Update on the pathophysiology of ankylosing spondylitis Thao PHAM Marseille France.

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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

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

HLA B27

p < 10-7

p < 10-5

HLA B27

p < 10-7

p < 10-5

IL1R1/R2

• 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

– HLA B27

– ARTS1

• 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

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

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

tapasin

ARTS 1

BIP: Binding Immunoglobulin ProteinTAP: Transporter Antigen Processing

Viral or bacterial peptidiques

tapasin

ARTS 1

CD8+CD4+

HLA-B27, B2M peptide trimolecular complex transportled to the cell surface via the Golgi apparatus

– HLA B27

– ARTS1

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+

IL12/STAT4

IL4/STAT6

T helper cells differenciation (Th)

Adapted from Coffman Nat Immunol 2006; Weaver. Annu Rev Immunol 2007; Koenders ARD 2006

IL4, IL10

Th0CD4+

IL12/STAT4

IL4/STAT6

IL4, IL10

Th17IL-6/TGF IL17TNFIL6

0T helper cells differenciation (Th)

Th0CD4+

IL12/STAT4

IL4/STAT6

IL4, IL10

T helper cells differenciation (Th)

Fibroblaste

Chondrocyte

Ostéoblaste

Epithelial cell

Macrophage

Keratinocyte

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.

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

n = 50

n = 67

42 %51 %49 %

* 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?

tapasin

ARTS 1

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

tapasin

ARTS 1

CD8+CD4+

BIP: Binding Immunoglobulin ProteinUPR : Unfolded Protein Response

BiPBiP

From Brionez et al. Current Opin Rheum 2008

tapasin

ARTS 1

CD8+CD4+

BIP: Binding Immunoglobulin ProteinUPR : Unfolded Protein Response

BiPBiP

BiPUPR

BiPBiP

Th0CD4+

IL12/STAT4

IL4/STAT6

IL4, IL10

0HLA B27 misfolding and the unfolded protein

respons (UPR) increase IL23 production

DeLay M et al. Arthritis Rheum 2009,;60: 2633–2643.

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

Update on the pathophysiology of ankylosing spondylitis Thao PHAM Marseille France.

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