ankylosing spondilitis Flashcards
What genetic risk factors for Ankylosing spondylits?
HLA-B27 IL-1R IL23 IL12B (B40) ERAP1
Is AS probably autoinflammatory or autoimmune?
middle of the scale
Who does AS affect more? What is the presentation?
Affects young males the most, inflammation leads to new bone formation and joint fusion in middle of the spine
2 other diseases in HLA-B27 associated wiht?
reactive arthritis and iritis, colitis-associated/psoriatic spondyloarthritis.
Who does RA affect more and what are symptoms?
females. symmetrical deforming polyarthritis (swelling around joints).
Is there genetic heritability with AS?
90% concordance with monozygotic twins.
Although many healthy people will have HLA-B27 as well.
What pathway is ERAP1 (identified vai GWAS for AS) involved in?
trimming peptides coming through TAP transporter for MHC I presentation.
4 theories of B27 causation?
1: presentation of an arthritogenic peptide
2) B27 intracellular misfolding induces UPR
3) misfolding/homodimer formation on cell surface activates immune cells.
4) Microbiome alteration.
Theory of arthitogenic peptide presentation as causation for HLA-B27 AS?
B27 known for presenting many viral antigens effectively, could present a mimicking antigen to break tolerance.
Problems with arthritogneic peptide theory?
No peptide has been identified, and HLA-BB27 transgenic mice with AS still get the disease when they are CD8-/-.
Although no mouse model disease in germ free mice
What is the intracellular misfolding theory of AS?
B27 misfolds in cytoplasm triggering UPR and Th17 responses.
innate immune recognition of aberrant B27 at cell surface?
B27 molecules have unbound cys67 which bind each other to form aberrant homodimers that can activate NK cells and T cells.
What population of NK and CD4 cells that are expanded in AS thought to bind to B27 homodimers?
KIR3DL2+ NK cells and CD4 T cells that are enriched for IL-17 production.
Also binds LILR on monocytes.
What phases of RA disease are there?
autoimmunity developed. Then something triggers the process to start. Macrophages, monocytes, neutrophils of the synovium tissue infiltrate and secrete inflammatory cytokines and activated T cells.
Chronic inflammation.
Activation of synovial fibroblasts extend across the joint and contribute to the degradation of cartilidge.
Activated osteoclasts are hyperactive and help mediate the degradation of bone as well.
What are the genes most associated with RA pathogenesis?
HLA DR4 PTPN22 PADI CTLA4 cytokine receptors (TNF/IL-1)
