Update pathogenesis of spondyloarthritis
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Update pathogenesis of spondyloarthritis
- 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-regulation •HLA-B27 mis-folding causing ER stress •Free form HLA-B27 homo-dimer •Th17/IL17, Th1/TNFα SpA Environmental factors •Infection, eg. Klebsiella pneumoniae •Trauma •Smoking Genetic background •HLA-B27, B60, B61 •ERAP-1 •IL23R, IL1, IL12… JC 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 stress Tam, 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
- 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
- 12. 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, IL12…etc. Wei JC, Tsai WC, Chou CT. Rheumatology 2004: 43: 839–42. JC Wei, SF Yang, RH Wong. Ann Rheuma Dis. 2009;68:1781–1786.
- 13. All somatic cells have HLA-B27, Why organ-specific? Sacroiliac joints Entheses Gut (IBD) Eye (uveitis) Skin (psoriasis)
- 14. Outline HLA-B27 biology Gut-enthesis linkage Organ-specific pathology • Enthesitis • New bone formation Take home message
- 16. • • Enthesis is a special organ with fibrocartilage Mechanical stress may expose self Ag like Versican and Aggrecan
- 17. Systemic IL-23 Expression in vivo Induces Highly Specific Entheseal Inflammation Entheseal inflammation at day 6 after administration of 3 μg IL23mc (bottom row) as compared to control treatment with human α1 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.
- 18. Why organ-specific? Organ-specific antigens recognition by B27-restricted T cell after stress or infection • Arthritogenic peptides theory
- 19. Outline HLA-B27 biology Organ-specific pathology • Enthesitis • New bone formation Gut-enthesis linkage Take home message
- 20. Gut, Enthesis, HLA-B27 & IL-23 in SpA Zhu et al Nat Med 18:1077-1086, 2012 Hu and O’Connell Nat Med 18:1009-1010,2012 Sherlock et al Nat Med 18:1069-1076, 2012
- 21. PsA SpA AS ReA IBD Immune dysregulation Th17, Th1,… Environmental factors Infection, trauma, food… Genetic background HLA-B27, ERAP-1, IL23R… JCC WEI, 2013
- 22. 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. TNFα and IL-17/22/23 are major cytokines mediating SpA.
- 23. We need more creative hypothesis and team-work!
- 24. Thank you! Comment & hypothesis? James Cheng-Chung WEI, MD, PhD jccwei@gmail.com +886 975 128095
Notas do Editor
- We had disclose B60, IL1 and Il12 in our studies.
- This cartoon shows you the difference.. For RA, the pathology is synovitis and marginal erosion mediated by TNF and osteoclase For SpA, the pathology stats from enthesitis, mediated by not only TNF, but also BMP/Wnt in later stage, causing new bone formation.
- Enthesitis is the halmark of SpA, Actually, enthesis is a special organ The insertion site is usually over stressed by trauma
- This is an importen paper last year in Nature Medicine about The entheseal stress hypothesis shown that Systemic After injection of IL23, at day 6, you can see severe inflammation in the enthesis, and then osteoblast expansion at day 18.
- So, my summary about organ specific are
- This is a very nice summary figure about pathogenesis of SpA. In B27+ subjects, the unfodled protein response initiated by gut bicrobiome and biomechanical stress, casusing transcription of inflam cytokines, esp IL23. IL-23 activate TH17 rxn in the enthesis and then cause inflam, and finally osteoproliferation
- In summary, I made this cartoon for my own hypothesus. SpA need a genetic background, such as.. After trigger by environmental factors, such as.. The immune dysregulation attack enthesis through Th17 and Th1 rxn With different genetic and Environmental factors, pts may have different phenotype, such as SpA or IBD.
- My take home message are
- By ending of my talk, I think “..