Uveitogenic Epitope(s) and Idiopathic Anterior Uveitis

描述（由申请人提供）：本申请的长期目标是研究葡萄膜炎的根本原因和病因学因素，并找到治疗这种疾病的方法。北加州流行病学研究最近的一份报告显示，美国老年人的发病率更高。不幸的是，葡萄膜炎患者的治疗选择有局限性，因为目前葡萄膜炎只能对症治疗。因此，需要持续的努力和未来的研究来开发有效和安全的治疗方法。特发性前葡萄膜炎（IAU）是人类最常见的眼内炎症形式，该疾病的复发性可导致永久性视力丧失。实验性自身免疫性前葡萄膜炎（EAAU）是一种器官特异性的眼部自身免疫性疾病，是人类IAU的动物模型。首席研究员（PI）实验室的研究已经确定，黑色素相关抗原（MAA）， EAAU中的自身抗原是I型胶原¿-2链[CI-¿2 (22 kDa)]的22 kDa片段。在目前的资助申请中，PI建议精确鉴定MAA中对葡萄膜原性至关重要的表位，确定MHC结合和TCR接触残基，并探索是否可以通过改变肽配体（apl）抑制EAAU。本提案的具体目的是：特异性目的1：鉴定MAA [(CI-¿2 (22 kDa)]的葡萄膜原性表位。特异性目的2：研究哪些氨基酸对EAAU至关重要，以及改变肽配体（api）在2A前葡萄膜炎中的作用。MHC和TCR接触氨基酸的鉴定api的产生及api对EAAU的抑制作用。拟议的研究尤其重要，因为它们将提供与IAU的病因发病机制相关的关键信息。此外，这些研究将促进基于抗原的治疗干预措施的发展，用于与显著发病率相关的人类IAU。

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.