/29)
Selectin (CD62)
Adhesion molecules
IL-1TNF-GM-CSFIL-6
IFN-IL-2IL-4IL-6
IgG
effectorT-cells
Stop inflammatory cells
IL-1TNF-GM-CSFIL-6
IFN-IL-2IL-4IL-6
IgG
effectorT-cells
VEGF
BMP
TGF-ETR
Facilitate extravasation
Nature of Immunity
Model of Host Immune Response
Immunopathogenesis of Autoimmune Dis.
Self Tolerance
Abnormal immune response
Therapeutic implication
Abnormal Immune ResponseAbnormal Immune Response
Immune deficiencyImmune deficiency
congenital
acquired
viral infection
splenectomy
physiologic change
immunosuppressive drugs
radiation
chronic diseases
Abnormal Immune ResponseAbnormal Immune Response
Gel & Coombs
Classification of Immune
Response (Hypersensitivity)
Gel & Coombs
Classification of Immune
Response (Hypersensitivity)
SRSA
Ag YY
Y
IgEMast cell
Type I
Anaphylaxis
IFN-IL-2IL-4IL-6IL-5
B-lymphocyte
Type II
Ab-mediated
IgG
Y
YYY
YY
YYY
Y
Y
Y Y
Target organ
LE cell
IFN-IL-2IL-4IL-6IL-5
B-lymphocyte
IgG
Type III
Immune complexY
Y
Y
Y
Y
Y
IL-1TNF-GM-CSFIL-6
IFN-IL-2IL-4IL-6
IgG
effectorT-cells
Type IVCell
mediated
Abnormal Immune ResponseAbnormal Immune Response
Autoimmunity
How ?
Nature of Immunity
Model of Host Immune Response
Immunopathogenesis of Autoimmune Dis.
Self Tolerance
Abnormal immune response
Therapeutic implication
Triggering InfectionTriggering Infection
Abnormal Immune Response
Geneticpredisposition Geneticpredisposition
DiseaseDisease
HLA Class I - B27 Class II- DR
- DWNon HLA
Bacteria Chlamydia
Yersinia
Salmonella
Shigella
Campylobactor
H. Pyroli
Virus
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 reactiveT-cell
proliferation, cytokines, B-cell activation,
cytolysis
proliferation, cytokines, B-cell activation,
cytolysis
self reactiveT-cell
Molecular mimicry
Molecular mimicry
Presentationof cryptic cell Presentation
of cryptic cell
Hypersensitivity to
persistent organism
or their antigens
Hypersensitivity to
persistent organism
or their antigens
Immune activation by superantigen
Immune activation by superantigen
Antigen activation
or disruption by
retroviruses
Antigen activation
or disruption by
retroviruses
self reactiveT-cell
Molecular mimicry
Molecular mimicry
Presentationof cryptic cell Presentation
of cryptic cell
Hypersensitivity to
persistent organism
or their antigens
Hypersensitivity to
persistent organism
or their antigens
Immune activation by superantigen
Immune activation by superantigen
Antigen activation
or disruption by
retroviruses
Antigen activation
or disruption by
retroviruses
microbe APC T-cell effector cells
cross reactivity(molecular mimicry)
self antigen
self reactiveT-cell
Molecular mimicry
Molecular mimicry
Presentationof cryptic cell Presentation
of cryptic cell
Hypersensitivity to
persistent organism
or their antigens
Hypersensitivity to
persistent organism
or their antigens
Immune activation by superantigen
Immune activation by superantigen
Antigen activation
or disruption by
retroviruses
Antigen activation
or disruption by
