ETIOLOGY VS PATHOGENESIS
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Transcript of ETIOLOGY VS PATHOGENESIS
ETIOLOGY VS PATHOGENESIS
Etiology- genetic predisposition- environmental factors: triggering/protective
Pathogenesis- nature of autoantigen(s)- effector mechanisms- regulatory circuits
Monozygotic twins
INTRAFAMILY CONCORDANCE RATES FOR MAJOR AUTOIMMUNE DISEASES
Type I diabetesGraves diseaseCrohn’s diseaseMultiple sclerosisSystemic lupus
erythematosusRheumatoid arthritisMyasthenia gravis
35-50 %
30-60 %
40 %
10-20 %
25-50 %
10-30 %
40 %
7 %
7 %
4 %
0-4 %
2-10 %
5-10 %
1-2 %
15 %
15 %
15 %
Monozygotic twins
Siblings
HLA identical siblings
HLA ASSOCIATIONS WITH AUTOIMMUNE DISEASES
Strong associationankylosing spondylitisceliac diseasetype 1 diabetesGoodpasture’s syndromepemphigus vulgarisacute anterior uveitis
Mild associationpsoriasismultiple sclerosisrheumatoid arthritisGrave’s diseaseHashimoto’s thyroiditisSystemic lupus erythematosusMyasthenia gravis
B27DQ2
DR3/4DR2DR4B27
CW6DR2DR4DR3DR5DR3
B8/DR3
905025161410
7.564
3.5333
AlleleRelative risk(Odd’s ratio)
Disease
The autoantigen gene (CHRNA) :The -subunit of AChR
Exon I Exon IIIntron I
Microsatellites
HB BB
ETIOLOGY OF AUTOIMMUNE DISEASES
Genetic Predisposition
Environement
Chance
Epigenetics
Thyroiditis score
weeks
NOD.H2k
CBA/J
5228108640
1
2
3
4
3
Comparative evolution of experimental allergic thyroiditis in CBA/J and congenic NOD.H2k mice
ANTIGEN MIMICRY AND GUILLAIN-BARRE SYNDROME
_______
Galβ1-3GalNAcβ1-4(NeuAcα2-3)Galβ1-
Lipooligosaccharide derived from
Campylobacter jejuni
Human GM1 ganglioside
In human peripheral nerves
(N. Yuki et al, PNAS 2004, 101, 31)
Induction of Guillain-Barré syndrome by immunization against a Campylobacter jejuni lipooligosaccharide
Yuki et al, PNAS 2004
MULTIPLICITY OF AUTOANTIBODIES IN INSULIN-DEPENDENT DIABETES
MELLITUS
Insulin
Glutamic acid decarboxylase (GAD)
IA-2 (tyrosine phosphatase)
p69
Gangliosides
Carboxypeptidase H
MULTIPLICITY OF AUTOANTIBODIES IN MYASTHENIA GRAVIS
Acetylcholine receptor
chain
chain
chain
Striated muscle
actin
actinin
myosin
titin
ryanodine receptor
rapsyn
3
20 40 60 80Days post-infection
2
1
00
Me
an c
linic
al s
core
Development of myelin specific T cells in SJL mice chronically infected by Theiler's virus
S.D. Miller et al, 1997
DT
H
E
ar s
we
lling
(
x 10
-4in
.) ±
SE
MDays post TMEV infection
34 42 52 58 81
20
30
10
0
TMEV VP270-86 PLP 139-151 PLP 178-191
T cell-mediatedinflammation
Ag1Ag2Ag3…
TH1
Ag1 + APC
TH1 / Ag1
APC + Ag1
TH1 / Ag1
APC + Ag2
TH1 / Ag2
Non immunologic inflammation
Triggering
Amplification+ chronicity
CANDIDATE VIRUSES IN AUTOIMMUNE DISEASES
Multiple sclerosisMeaslesHTLV-1 and other retroviruses (MSRV, HRES-1)HHV 6Other viruses: EBV, JCV, varicella, HSV1/2, rubella
Insulin dependent diabetes mellitusRubellaEnteroviruses (Cocksackie A and B, Echovirus 6 and 9)Endogenous retroviruses Other viruses: mumps, CMV, rotavirus
0 5 10 15 20 25 30 35 40 45 50 55 60
Age
Mul
tiple
Scl
eros
is In
cide
nce
Rat
e
Late EBV Infection With IM
Early EBV Infection Without IM
No EBV Infection
Thacker et al. Annals Neurol 2006
High hygiene,No EBV
High hygiene,+ EBV
219
159
175
175 17
8140
198135
119
6075
75
130
60
100
102
57
57
116
95
67
69
126
106
116
75129
112
124
89
110
69
60
6143
70
574252
48
225
100
141
136
93
88
107
115
145
66
Kurtzke et al. Neurology 1985, 35, 672-678.
