HLA-B27 and Experimental Spondyloarthropathy

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DESCRIPTION (provided by applicant): The class IMHC allele HLA-B27 is found with high prevalence in patients with ankylosing spondylitis and related diseases (spondyloarthritis, SpA). It is known that B27, ordinarily a normal immune component, itself participates in SpA, but how it does so is unknown. SpA is also associated with inflammatory bowel disease (IBD), and with intracellular bacterial infection. Our goal is to identify how B27 causes SpA and chronic inflammation. In this project this goal will be pursued in an animal model. B27 transgenic rats with a high transgene copy number and expression spontaneously develop a disease (rat SpA) that resembles human SpA, with arthritis and colitis, whereas genetically identical rats with low B27, or with high transgene content of another allele, HLA-B7, remain healthy. Germfree B27 rats remain healthy. Like human SpA, rSpA responds to anti-TNF therapy. It is known that in human cell lines and in the B27 rats that B27 heavy chain undergoes misfolding within the endoplasmic reticulum of leukocytes, triggering the unfolded protein response (UPR) and creating B27 heavy chain oligomers. In Specific Aim I, the hypothesis will be tested that this misfolding and/or UPR process of B27 participates in the pathogenesis of rSpA. Several possible mechanisms for this will be investigated through a variety of biochemical and genetic approaches. It will be tested whether B27 itself, or the subsequent UPR: [1] alters bacterial sensing by Toll-like receptors or the IBD-associated Nod2 protein; [2] triggers one or more pathways that cause dysfunction of dendritic cells; [3] alters the pathways activated by intracellular bacterial invasion; [4] cause inappropriate apoptosis of critical cells; [5] causes deposition of p2-microglobuin and subsequent arthritis. All of these findings will be correlated with the clinical outcome in the various transgenic lines. In Specific Aim II, the classical hypothesis will be tested that disease results from peptide presentation by B27. Rats with a recently produced CDS null mutant will be crossed with B27 rats to assess the effect on rSpA of interfering with T cell recognition of MHC class I. Findings in both specific aims will be followed up by experiments to produce additional relevant transgenic and knockout rats. Overall, the project should contribute substantially to resolving several important issues about the role of HLA-B27 and innate immunity in chronic inflammatory disease.