retroviruses
autoreactive T-cells
Normal tissue Self AgSelf Ag
self reactiveT-cell
Molecular mimicry
Molecular mimicry
Presentationof cryptic cell Presentation
of cryptic cell
Hypersensitivity to
persistent organism
or their antigens
Hypersensitivity to
persistent organism
or their antigens
Immune activation by superantigen
Immune activation by superantigen
Antigen activation
or disruption by
retroviruses
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, CRetrovirus inf.Herpes zosterPrion
C. trachomatis persistent infection in chronic arthritis
M. Tuberculosis infection that caused intractable autoimmune disease
self reactiveT-cell
Molecular mimicry
Molecular mimicry
Presentationof cryptic cell Presentation
of cryptic cell
Hypersensitivity to
persistent organism
or their antigens
Hypersensitivity to
persistent organism
or their antigens
Immune activation by superantigen
Immune activation by superantigen
Antigen activation
or disruption by
retroviruses
Antigen activation
or disruption by
retroviruses
IL-1TNF-GM-CSFIL-6
IFN-IL-2IL-4IL-6
IgG
effectorT-cells
antigen
superantigen
HLA-DR
Antigen Presentation
LFA-3
ICAM -1
Trimolecular complex
HLA-DRCD3
CD4
CD2
LFA-1
V
TcR
LFA-3
ICAM -1
Trimolecular complex
HLA-DR
V
TcR
Normal T-cell activationNormal T-cell activation
SUPERANTIGEN
HLA-DR
V
TcRV
TcR
Activate T-cell without Ag processingActivate T-cell without Ag processing
CD4CD5
ICAM -1
Treatment of Kawasaki’s disease by giving intravenous immunoglobulin (IVIG)
V
TcR
Y
YYY
YY
Y
Y
Y
CD4CD5
HLA-DR
ICAM -1
Y
Y
self reactiveT-cell
Molecular mimicry
Molecular mimicry
Presentationof cryptic cell Presentation
of cryptic cell
Hypersensitivity to
persistent organism
or their antigens
Hypersensitivity to
persistent organism
or their antigens
Immune activation by superantigen
Immune activation by superantigen
Antigen activation
or disruption by
retroviruses
Antigen activation
or disruption by
retroviruses
Nature of Immunity
Model of Host Immune Response
Immunopathogenesis of Autoimmune Dis.
Self Tolerance
Abnormal immune response
Therapeutic implication
IL-1TNF-GM-CSFIL-6
IFN-IL-2IL-4IL-6
IgG
VCAM-1 ICAM-1
effectorT-cells
1
2
3
4
CollagenaseMMP
PGs
56
7
8
IL-1TNF-GM-CSFIL-6
IFN-IL-2IL-4IL-6
IgG
VCAM-1 ICAM-1
effectorT-cells
1
2
3
4
CollagenaseMMP
PGs
56
7
8
avoid Ag exposure antimicrobial
IL-1TNF-GM-CSFIL-6
IFN-IL-2IL-4IL-6
IgG
VCAM-1 ICAM-1
effectorT-cells
1
2
3
4
CollagenaseMMP
PGs
56
7
8
Antimalarial drug
change pH in
phagosome
IL-1TNF-GM-CSFIL-6
IFN-IL-2IL-4IL-6
IgG
VCAM-1 ICAM-1
effectorT-cells
1
2
3
4
CollagenaseMMP
PGs
56
7
8
HLA-DR
TcR TcRTcR
CD3
CD4CD4CD2LFA-3
ICAM-1
Ag
TRIMOLECULAR COMPLEX
& COSTIMULATORY PATHWAY
APC TH
CD80/86 (B7) CD28CTLA4 (CD154)CTLA4 (CD154)
Cytotoxic T lymphcyte-associated antigen 4= immunoregulatory protein
? RA refractory to TNF- inhibitor? RA subset? SLE mice
CD40
CTLA4-Ig - CTLA4-Fc - LEA29Y
CTLA4-Ig - CTLA4-Fc - LEA29Y
LFA-1 (CD11a/CD18)LFA-1 (CD11a/CD18)
CD40LCD40L
BCD40
HLA-DR