Case/control ratios of MS *100 by state of EAD – based on > 5,300 MS cases in US Army Veterans
119112
Relative risk of MS for white males of World War II or the Korean conflict by tier of residence at birth and at entry into active duty (EAD), coterminous US only.
Adapted from Kurtzke et al. Neurology 1985
P for no change in birthplace risk: All=0.0003; North=0.003; Middle=0.002; South=0.57
North
0,711.0 (ref)
1,31
N M S
1,131.20 1.0 (ref)
North Middle South
0,520.82
1.0 (ref)
N M S
Middle
South
EAD Tier
Tier of birth
5.3
1.9 (56-74)
3.78
1.69 24
0.96 (mortality or incidence)
2.2
5
1.1
2.24
3.94
3.3
1.72
Incidence of multiple sclerosis(per 100,000)
24 (77-85)
9.4
7.3 (66-89)
8.05 (54-86)
11.5 (67-90)
19.9
10.9 (85-88)
7.7
19.7
35.8 (87-99)
13.7
Incidence of IDDM(per 100,000)
IDDM incidence in children of migrants from Pakistan to Yorkshire
Staines A. (1997) and Bodansky H.J. (1992)
0
2
4
6
8
10
12
Pakistan Migrant's children
Yorkshire
Incidence of diabetes / 105
IBD & Industrialization and urbanization
IDDM
Multiple sclerosis
Crohn's disease
Asthma
55
Incidence of prototype infectious disease and immune disorders over 4 decades
75 85 95
100
50
Infectious disease
%
100
200
Immune disorders
%300
0
65
Hepatitis A
Rheumatic fever
Measles
Tuberculosis
55 75 85 9565
FACTORS CONTRIBUTING TO THE APPEARANCE OF INFECTIONS
Sources of pathogenic agents
- drinking water
- food (cold storage)
- climate
- housing conditions
- hygiene (worms….)
Anti-infectious defense
- nutrition
- antibiotics
- vaccination
CAUSAL LINK
• ANIMAL MODELS
• CLINICAL TRIALS (PROOF OF CONCEPT)
Effect of infections on diabetes incidence in female NOD mice
0
Age (weeks)
20 40 60 800
25
0
50
75
100
20 40 60 80
% d
iab
etic
Decontamination (isolation)
G1 (n = 177) G2 (n = 200)
G1 (n = 236) G2 (n = 210)
PREVENTION OF IDDM IN NOD MICE BY INFECTIOUS AGENTS
Bacteria streptococcisalmonellamycobacteria (CFA, BCG, …)
Viruses LCMVMHVLDHV
Parasites schistosomaoxyures
Age (days)
0
20
40
60
80
100%
100 200 300 100 200 300
Controls
Mice infected
Effect of malaria in B / W mice
Proteinurie Mortality
B. M. Greenwood et al, 1970
MECHANISMS
1. Antigenic competition
Effect on antigen presentation
- preemption (phagocytosis)
- antigen processing
- antigen binding to MHC molecules
Competition for homeostatic signals
2. Antigen-induced immunoregulation(by-stander suppression)
Th1/Th2 cells
Th3 cells
NKT cells
CD25+ T cells
Th2 cytokines are not
involved
0
20
40
60
80
3 7 11 15 18 23 31 35 38 4327
anti-IL-10R
NOD témoins
NOD OM-85+ anti-IL-10R
NOD OM-85
0
20
40
60
80
100
3 7 11 15 19 23 27 31
OM-85
NOD OM-85
NOD IL-4-/- controls
NOD IL-4-/- OM-85
Age (weeks)
Age (weeks)
OM-85
% d
iab
etes
% d
iab
etes
,,,,,,,,,,,,,,,,,,
,,,,,
,
,,
,,
,,
,,,,,,, ,
,,,, ,,, ,,,, ,,,, ,
, , , ,
, , ,
,
,,,
, , ,
TGF- antibody treatment abrogates diabetes protection by OM-85
0
20
40
60
3 7 11 15 19 23 27Age (weeks)
OM-85 anti-TGF-
NOD OM-85
NOD controls
NOD OM-85+ anti-TGF-
% d
iab
etes
,,,, ,, ,,
,,, ,,,
,,,, ,,
Rôle of natural regulatory CD4+CD25+ T cells
3 7 11 1519 23 27 31
Age (weeks)
20
40
60
0
% d
iab
etes
NOD CD28-/- OM-85
NOD CD28-/- controls
OM-85
3. Non-antigen-mediated effects
Toll-like receptors (regulatory cytokines)
