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Update on the pathophysiology of ankylosing spondylitis

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

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Update on the pathophysiology of ankylosing spondylitis

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  1. Update on the pathophysiology of ankylosingspondylitis Thao PHAM Marseille France

  2. 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

  3. 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% • AS is not a monogenic disease • Susceptibility genes located outside the major histocompatibility complex (MHC) region Carter KW et al. Rheumatology 2007;46:763–71. Reveille J. Best Pract Res Clin Rheumatol 2006;20:601–9.

  4. Case-control studies Patients Controls Susceptibiliy allele Difference of allele distribution between cases and controls Protective allele

  5. 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

  6. Genome wide screening HLA B27 p < 10-7 p < 10-5 Reveille J et al. ArthritisRheum 2008;58;S609.

  7. Genome wide screening HLA B27 p < 10-7 p < 10-5 Reveille J et al. ArthritisRheum 2008;58;S609.

  8. Genome wide screening ARTS1 HLA B27 IL23R IL1R1/R2 p < 10-7 p < 10-5 Reveille J et al. ArthritisRheum 2008;58;S609.

  9. 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 polygenicdisease

  10. 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

  11. 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.

  12. 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) ARTS1 is responsible for processing peptides to optimal length for the presentation by HLA class I molecules Haroon N et al. ArthritisRheum 2008;58;S353.

  13. ARTS 1 (or ERAP 1 or ERAAP) Brionez et al. Current Opinion in Rheumatology 2008,20:384–391.

  14. APC (macrophage, DC) Endoplasmicreticulum ARTS 1 calnexin calreticulin BiP tapasin hβ2m TAP B27 heavy chain (HC) Viral or bacterial peptidiques BIP: BindingImmunoglobulinProtein TAP: Transporter AntigenProcessing Adapted from Brionez et al. Current Opin Rheum 2008

  15. CD4+ CD8+ NK HLA-B27, B2M peptide trimolecular complex transportled to the cell surface via the Golgi apparatus Endoplasmicreticulum ARTS 1 calnexin calreticulin BiP tapasin hβ2m TAP B27 heavy chain (HC) Viral or bacterial peptidiques APC (macrophage, DC) BIP: BindingImmunoglobulinProtein TAP: Transporter AntigenProcessing Adapted from Brionez et al. Current Opin Rheum 2008

  16. 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 polygenicdisease

  17. A success of the genome wide SNPs screening Duerr R et al. Science 2006 314, 1461-3.

  18. IL23R polymorphisms • 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.

  19. 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.

  20. Is IL17/IL23 axis the key of AS physiopathology?

  21. T helpercellsdifferenciation (Th) IFNγ IL12/STAT4 Th0 CD4+ IL4/STAT6 Th2 Th1 IL4, IL10 AdaptedfromCoffman Nat Immunol 2006; Weaver. AnnuRevImmunol 2007; Koenders ARD 2006

  22. T helpercellsdifferenciation (Th) IFNγ IL12/STAT4 IL17 TNF IL6 IL-6/TGF Th0 CD4+ Th17 IL4/STAT6 TGF/IL10 Th2 Th1 IL4, IL10 TReg AdaptedfromCoffman Nat Immunol 2006; Weaver. AnnuRevImmunol 2007; Koenders ARD 2006

  23. T helpercellsdifferenciation (Th) IFNγ IL 23 IL12/STAT4 IL17 TNF IL6 IL-6/TGF Th0 CD4+ Th17 IL4/STAT6 TGF/IL10 Th2 Th1 IL4, IL10 TReg AdaptedfromCoffman Nat Immunol 2006; Weaver. AnnuRevImmunol 2007; Koenders ARD 2006

  24. Interleukin 17 Fibroblaste Inflammation Cartilage damage Bone erosion Psoriasis Inflammatory bowel disease IL 23 Chondrocyte IL 17 Th17 Ostéoblaste Macrophage Keratinocyte Epithelial cell

  25. Interleukin 23 • 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 IL-12 IL-23 p35 p40 p40 p19 IL-12 Rβ1 Rβ2 IL-12 Rβ1 IL-23R Kastelein et al. Ann Rev Immunol 2007;25:221–42.

  26. Anti-IL12/23 (p40) monoclonal antibody • RCT in psoriasis, Crohn’sdisease and PsoriaticArthritis Placebo (n = 70) → ustekinumab x 2 on W12 et W16 (n = 56) Ustekinumab x 4 on W0, W1, W2, W3 (n = 76) 60 49 % 51 % 42 %* 42 % n = 50 40 45 % 41 % n = 67 ACR 20 responders (%) 34 % 20 * p < 0,001 vs placebo 14 % 0 weeks 0 4 8 12 16 20 24 28 32 36 Leonardi C et al. Lancet 2008; 371: 1665–74. Gottlieb A. Lancet 2009;373:633-40

  27. What is the link with HLA B27?

  28. CD4+ CD8+ NK HLA-B27, B2M peptide trimolecular complex transportled to the cell surface via the Golgi apparatus Endoplasmicreticulum ARTS 1 calnexin calreticulin BiP tapasin hβ2m TAP B27 heavy chain (HC) Viral or bacterial peptidiques APC (macrophage, DC) BIP: BindingImmunoglobulinProtein TAP: Transporter AntigenProcessing Adapted from Brionez et al. Current Opin Rheum 2008

  29. BiP BiP BiP BiP BiP BiP CD4+ CD8+ NK Endoplasmicreticulum ARTS 1 calnexin calreticulin ERp57 BiP tapasin hβ2m TAP B27 heavy chain (HC) Viral or bacterial peptidiques APC (macrophage, DC) BIP: BindingImmunoglobulinProtein UPR : UnfoldedProteinResponse From Brionez et al. Current Opin Rheum 2008

  30. BiP BiP BiP BiP BiP BiP CD4+ CD8+ NK Endoplasmicreticulum UPR ARTS 1 calnexin calreticulin ERp57 BiP tapasin hβ2m TAP B27 heavy chain (HC) Viral or bacterial peptidiques APC (macrophage, DC) BIP: BindingImmunoglobulinProtein UPR : UnfoldedProteinResponse From Brionez et al. Current Opin Rheum 2008

  31. HLA B27 misfolding and the unfolded protein respons(UPR) increase IL23 production UPR + IFNγ IL 23 IL12/STAT4 IL17 TNF IL6 IL-6/TGF Th0 CD4+ Th17 IL4/STAT6 Th2 TGF/IL10 Th1 IL4, IL10 TReg DeLay M et al. Arthritis Rheum 2009,;60: 2633–2643.

  32. 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.

  33. Conclusion • 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

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