TcR TcRTcR
CD3
CD4CD4
CD2LFA-3
ICAM-1
Ag
APC TH
CD80/86 (B7) CD28CTLA4 (CD154)CTLA4 (CD154)
CD40 CD40LCD40L
TRIMOLECULAR COMPLEX
& COSTIMULATORY PATHWAY
Anti CD40L mAb( IDEC-131, hu5c8, BG9588, Biogen )
Anti CD40L mAb( IDEC-131, hu5c8, BG9588, Biogen )
RA
T
B
CD40
SLEB
CD40
B CD
40
B CD
40
LFA-1 (CD11a/CD18)LFA-1 (CD11a/CD18)
JJ316JJ316anti rat CD28 mAb
HLA-DR
TcR TcRTcR
CD3
CD4CD4
CD2LFA-3
ICAM-1
Ag
APC TH
CD80/86 (B7) CD28CTLA4 (CD154)CTLA4 (CD154)
CD40
TRIMOLECULAR COMPLEX
& COSTIMULATORY PATHWAY
efalizumabefalizumab: humanized mAb CD11a: humanized mAb CD11a
psoriasis
LFA-1 (CD11a/CD18)LFA-1 (CD11a/CD18)
CD40LCD40L
JJ316JJ316
HLA-DR
TcR TcRTcR
CD3
CD4CD4
CD2LFA-3
ICAM-1
Ag
APC TH
CD80/86 (B7) CD28CTLA4 (CD154)CTLA4 (CD154)
CD40
TRIMOLECULAR COMPLEX
& COSTIMULATORY PATHWAY
LFA-1 (CD11a/CD18)LFA-1 (CD11a/CD18)
CD40LCD40L
Anti-CD3 : HuOKT31 (Ala-Ala)
JJ316JJ316
IL-1TNF-GM-CSFIL-6
IFN-IL-2IL-4IL-6
IgG
VCAM-1 ICAM-1
effectorT-cells
1
2
3
4
CollagenaseMMP
PGs
56
7
8
CAMPATH-1HCAMPATH-1H
Profound peripherallymphopenia
IL-1TNF-GM-CSFIL-6
IFN-IL-2IL-4IL-6
IgG
VCAM-1 ICAM-1
effectorT-cells
1
2
3
4
CollagenaseMMP
PGs
56
7
8
IL-2 DAB IL-2DAB IL-2
IL-1TNF-GM-CSFIL-6
IFN-IL-2IL-4IL-6
IgG
VCAM-1 ICAM-1
effectorT-cells
1
2
3
4
CollagenaseMMP
PGs
56
7
8
Rituximebanti-CD20Rituximebanti-CD20
B
CD20
immaturematurenaive
B
CD20
memory
B
CD20
P
Plasma cell
Rituximebanti-CD20Rituximebanti-CD20
B-cell depletion
Autoimmune with antibody production
refractory Wegener granulomatosis, SLE with AIHA, ITP
essential mixed cryoglobulinemia, RA (? RF+ve)
IL-1TNF-GM-CSFIL-6
IFN-IL-2IL-4IL-6
IgG
VCAM-1 ICAM-1
effectorT-cells
1
2
3
4
CollagenaseMMP
PGs
56
7
8IVIG
IL-1TNF-GM-CSFIL-6
IFN-IL-2IL-4IL-6
IgG
VCAM-1 ICAM-1
effectorT-cells
1
2
3
4
CollagenaseMMP
PGs
56
7
8
Biologic response modifier(Targeting therapy)
IL-1TNF-GM-CSFIL-6
IFN-IL-2IL-4IL-6
IgG
VCAM-1 ICAM-1
effectorT-cells
1
2
3
4
CollagenaseMMP
PGs
56
7
8
ET-1®TGF-
TNF- 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)
IFNrecombinant IFN- recombinant IFN-
IL-6 IL-6 mAb soluble IL-6R
Biologic response modifier
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- anti-TGF-
VEGFsoluble VEGFR1-Fc
Alternative targets of cytokine modifying Rx
TNF modelTNF model
IL-1TNF-GM-CSFIL-6
IFN-IL-2IL-4IL-6
IgG
VCAM-1 ICAM-1
effectorT-cells
1
2
3
4
CollagenaseMMP
PGs
56
7
8
block adhesionmolecules
HLA DR+
CD 44LFA-1
CLA
P & E Slectin (CD62)
ICAM-1
ICAM-2VCAM-1 (CD106)
VLA-4(CD49/29)
Anti-human-ICAM-1 Ab (enlimomab)Anti-human-ICAM-1 Ab (enlimomab)
ADHESION MOLECULES
anti VCAM-1anti VCAM-1
mAb E-selectinmAb E-selectin
humanized anti–v3
(integrin mAb)
humanized anti–v3
(integrin mAb)
Humanized 4-1, 4-7 mAb (Natalizumab)2ME2 (2 methoxyextradiol) antiangiogenesis
IL-1TNF-GM-CSFIL-6
IFN-IL-2IL-4IL-6
IgG
VCAM-1 ICAM-1
effectorT-cells
1
2
3
4
CollagenaseMMP
PGs
56
7
8
Anti-inflammatory agents
NO synthetaseSuperoxide dismutase
OR
OR
Searching for the secretinside basic immunology
And finally….
