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Basic Immunology
for internist
Ratanavadee Nanagara, M.D.
Allergy-Immunology-Rheumatology Unit
Department of Medicine
KhonKaen University
Nature of Immunity
Self Tolerance
Model of Host Immune Response
Abnormal immune response
Immunopathogenesis of Autoimmune Dis.
Therapeutic implication
The Nature of Immunity
Cardinal features of IR
specific
memory
discrimination
Type of Recognition & Defense
Non-specific (innate)
Specific (adaptive)
Non-specific immune response
Physical barriers
Chemical property
Cells: professional phagocytes
Cytokines
Complement
Fatty acids
Normal bacterial
skin flora
Physical & chemical 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
Specific immune response
1. Antigen specific
?
2. Discrimination self/non-self
Specific Immune Response
1. Antigen specific
 2. Discrimination self/non-self
Nature of Immunity
Self Tolerance

Model of Host Immune Response
Abnormal immune response
Immunopathogenesis of Autoimmune Dis.
Therapeutic implication
Discrimination
?
immune cell
self Ag
Self tolerance
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”
Specific Immune Response
CMIR
HIR
Nature of Immunity
Self Tolerance
Model of Host Immune Response
Abnormal immune response

Immunopathogenesis of Autoimmune Dis.
Therapeutic implication
Non-specific (innate) IR
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
Specific (adaptive) IR
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
Nature of Immunity
Self Tolerance
Model of Host Immune Response
Abnormal immune response

Immunopathogenesis of Autoimmune Dis.
Therapeutic implication
Abnormal Immune Response

Immune deficiency
congenital
viral infection
physiologic change
radiation
splenectomy
chronic diseases
acquired
immunosuppressive drugs
Abnormal Immune Response

Gel & Coombs
Classification of Immune Response
(Hypersensitivity)
 Type I
- IgE mediated
 Type II - Ab mediated
 Type III - Immune complex
 Type IV - Delayed-type
Abnormal Immune Response

Autoimmunity
How ?
Nature of Immunity
Self Tolerance
Model of Host Immune Response
Abnormal immune response
Immunopathogenesis of Autoimmune Dis.
Therapeutic implication

Triggering
Infection
Bacteria
Genetic
predisposition
HLA
Abnormal
Class I - B27
Class II- DR Immune Response
- DW
Non HLA
Chlamydia
Yersinia
Salmonella
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
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
Nature of Immunity
Self Tolerance
Model of Host Immune Response
Abnormal immune response
Immunopathogenesis of Autoimmune Dis.
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
Biologic response modifier
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
Alternative targets of cytokine modifying Rx
Signal
transduction
vx-745 (inh. p38 MAPK pathway)
Chemokines
recombinant human IL-18 binding protein
c-Jun-N terminal kinase inhibitor
calcineurin inhibition (post R signaling)
CIS3/SOCS3 (signaling repressor)
humanized CXCL8/IL-8 Ab
oral CCR1-antagonist
ET-1
TGF-b
ET-1 receptor antagonist
VEGF
soluble VEGFR1-Fc
anti-TGF-b
TNF model
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
anti VCAM-1
VCAM-1
(CD106)
Anti-human-ICAM-1 Ab (enlimomab)
ICAM-1
ICAM-2
mAb E-selectin
P & E Slectin (CD62)
VLA-4
CLA
(CD49/29)
LFA-1
CD 44
humanized anti–avb3
(integrin mAb)
HLA DR+
ADHESION MOLECULES
Humanized 4-1, 4-7 mAb (Natalizumab)
2ME2 (2 methoxyextradiol) antiangiogenesis
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
Cytokine function: TNF model
- 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
Signal Transduction
stimulus
specific
receptor
signal transduction
transcription
translation
posttranscription
Protein kinease
pathways
Receptor
Translocation of
associating
transcription factors
proteins
cell surface
cytoplasm
nucleus
proteins
HLA-DR
mRNA
stimulus
specific
receptor
signal transduction
transcription
translation
posttranscription
Protein kinease
pathways
Receptor
Translocation of
associating
transcription factors
proteins
JNK inhibitor
RANKL
TRAF inhibitor
AMG162
Humanized Ab
Antiresorptive during bone remodeling
MAPK inhibitor
Scio-469 (oral )
phase IIb
Calcineurin
inhibitor
siRNA
TNF blockade
mouse model
proteins
HLA-DR
mRNA
Infection
and
Host defense
Implication
infection
and
immunity
exercise
and
immunity
ด่ านป้องกันการติดเชื้อ
physical
barriers
non-specific cells

PMN
specific IR
IC killing defect
abn lymphocyte
function
T-cell
disruption
neutropenia
dendritic cell (APC)
ชนิดของการติดเชื้อ
การตอบสนองหลัก
HIR
bacteria
virus
TB
CMIR
fungus
NK cells
IC bacteria
Efficiency of Immune Response
genes
extreme age
hormone
(steroid)
pH
change of flora
disrupted
barriers
socioeconomic
status
cilia
physilogic change
Exercise
and
Immunity
Exercise & IR
acute boat
of exercise
chronic
exercise
(at least 16 wk)
(NK cells)
เป็ นไข้ หวัด ออกกาลังกายได้ หรื อไม่
การออกกาลังกายในผู้ตดิ เชื้อ HIV / AIDS
การออกกาลังกายป้องกันโรคมะเร็งได้ หรื อไม่
immune ↔ infection
acute vs chronic
Immune Response
relaxation exercise