1 / 34

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).

dyami
Download Presentation

Update on the pathophysiology of ankylosing spondylitis

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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

More Related