Cytokine function: TNF model
- receptors
- down regulation
- signal transduction
TNFR-I (p55, CD120a)
TNFR-II (p75, CD120b)
2 types ofTNF receptor
Dead signal → apoptosisDown regulation
mechanism
TNF--TNFR complex
endocytosis
soluble TNFRsproduction
LPS
Location of TNFR in steady state
expressconstitutively
Inducible
TNF- overproduction
→ cytokines productionTNFR cleaved into
soluble TNFRs
Kinase cascade (MAPK, NIK, caspase)
Transcription factors (AP-1, NF-B)
TNFR II
TNFR I
TNFR associated factors (TRAF 1-6)
caspase
NIK
MAPK
RIP: R. interacting protein
TRADD- TNFR I asso death domain FADD: factor asso death domain
NF-BNF-B
AP-1AP-1
IL-1, IL-6, IL-8, IL-10, GM-CSFAdhesion molecules PGE2, collagenase
Signal Transduction
Protein transcription
TNF-, IL-1, IL-6, IL-8, COX2, INOS
• Transcription associated protein
• Protein kinase cascade
• Transcription factors
Rx targetRx target
TNF family proteins
fas
TRAIL dead R 4
TRAIL = TNF related apoptosis-inducing ligand
TRAIL dead R 5
BAFF-RBLyS
APRIL TACI
BCMA
LymphocyteLymphocyte
Therapeutic implication
Humanized mAbHumanized mAb
anti fas mAbanti fas mAb
IgIg
BAFF-R = B-cell activating factor receptorTACI = transmembrane activator and calcium modulator and cyclophilin ligand-interactorBCMA = B-cell maturation
BLyS = B-lymphocyte stimulator (increase serum level in SLE) differentiation, activation, survivalAPRIL = a proliferation inducing ligand
BelimumabLymphostat RA, SLE
Signal Transduction
HLA-DR
stimulusspecificreceptor
signal transduction transcriptiontranslation
proteins
Receptor associating
proteins
Protein kineasepathways
Translocation oftranscription factors
mRNAmRNA
post-transcription
cell surface cytoplasm nucleus
HLA-DR
stimulusspecificreceptor
signal transduction transcriptiontranslation
proteins
Receptor associating
proteins
Protein kineasepathways
Translocation oftranscription factors
mRNAmRNA
post-transcription
MAPK inhibitor Scio-469 (oral )
phase IIb
MAPK inhibitor Scio-469 (oral )
phase IIb
RANKL
AMG162 Humanized Ab
AMG162 Humanized Ab
Antiresorptive during bone remodeling
siRNATNF blockademouse model
siRNATNF blockademouse model
Calcineurin
inhibitor
Calcineurin
inhibitor
JNK inhibitorJNK inhibitor
TRAF inhibitorTRAF inhibitor
Infection
and
Host defense
infection
and
immunity
infection
and
immunity
ImplicationImplication
exercise
and
immunity
exercise
and
immunity
physicalbarriers
dendritic cell (APC)
neutropenianeutropeniadisruptiondisruption
IC killing defectIC killing defectPMN
T-cell
ด่�านป้�องกั�นกัารติ�ด่เชื้��อด่�านป้�องกั�นกัารติ�ด่เชื้��อnon-specific cells specific IR
abn lymphocyte function
abn lymphocyte function
HIRYYYY
CMIR
NK cells
bacteria
TB
virus
fungus
IC bacteria
ชื้น�ด่ของกัารติ�ด่เชื้��อ
ชื้น�ด่ของกัารติ�ด่เชื้��อ
กัารติอบสนองหลั�กั
กัารติอบสนองหลั�กั
Efficiency of Immune ResponseEfficiency of Immune Response
change of flora
physilogic change
pH cilia
disruptedbarriers
extreme agegenes socioeconomic
statushormone(steroid)
Exercise
and
Immunity
Exercise & IRExercise & IR
(NK cells)chronic exercise
(at least 16 wk)
acute boat of exercise
กัารออกักั�าลั�งกัายในผู้��ติ�ด่เชื้��อ HIV / AIDSกัารออกักั�าลั�งกัายในผู้��ติ�ด่เชื้��อ HIV / AIDS
เป้�นไข�หวั�ด่ ออกักั�าลั�งกัายได่�หร�อไม่�
กัารออกักั�าลั�งกัายป้�องกั�นโรคม่ะเร%งได่�หร�อไม่�
Immune Response
immune ↔ infection
acute vs chronic
relaxation exercise