Update on the pathophysiology of ankylosing spondylitis
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Transcript of Update on the pathophysiology of ankylosing spondylitis
Update on the pathophysiology of
ankylosing spondylitis
Thao PHAMMarseilleFrance
AS and HLA-B27 association
• 1973
– Schlosstein (US)
• AS was associated with HLA-B27 : 88% (vs 8% controls)
– DA Brewerton (GB)
• AS was associated with HLA-B27 : 96% (vs 4% controls)
Molecular mechanisms underlying the association of HLA-B27 with AS are still unclear
AS and HLA-B27 association
• Association between HLA B27 and SA – 90% AS express HLA B27
– 5% HLA B27+ develop AS
• Family studies Recurrence risk– Monogenic disease
– Polygenic disease
• Twin studies Concordance rates– dizygotic 23% vs monozygotic 63%
Carter KW et al. Rheumatology 2007;46:763–71. Reveille J. Best Pract Res Clin Rheumatol 2006;20:601–9.
AS is not a monogenic diseaseSusceptibility genes located outside the major histocompatibility
complex (MHC) region
Patients Controls
Susceptibiliy allele
Protective alleleDifference of allele distribution between cases and controls
Case-control studies
Case-control studies
At a « limited level »• Linkage studies
– Several SNPs (single nucleotide polymorphisms)
At a « very big level »• Genome wide screening
– “hypothesis-free” genetics research
– > 10.000 SNPs
• Wellcome Trust Case Control Consortium (WTCCC)
• 1000 AS and 1500 controls
Genome wide screening
HLA B27
Reveille J et al. Arthritis Rheum 2008;58;S609.
p < 10-7
p < 10-5
Genome wide screening
HLA B27
Reveille J et al. Arthritis Rheum 2008;58;S609.
p < 10-7
p < 10-5
Genome wide screening
HLA B27
Reveille J et al. Arthritis Rheum 2008;58;S609.
p < 10-7
p < 10-5
IL23R
IL1R1/R2
ARTS1
• 4 identified and validated candidate genes for a role
in ankylosing spondylitis
– HLA B27
– interleukin-1 (IL-1) gene cluster
– ARTS1
– IL-23 receptor gene (IL-23R)
AS is a polygenic disease
• 4 identified and validated candidate genes for a role
in ankylosing spondylitis
– HLA B27
– interleukin-1 (IL-1) gene cluster
– ARTS1
– IL-23 receptor gene (IL-23R)
AS is a polygenic disease
• ARTS 1 : Aminopeptidase regulator of TNFR1 shedding
• Endoplasmic reticulum aminopeptidase
• Two known effects of ARTS 1
– cleavage of cytokine receptors(IL-1, IL-6, TNF) from the cell
surface
– cleavage of the N-terminus of peptide precursors in the
reticulum optimal length for the presentation by HLA
class I molecules
ARTS 1 (or ERAP 1 or ERAAP)
Burton et al. Nat Genet 2007;39:1329-37. Hammer GE et al. Immunity 2007; 26:397–406.
• Functional analysis
– 80 AS with active disease
– No correlation between ARTS1
• Acute phase reactants
• Plasmatic levels of sTNFRI, sIL-1R et sIL-6R
ARTS 1 (or ERAP 1 or ERAAP)
Haroon N et al. Arthritis Rheum 2008;58;S353.
ARTS1 is responsible for processing peptides to optimal length for the presentation by HLA class I molecules
ARTS 1 (or ERAP 1 or ERAAP)
Brionez et al. Current Opinion in Rheumatology 2008,20:384–391.
Adapted from Brionez et al. Current Opin Rheum 2008
B27 heavy chain (HC)
calnexin calreticulin
BiP
TAP
tapasin
ARTS 1
BIP: Binding Immunoglobulin ProteinTAP: Transporter Antigen Processing
Viral or bacterial peptidiques
hβ2m
Adapted from Brionez et al. Current Opin Rheum 2008
B27 heavy chain (HC)
calnexin calreticulin
BiP
TAP
tapasin
ARTS 1
NK
BIP: Binding Immunoglobulin ProteinTAP: Transporter Antigen Processing
Viral or bacterial peptidiques
hβ2m
CD8+CD4+
HLA-B27, B2M peptide trimolecular complex transportled to the cell surface via the Golgi apparatus
• 4 identified and validated candidate genes for a role
in ankylosing spondylitis
– HLA B27
– interleukin-1 (IL-1) gene cluster
– ARTS1
– IL-23 receptor gene (IL-23R)
AS is a polygenic disease
A success of the genome wide SNPs screening
Duerr R et al. Science 2006 314, 1461-3.
• Significant association between IL23R gene and Crohn’s disease
– Uncommon coding variant confers strong protection against
Crohn’s disease
• rs11209026 : OR (0,26; 95% CI : 0,15 – 0,43)
– Additional non coding variants are independently associated
• Replication in independant cohorts
Duerr R, et al. Science 2006;314:1461-3.
IL23R polymorphisms
• Significant association between IL23R gene and
• Psoriasis
– Cargill M et al. Am J Hum Genet 2007;80(2):273-90.