Superantigens (depletion of T cell subsets)
Immunosuppressive proteins
Immune response of dendritic cell to TLR agonists
Th1IL-2,
TNF-, IFN-
vvv v
vv
vvvv
TLR4
TLR5
TLR2
FlagellinEndotoxins or LPSMycobacterial soluble factorProteine MMLVMannanFibrinogenHSP70, HSP60HyaluronanBeta-defensinSurfactant Protein A
LipoproteinsZymosanP. Gingivalis LPSLipoteichoic acidLipoarabinomannanHCMVTrypanosoma cruzi GPIKOmpAHSP70
vv
vv TLR7
vv TLR9
TLR3
TLR1
TLR11
vv TLR8
vvTLR6
Bacterial DNA (CpG)Herpes simplex virus 2
upec
ImidazoquinolinedsARN
ssARNPoly(I:C)
Lipopeptide
lipopeptide
IRF3NF-BAP-1
ImidazoquinolineMyD-88 TRIF
Th2IL-4, IL-5,
IL-10, IL-13
IFN
Regulatory T cells
Allergy & Autoimmunity
TLR2, TLR3,TLR4 and TLR7 agonists delay T1D onset
Type 1 diabetes
Dia
bete
s in
cide
nce
(%)
Age (weeks)
TLR2 TLR3 TLR4 TLR7
0
10
20
30
40
50
60
70
80
0 5 10 15 20 25
Non treatedP40
p=0.0064
Treatment
0102030405060708090
100
5 15 25
Non treatedPoly(I:C)
p=0.000450
10
20
30
40
50
60
70
80
5 10 15 20 25
Non treatedLPS
p=0.00850
102030405060708090
5 10 15 20 25
Non treatedR848
p=0.0143
Similar protective results were obtained with TLR agonists : synthetic lipopetide Pam3CSK4 (TLR2 agonist) or dsRNA Poly(I)Poly(C) …
TLR2 agonist stimulates splenocytes to produce IL-10 and TGF-via MyD88
IL-10 TGF-
0
20
40
60
80
100
120
140
160
180
- 2 20
MyD88+/+
MyD88-/-
P40 (g/ml)
0
100
200
300
400
500
600
700
800
900
1000
- 2 20
MyD88+/+
MyD88-/-
P40 (g/ml)
p=0,0042
p=0,2848
NOD CD1d+/+ NOD CD1d-/-
Protection mediated by a TLR3 agonist is dependent on iNKT cells
TLR3-induced protection is IL-4-dependent
0
10
20
30
40
50
60
70
80
90
100
5 10 15 20 25
NOD WT Non treatedNOD WT Poly(I)Poly(C)NOD IL4 KO Non treatedNOD IL4 KO Poly(I)Poly(C)
Incid
en
ce o
f d
iab
ete
s (
%)
Age (weeks)
NOD.MyD88−/− mice are resistant to the development of type 1 diabetes
0
20
40
60
80
100
0 5 10 15 20 25 30
Weeks of age
Inci
denc
e of
dia
bete
s (%
)
MyD88w t
MyD88Ko
Type 1 diabetes
Allergic asthma model
Immunization100 µg OVA + Alum i.p.
D0 D10Measurement of airwayhyperreactivity to metacholine
Sacrifice and collection ofSera (cytokines, IgE)BALFs (cells, cytokines)Lungs (cytokines)
D6, D7, D8 : treatment with TLR agonist
D7, D8, D9
OVA challenge
NOD.MyD88−/− mice are hyperreactive to allergic asthma
Allergic
asthma
NOD.MyD88−/− mice died during the protocol of experimental allergic asthma
at the time of the second challenge.
When mice were decontaminated, death occured between the first and the second challenge. (5 independent experiments, 40 mice)
Prevention of allergic asthma by a TLR2 agonist
Allergic
asthma
-2 -1 0 1 2 3 4 5 6 7 8 9
1.53.04.56.07.59.0
OVA/P40
Saline/Vehicle Saline/P40
OVA/Vehicle
Pen
h
OVA Saline OVA Saline0
1500
3000
4500
6000
P40-treated Vehicle-injected
p=0,0357
Lung
eot
axin
leve
l (pg
/ml)
OVA Saline OVA Saline0
50
100
150
200 p=0,0736
Lung
IL-4
leve
l (pg
/ml)
P40-treated VehicleP40-treated Vehicle
Similar results using the TLR4 agonist LPS
CNRS UMR 8147 Paris
N. ThieblemontA. Aumeunier
E. BardelM. Dy
F. GrelaA. Ramadan
INSERM U580 Paris
J. F. BachM. A. Alyanakian
L. ChatenoudC. Gouarin
INSERM U564 Angers
P. Jeannin
Department of Host disease Osaka
S. Akira
Acknowledgements