Update Pathogenesis of
Spondyloarthritis
James Cheng-Chung WEI, MD, PhD
Chief, Division of Allergy, Immunology and Rheumat...
Outline
HLA-B27 biology
 Gut-enthesis linkage
 Organ-specific pathology
• Enthesitis
• New bone formation
 Take home me...
Figure 1. Spectrum of Spondyloarthritis. AS, ankylosing spondylitis; PsA, psoriatic
arthritis; ReA, reactive arthritis; IB...
Immune dys-regulation

•HLA-B27 mis-folding causing ER stress
•Free form HLA-B27 homo-dimer
•Th17/IL17, Th1/TNFα

SpA
Envi...
Why HLA-B27?
90% of AS patients are B27+
HLA-B27 Biology
Homodimer & Unfolded ER stress

Tam, LS, Jieruo, G, Yu, D. Nat Rev Rheumatol 2010; 6:399.
Why only 5% HLA-B27+
subjects develop AS?
20% if family history of SpA
HLA-B27 transgenic rats
The Gut in SpA








Ileocolonoscopy and biopsy found
subclinical gut inflammation in about 50%
of patients with SpA...
Gut Microbials in AS
•

•

•

•

An increased Klebsiella pneumonia in the fecal
cultures and anti-KP antibodies were assoc...
Why only 5% HLA-B27+
subjects develop AS?




Environmental factors
• Infection, esp. in the guts
• Mechanical stress
• ...
All somatic cells have HLA-B27,

Why organ-specific?
Sacroiliac joints
Entheses
Gut (IBD)
Eye (uveitis)
Skin (psoriasis)
Outline
HLA-B27 biology
 Gut-enthesis linkage
 Organ-specific pathology
• Enthesitis
• New bone formation
 Take home me...
•
•

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

Entheseal inflammation at day 6 after ad...
Why organ-specific?


Organ-specific antigens recognition by
B27-restricted T cell after stress or
infection
• Arthritoge...
Outline
HLA-B27 biology
 Organ-specific pathology
• Enthesitis
• New bone formation
 Gut-enthesis linkage
 Take home me...
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
She...
PsA
SpA AS
ReA

IBD

Immune dysregulation
Th17, Th1,…

Environmental factors
Infection, trauma, food…

Genetic background
...
Take home message








Enthesitis and new bone formation are major
pathology of SpA.
Genetic factors are highly imp...
We need more creative hypothesis
and team-work!
Thank you!
Comment & hypothesis?
James Cheng-Chung WEI, MD, PhD
jccwei@gmail.com
+886 975 128095
Update pathogenesis of spondyloarthritis
Update pathogenesis of spondyloarthritis
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  • 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 “..
  • Update pathogenesis of spondyloarthritis

    1. 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. 2. Outline HLA-B27 biology  Gut-enthesis linkage  Organ-specific pathology • Enthesitis • New bone formation  Take home message 
    3. 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. 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. 5. Why HLA-B27? 90% of AS patients are B27+
    6. 6. HLA-B27 Biology Homodimer & Unfolded ER stress Tam, LS, Jieruo, G, Yu, D. Nat Rev Rheumatol 2010; 6:399.
    7. 7. Why only 5% HLA-B27+ subjects develop AS? 20% if family history of SpA
    8. 8. HLA-B27 transgenic rats
    9. 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. 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. 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, 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.
    12. 12. All somatic cells have HLA-B27, Why organ-specific? Sacroiliac joints Entheses Gut (IBD) Eye (uveitis) Skin (psoriasis)
    13. 13. Outline HLA-B27 biology  Gut-enthesis linkage  Organ-specific pathology • Enthesitis • New bone formation  Take home message 
    14. 14. • • Enthesis is a special organ with fibrocartilage Mechanical stress may expose self Ag like Versican and Aggrecan
    15. 15. 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.
    16. 16. Why organ-specific?  Organ-specific antigens recognition by B27-restricted T cell after stress or infection • Arthritogenic peptides theory
    17. 17. Outline HLA-B27 biology  Organ-specific pathology • Enthesitis • New bone formation  Gut-enthesis linkage  Take home message 
    18. 18. 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
    19. 19. PsA SpA AS ReA IBD Immune dysregulation Th17, Th1,… Environmental factors Infection, trauma, food… Genetic background HLA-B27, ERAP-1, IL23R… JCC WEI, 2013
    20. 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. TNFα and IL-17/22/23 are major cytokines mediating SpA.
    21. 21. We need more creative hypothesis and team-work!
    22. 22. Thank you! Comment & hypothesis? James Cheng-Chung WEI, MD, PhD jccwei@gmail.com +886 975 128095
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