Uveitogenic Epitope(s) and Idiopathic Anterior Uveitis

描述（由申请人提供）：目前提案的长期目标是研究葡萄膜炎的根本原因和病因学因素，以及找到治愈这种疾病的方法。北方加州流行病学研究最近的一份报告表明，美国老年人口的患病率较高。不幸的是，葡萄膜炎患者可用的治疗选择具有局限性，因为目前葡萄膜炎仅通过手术治疗。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，其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（Experimental autoimmune anterior uveitis，EAAU）是一种眼器官特异性自身免疫性疾病，可作为人类IAU的动物模型。主要研究者（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型胶原蛋白<$-2链的22 kDa片段[CI-<$2（22 kDa）]。在当前的资助申请中，PI建议精确鉴定MAA中对葡萄膜致敏性至关重要的表位，确定MHC结合和TCR接触残基，并探索EAAU是否可被改变的肽配体（APLs）抑制。具体目标1：鉴定MAA [（CI-2（22 kDa））]的致葡萄膜表位具体目标2：研究哪些氨基酸对EAAU至关重要以及改变的肽配体（APLs）在前葡萄膜炎2A中的作用。MHC和TCR接触氨基酸2B的鉴定。APLs的产生和APLs对EAAU的抑制。 拟议的研究是特别密切相关的，因为他们将提供关键信息的病因发病机制的IAU。此外，这些研究将有助于开发基于抗原的治疗干预措施，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.