Uveitogenic Epitope(s) and Idiopathic Anterior Uveitis

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DESCRIPTION (provided by applicant): Long-term objectives of the current proposal are to study the fundamental causes and etiologic factors responsible for uveitis as well as to find a cure for this disease. A recent report from the Northern California Epidemiology Study suggested a higher disease rate for the older population in the US. Unfortunately, treatment options available to uveitis patients have limitations because currently uveitis is treated symptomatically only. Therefore, continuous efforts and future investigations are needed to develop efficient and safe therapies. Idiopathic anterior uveitis (IAU) is the most common form of intraocular inflammation in humans and the recurrent nature of the disease can lead to permanent loss of vision. Experimental autoimmune anterior uveitis (EAAU) is an organ specific autoimmune disease of the eye which serves as an animal model of human IAU. Studies from the Principal Investigator's (PI) laboratory have established that melanin associated antigen (MAA), autoantigen in EAAU is a 22 kDa fragment of type I collagen ¿-2 chain [CI- ¿2 (22 kDa)]. In the current grant proposal the PI proposes to precisely identify the epitope(s) in MAA that is/are crucial for the uveitogenicity, determine MHC binding and TCR contact residues and explore if EAAU can be inhibited by Altered Peptide Ligands (APLs). The specific aims of this proposal are: Specific Aim 1: To identify uveitogenic epitope(s) of MAA [(CI-¿2 (22 kDa)] Specific Aim 2: To investigate which amino acids are crucial for EAAU and role of Altered Peptide Ligands (APLs) in anterior uveitis 2A. Identification of MHC and TCR contact amino acids 2B. Generation of APLs and inhibition of EAAU by APLs. The proposed studies are particularly germane because they would provide critical information related to etio-pathogenesis of IAU. Additionally, these studies will facilitate the development of antigen based therapeutic interventions for human IAU which is associated with significant morbidity.