update pathogenesis of spondyloarthritis
TRANSCRIPT
Update Pathogenesis of Spondyloarthritis
James Cheng-Chung WEI, MD, PhD
Chief, Division of Allergy, Immunology and RheumatologyDirector, Chinese Medicine Clinical Trial Center
Associate Professor, Chung Shan Medical University
OutlineOutline
HLA-B27 biologyHLA-B27 biology Gut-enthesis linkageGut-enthesis linkage Organ-specific pathologyOrgan-specific pathology
• Enthesitis Enthesitis • New bone formation New bone formation
Take home messageTake home message
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
SpA
Genetic background•HLA-B27, B60, B61•ERAP-1•IL23R, IL1, IL12…
Environmental factors•Infection, eg. Klebsiella pneumoniae•Trauma•Smoking
Immune dys-regulation•HLA-B27 mis-folding causing ER stress•Free form HLA-B27 homo-dimer•Th17/IL17, Th1/TNF
JC Wei. Chronic Inflammation. Nova Science Publishers, Inc. 2013
Why HLA-B27?Why HLA-B27?
90% of AS patients are B27+90% of AS patients are B27+
Tam, LS, Jieruo, G, Yu, D. Nat Rev Rheumatol 2010; 6:399.
HLA-B27 Biology HLA-B27 Biology Homodimer & Unfolded ER stress Homodimer & Unfolded ER stress
Why only Why only 5%5% HLA-B27+ HLA-B27+ subjects develop AS?subjects develop AS?
20% if family history of SpA20% if family history of SpA
HLA-B27 transgenic rats
The Gut in SpAThe Gut in SpA
Ileocolonoscopy and biopsy found Ileocolonoscopy and biopsy found subclinical gut inflammation in about 50% subclinical gut inflammation in about 50% of patients with SpAof patients with SpA
Symptomatic inflammatory bowel disease Symptomatic inflammatory bowel disease (IBD) in 6.5% of SpA(IBD) in 6.5% of SpA
Sacroiliitis and spondylitis occurs in 1 to Sacroiliitis and spondylitis occurs in 1 to 26% of patients with IBD26% of patients with IBD
SpA and IBD: share similar gene(1q32, STAT3, SpA and IBD: share similar gene(1q32, STAT3, IL-12B, IL-23R), TH17, and innate immunity.IL-12B, IL-23R), TH17, and innate immunity.
Gut Microbials in ASGut Microbials in AS
• An increased An increased Klebsiella pneumoniaKlebsiella pneumonia in the fecal in the fecal cultures and anti-KP antibodies were associated cultures and anti-KP antibodies were associated with degree of gut inflammation with degree of gut inflammation in ASin AS
• Chalmydia, Shigella, Salmonella, Yersinia, and Chalmydia, Shigella, Salmonella, Yersinia, and Campylobacter Campylobacter species are arthritogenic in ReAspecies are arthritogenic in ReA
• Molecular mimicry Molecular mimicry between between K.p.K.p. and self Cross- and self Cross-reactive Antigens HLA-B27 & collagenreactive Antigens HLA-B27 & collagen
• TLR and innate immunity play a roleTLR and innate immunity play a role
Rashid T, Ebringer A. Discov Med. 2011 Sep;12(64):187-94
Why only Why only 5%5% HLA-B27+ HLA-B27+ subjects develop AS?subjects develop AS?
Environmental factorsEnvironmental factors• Infection, esp. in the gutsInfection, esp. in the guts• Mechanical stressMechanical stress• SmokingSmoking
Multiple genes interaction, eg. HLA-B60, Multiple genes interaction, eg. HLA-B60, ERAP-1, IL23R, IL1, IL12…etc.ERAP-1, IL23R, IL1, IL12…etc.
Wei JC, Tsai WC, Chou CT. Rheumatology 2004: 43: 839–42.Wei JC, Tsai WC, Chou CT. Rheumatology 2004: 43: 839–42.JC Wei, SF Yang, RH Wong. Ann Rheuma Dis. 2009;68:1781–1786. JC Wei, SF Yang, RH Wong. Ann Rheuma Dis. 2009;68:1781–1786.
All somatic cells have HLA-B27, All somatic cells have HLA-B27,
Why organ-specific?Why organ-specific?
Sacroiliac jointsSacroiliac jointsEnthesesEnthesesGut (IBD)Gut (IBD)
Eye (uveitis)Eye (uveitis)Skin (psoriasis)Skin (psoriasis)
OutlineOutline
HLA-B27 biologyHLA-B27 biology Gut-enthesis linkageGut-enthesis linkage Organ-specific pathologyOrgan-specific pathology
• Enthesitis Enthesitis • New bone formation New bone formation
Take home messageTake home message
• Enthesis is a special organ with fibrocartilage
• Mechanical stress may expose self Ag like Versican and Aggrecan
Systemic IL-23 Expression in vivo Induces Highly Specific Entheseal Inflammation
Adapted from: Sherlock JP et al. Nat Med 2012;18:1069-76 (with permission)
Entheseal inflammation at day 6 after administration of 3 μg IL-23mc (bottom row) as compared to control treatment with human α1 anti-trypsin minicircle (hAATmc, top row) in B10.RIII mice.
Histology of periosteal disease and osteoblast expansion at day 18 after treatment in B10.RIII mice.
* Entheseal tendon-bone interface.
Why organ-specific?Why organ-specific?
Organ-specific antigens recognition by Organ-specific antigens recognition by B27-restricted T cell after B27-restricted T cell after stressstress or or infectioninfection
• Arthritogenic peptides theoryArthritogenic peptides theory
OutlineOutline
HLA-B27 biologyHLA-B27 biology Organ-specific pathologyOrgan-specific pathology
•Enthesitis Enthesitis •New bone formation New bone formation
Gut-enthesis linkageGut-enthesis linkage Take home messageTake home message
Gut, Enthesis, HLA-B27 & IL-23 in SpAGut, 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
Genetic backgroundHLA-B27, ERAP-1, IL23R…
Environmental factors
Infection, trauma, food…
Immune dysregulation
Th17, Th1,…
SpASpA AS IBDReA
PsA
JCC WEI, 2013
Take home message Enthesitis and new bone formation are major Enthesitis and new bone formation are major
pathology of SpA.pathology of SpA. Genetic factors are highly important in AS, Genetic factors are highly important in AS,
esp. HLA-B27, ERAP-1, IL23R.esp. HLA-B27, ERAP-1, IL23R. Environmental factors, esp. gut microbials, Environmental factors, esp. gut microbials,
mechanical stress and smoking play a role.mechanical stress and smoking play a role. TNFTNF and IL-17/22/23 are major cytokines and IL-17/22/23 are major cytokines
mediating SpA.mediating SpA.
We need more creative hypothesis We need more creative hypothesis and team-work!and team-work!