• Psoriatic arthritis
– Filer C et al. Arthritis Rheum 2008;58:3705–09.
• Ankylosing spondylitis
– Wellcome Trust Case Control Consortium. Nat Genet
2007;39(11):1329-37.
IL23R polymorphisms
Is IL17/IL23 axis the key of AS
physiopathology?
Th0CD4+
Th2
Th1
IL12/STAT4
IL4/STAT6
T helper cells differenciation (Th)
Adapted from Coffman Nat Immunol 2006; Weaver. Annu Rev Immunol 2007; Koenders ARD 2006
IFNγ
IL4, IL10
Th0CD4+
Th2
Th1
IL12/STAT4
IL4/STAT6
IFNγ
IL4, IL10
Th17IL-6/TGF IL17TNFIL6
TReg
TGF
/IL1
0T helper cells differenciation (Th)
Adapted from Coffman Nat Immunol 2006; Weaver. Annu Rev Immunol 2007; Koenders ARD 2006
Th0CD4+
Th2
Th1
IL12/STAT4
IL4/STAT6
IFNγ
IL4, IL10
Th17IL-6/TGF IL17TNFIL6
TReg
TGF
/IL1
0
IL 23
T helper cells differenciation (Th)
Adapted from Coffman Nat Immunol 2006; Weaver. Annu Rev Immunol 2007; Koenders ARD 2006
Fibroblaste
Chondrocyte
Ostéoblaste
Epithelial cell
Macrophage
Keratinocyte
Th17
IL 23
IL 17
Inflammation
Cartilage damage
Bone erosion
Psoriasis
Inflammatory bowel
disease
Interleukin 17
• IL23 member of the IL6 family• Cytokine proinflammatoire, hétérodimérique
– 2 subunits: p19 and p40– IL23R is also heterodimeric
• Allows survival and expansion of Th17 response
Interleukin 23
Kastelein et al. Ann Rev Immunol 2007;25:221–42.
p35
IL-12 IL-23
p40 p40 p19
IL-12 Rβ1 Rβ2 IL-12 Rβ1 IL-23R
Anti-IL12/23 (p40) monoclonal antibody
• RCT in psoriasis, Crohn’s disease and Psoriatic Arthritis
Placebo (n = 70) → ustekinumab x 2 on W12 et W16 (n = 56)
Ustekinumab x 4 on W0, W1, W2, W3 (n = 76)
0 4 8 12 16 20 24 28 32 360
20
40
60
ACR
20 re
spon
ders
(%)
weeks
n = 50
n = 67
42 %51 %49 %
42 %*
45 %
14 %
41 %
34 %
* p < 0,001 vs placebo
Leonardi C et al. Lancet 2008; 371: 1665–74. Gottlieb A. Lancet 2009;373:633-40
What is the link with HLA B27?
Adapted from Brionez et al. Current Opin Rheum 2008
B27 heavy chain (HC)
calnexin calreticulin
BiP
TAP
tapasin
ARTS 1
NK
BIP: Binding Immunoglobulin ProteinTAP: Transporter Antigen Processing
Viral or bacterial peptidiques
hβ2m
CD8+CD4+
HLA-B27, B2M peptide trimolecular complex transportled to the cell surface via the Golgi apparatus
From Brionez et al. Current Opin Rheum 2008
B27 heavy chain (HC)
calnexin calreticulin
BiP
TAP
tapasin
ARTS 1
CD8+CD4+
NK
BIP: Binding Immunoglobulin ProteinUPR : Unfolded Protein Response
Viral or bacterial peptidiques
hβ2m
BiPBiP
BiP
BiPBiP
BiP
ERp57
From Brionez et al. Current Opin Rheum 2008
B27 heavy chain (HC)
calnexin calreticulin
BiP
TAP
tapasin
ARTS 1
CD8+CD4+
NK
BIP: Binding Immunoglobulin ProteinUPR : Unfolded Protein Response
Viral or bacterial peptidiques
hβ2m
BiPBiP
BiPUPR
BiPBiP
BiP
ERp57
Th0CD4+
Th2
Th1
IL12/STAT4
IL4/STAT6
IFNγ
IL4, IL10
Th17IL-6/TGF IL17TNFIL6
TReg
TGF
/IL1
0HLA B27 misfolding and the unfolded protein
respons (UPR) increase IL23 production
IL 23
DeLay M et al. Arthritis Rheum 2009,;60: 2633–2643.
UPR
+
Proposed mechanism linking activation of the unfolded protein response (UPR) as a consequence of HLA–B27 misfolding to activation of the
interleukin-23 (IL-23)/IL-17 axis
DeLay M et al. Arthritis Rheum 2009,;60: 2633–2643.
• Hypotheses regarding the role for HLA-B27 – HLA-B27 may modulate the inflammatory response to
infectious agents
• via antigen recognition of arthritogenic peptides and/or molecular mimicry involving the adaptive and innate immune systems (ARTS1)
• via misfolding stress response unfolded protein response induce inflammatory factors such as IL-23
Conclusion