Understanding uveitis in a multi-system disease model of spondyloarthropathy

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DESCRIPTION (provided by applicant): Spondyloarthropathies (SpAs) are chronic, immune-mediated, inflammatory disorders, of which ankylosing spondylitis (AS) is the most common. On average SpA affects ~1% of the general human population. Uveitis is a frequent extra-articular organ afflicted in such diseases. Indeed AS-associated uveitis is the most frequently observed type of uveitis in patients. Yet, the pathogenesis of uveitis is poorly understood in part due to a current lack of experimental models. We have recently discovered that uveitis occurs in an established mouse model of proteoglycan-induced arthritis (PGIA), wherein experimental immunity to the cartilage proteoglycan results in progressive polyarthrits and spondylitis. To our knowledge this is the first murine model of disease that will allow us to study the eye's susceptibility to disease in presence of arthritis and spondylitis as occurs clinically in patients. Moreover, our data support different ongoing mechanisms of disease in the eye versus joint and spine as deficiency in the Th1-related cytokine, IFNg, markedly exacerbates uveitis but diminishes the severity of arthritis and spondylitis. Th17 response appears to play a dominant role in uveitis in the absence of IFNg. These observations could have a huge impact on how we treat uveitis in a multi-system disease. The studies proposed here will inform us about mechanisms involved in the uveitis aspect of disease and will be important to our understanding of SpA development as well. We propose to identify the function of T cell effector responses in the pathogenesis of uveitis and define how they relate to joint and spine disease. We will determine whether mechanisms of the eye can be distinguished from the joint and spine and will explore the regulatory role for IFNg in controlling the eye's sensitivity to disease and Th17 response. We will explore how therapeutic intervention affects specific organs. This model will be a valuable tool for discovery of mechanisms controlling eye disease as it relates to systemic form of disease and will have considerable implications for understanding SpA pathogenesis as well. PUBLIC HEALTH RELEVANCE: We recently discovered that immunity to cartilage proteoglycan in mice results in uveitis accompanied by arthritis and spondylitis. Ankylosing spondylitis and its closely related inflammatory joint diseases are the most commonly diagnosed systemic illness associated with uveitis. Mouse models of uveitis are rare and no prior murine model of disease exists for uveitis that also involves arthritis and spondylitis. The novelty of this model provides great opportunity to understand mechanisms of a relatively common but poorly understood disease.