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