Exploring the pathogenesis of Juvenile Idiopathic Arthritis-uveitis using rat models of uveitis and arthritis.
Osinchuk, Stephanie 1984-
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Purpose: The etiology and pathogenesis of uveitis associated with Juvenile Idiopathic Arthritis (JIA) are poorly understood. The purpose of this rat-based research is to explore the potential of a shared collagen based self-antigen within the joint and eye in the rat as a factor involved in the etiopathogenesis of arthritis and associated uveitis. As young age and female sex are risk factors for uveitis in children with JIA, their influence on experimental autoimmune anterior uveitis in the rat was evaluated by ophthalmic evaluation with biomicroscopic, light microscopic ocular examinations, and pro-inflammatory vitreous cytokine profiles. Methods: Adult and juvenile male and female Lewis rats were inoculated intradermally with either: intact type I collagen derived from bovine skin, type II collagen, or derivatives of type I collagen including melanin associated antigen (MAA) or soluble MAA which was digested in Staphylococcal V8 protease, Streptococcus streptokinase C, or matrix metalloproteinase (MMP)-1. Inoculations were repeated up to three times at intervals of 1 or 4 weeks. Biomicroscopic and indirect ophthalmic examinations were completed in live rats at baseline and biomicroscopic examinations were repeated three time per week throughout the study period by a masked Diplomate of the American College of Veterinary Ophthalmologists (ACVO). At the end of the observation period globes were enucleated and vitreous was aspirated. Histopathology slides of the globes were reviewed by a masked Diplomate ACVO. Rats treated with insoluble MAA had clinical uveitis scores, ocular histopathological scores, and cytokine analysis compared between age and sex groups and control animals. An array of 27 cytokines were quantified with a multiplex bead-based immunoassay on vitreous from rats treated with MMP-1 digested type I collagen derived from bovine skin, or type II collagen derived from bovine cartillage, and rats treated with insoluble melanin associated antigen. Immunohistochemical labels for CD43 and CD45RC were compared between solubilized MAA groups and control animals. Results: None of the rats inoculated with any form of type I collagen derived from bovine skin, or type II collagen derived from bovine cartilage, developed uveitis that could be detected clinically or light microscopically. 28/44 rats inoculated with intact type II collagen developed arthritis. Vitreous cytokine levels did not differ between any treatment group and controls. All rats inoculated with insoluble MAA developed uveitis on biomicroscopic and light microscopic examination and no differences were identified between age and sex groups. Uveitis was present in 3/12 Staphylococcus aureus V8 protease MAA inoculated rats and 2/12 streptokinase C solubilized MAA inoculated rats. Conclusions: None of the digested or intact forms of type I collagen derived from bovine skin, or type II collagen derived from bovine cartilage, resulted in uveitis in the Lewis rat. While type II collagen induced arthritis, digestion of type II collagen renders it non-pathogenic. Streptococcus streptokinase C and Staphylococcus aureus V8 protease digested MAA induced uveitis in some rats when inoculations are repeated three times. Insoluble MAA induced uveitis in all rats and no difference in disease incidence, severity, or onset was observed between sexes or age groups in rats inoculated with MAA.
DegreeMaster of Science (M.Sc.)
DepartmentSmall Animal Clinical Sciences
ProgramSmall Animal Clinical Sciences
SupervisorGrahn, Bruce; Sandmeyer, Lynne
CommitteeSandmeyer, Lynne; Rosenberg, Alan; Richards, Tara; Shmon, Cindy
Copyright DateDecember 2019
Autoimmune Uveitis, Cytokines, Inflammation, Melanin Associated Antigen, Uveitis