Immunity to versican and ankylosing spondylitis

University Of California Irvine, Irvine CA

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Abstract

DESCRIPTION (provided by applicant): Ankylosing spondylitis (AS) is a common chronic inflammatory disease with an estimated prevalence of 0.2- 0.6% in North America and Europe. The pathogenesis of AS is poorly understood and current therapy does not prevent deformity and disability in most patients. The disorder typically affects the axial skeleton and involves spondylitis and sacroiliitis, as well as enthesitis. Until now, no AS-specific animal model has been available. In this proposal, we demonstrate that human versican is expressed at high levels in the human and rat intervertebral disc, sacroiliac joint, and entheses. We show that BALB/c mice immunized with recombinant human versican globular domain 1 (VG1) develop spondylitis, sacroiliitis, enthesitis and extra-articular uveitis, in the absence of any significant expression of clinical peripheral arthritis, all signatures of the pathobiology of AS. To our knowledge, this is the only model in which one can observe axial skeletal inflammation with little peripheral arthritis. We hypothesize that versican, a naturally occurring component of the intervertebral disc and sacroiliac joint, serves as an AS-specific autoantigen and is causally related to the pathogenesis of AS. This hypothesis can be tested in susceptible animals immunized with versican and by attempting to transfer AS-like pathology in syngeneic mice using well-characterized antigen-specific T cells. The detailed pathogenic mechanisms, especially the role of HLA-B27 molecules, can also be investigated in BALB/c mice and in HLA-B27 transgenic animals. We believe that our proposal is of general interest in terms of this relatively common, but ill-defined, human disease and will provide a prototype model, which should provide a better understanding of the pathogenesis of AS and the development of new immune therapies for AS. Of the human cartilage matrix molecules, VG1, the G1 domain of aggrecan (AG1), and link protein (LP) share both axial and peripheral arthritis. We hypothesize that autoimmunity to these antigens is causally involved in the pathogenesis of rheumatoid arthritis (RA) and/or ankylosing spondylitis. This proposal focuses on VG1 and its pathogenic role in spondyloarthropathy (SpA)-Iike diseases, including its typical form AS, in animals. We plan to determine whether VG1 is an autoantigen in the VGl/spondylitis/sacroiliitis model in BALB/c mice and the immune mechanisms by which it selectively induces spondylitis and sacroiliitis in BALBIc mice. We also intend to identify the role of HLA-B27 in the pathogenesis of the VGI/model using human HLA-B*2705 transgenic animals.