update pathogenesis of spondyloarthritis

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  • 1.Update Pathogenesis of Spondyloarthritis James Cheng-Chung WEI, MD, PhD Chief, Division of Allergy, Immunology and Rheumatology Director, Chinese Medicine Clinical Trial Center Associate Professor, Chung Shan Medical University

2. Outline HLA-B27 biology Gut-enthesis linkage Organ-specific pathology Enthesitis New bone formation Take home message 3. Figure 1. Spectrum of Spondyloarthritis. AS, ankylosing spondylitis; PsA, psoriatic arthritis; ReA, reactive arthritis; IBD, inflammatory bowel diseases-associated arthritis; USpA, undifferentiated spondyloarthritis. JC Wei. Chronic Inflammation: Causes, Treatment Options and Role in Disease.Nova Science Publishers, Inc. 2013 4. Immune dys-regulationHLA-B27 mis-folding causing ER stress Free form HLA-B27 homo-dimer Th17/IL17, Th1/TNFSpA Environmental factorsInfection, eg. Klebsiella pneumoniae Trauma SmokingGenetic background HLA-B27, B60, B61 ERAP-1 IL23R, IL1, IL12JC Wei. Chronic Inflammation.Nova Science Publishers, Inc. 2013 5. Why HLA-B27? 90% of AS patients are B27+ 6. HLA-B27 Biology Homodimer & Unfolded ER stressTam, LS, Jieruo, G, Yu, D. Nat Rev Rheumatol 2010; 6:399. 7. Why only 5% HLA-B27+ subjects develop AS? 20% if family history of SpA 8. HLA-B27 transgenic rats 9. The Gut in SpA Ileocolonoscopy and biopsy found subclinical gut inflammation in about 50% of patients with SpA Symptomatic inflammatory bowel disease (IBD) in 6.5% of SpA Sacroiliitis and spondylitis occurs in 1 to 26% of patients with IBD SpA and IBD: share similar gene(1q32, STAT3, IL-12B, IL-23R), TH17, and innate immunity. 10. Gut Microbials in AS An increased Klebsiella pneumonia in the fecal cultures and anti-KP antibodies were associated with degree of gut inflammation in AS Chalmydia, Shigella, Salmonella, Yersinia, and Campylobacter species are arthritogenic in ReA Molecular mimicry between K.p. and self Crossreactive Antigens HLA-B27 & collagen TLR and innate immunity play a role Rashid T, Ebringer A. Discov Med. 2011 Sep;12(64):187-94 11. Why only 5% HLA-B27+ subjects develop AS? Environmental factors Infection, esp. in the guts Mechanical stress Smoking Multiple genes interaction, eg. HLA-B60, ERAP-1, IL23R, IL1, IL12etc. Wei JC, Tsai WC, Chou CT. Rheumatology 2004: 43: 83942. JC Wei, SF Yang, RH Wong. Ann Rheuma Dis. 2009;68:17811786. 12. All somatic cells have HLA-B27,Why organ-specific? Sacroiliac joints Entheses Gut (IBD) Eye (uveitis) Skin (psoriasis) 13. Outline HLA-B27 biology Gut-enthesis linkage Organ-specific pathology Enthesitis New bone formation Take home message 14. Enthesis is a special organ with fibrocartilage Mechanical stress may expose self Ag like Versican and Aggrecan 15. Systemic IL-23 Expression in vivo Induces Highly Specific Entheseal InflammationEntheseal inflammation at day 6 after administration of 3 g IL23mc (bottom row) as compared to control treatment with human 1 anti-trypsin minicircle (hAATmc, top row) in B10.RIII mice. * Entheseal tendon-bone interface. Adapted from: Sherlock JP et al. Nat Med 2012;18:1069-76 (with permission)Histology of periosteal disease and osteoblast expansion at day 18 after treatment in B10.RIII mice. 16. Why organ-specific? Organ-specific antigens recognition by B27-restricted T cell after stress or infection Arthritogenic peptides theory 17. Outline HLA-B27 biology Organ-specific pathology Enthesitis New bone formation Gut-enthesis linkage Take home message 18. Gut, Enthesis, HLA-B27 & IL-23 in SpAZhu et al Nat Med 18:1077-1086, 2012 Hu and OConnell Nat Med 18:1009-1010,2012 Sherlock et al Nat Med 18:1069-1076, 2012 19. PsA SpA AS ReAIBDImmune dysregulation Th17, Th1,Environmental factors Infection, trauma, foodGenetic backgroundHLA-B27, ERAP-1, IL23RJCC WEI, 2013 20. Take home message Enthesitis and new bone formation are major pathology of SpA. Genetic factors are highly important in AS, esp. HLA-B27, ERAP-1, IL23R. Environmental factors, esp. gut microbials, mechanical stress and smoking play a role. TNF and IL-17/22/23 are major cytokines mediating SpA. 21. We need more creative hypothesis and team-work! 22. Thank you! Comment & hypothesis? James Cheng-Chung WEI, MD, PhD jccwei@gmail.com +886 975 128095

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