Idiopathic Anterior Uveitis and Type I Collagen

描述（由申请人提供）：特发性急性前葡萄膜炎（AAU）是人类最常见的眼内炎症。该疾病的复发性可导致永久性视力丧失，继发并发症为黄斑囊样水肿、后囊下白内障和青光眼。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，可作为特发性人前葡萄膜炎的模型。它是由Lewis大鼠对来自牛虹膜和睫状体的抗原产生抗原特异性CD4+ T细胞反应而产生的。我们纯化了致葡萄球菌抗原以达到同质性，最近我们实验室的结果表明，该致葡萄球菌抗原是牛I型胶原α -2链的一个22 kDa片段，我们称之为CI-alpha2 （22 kDa）。我们的结果进一步表明，EAAU的致病抗原是组织特异性的，仅局限于眼睛。虽然人类AAU历来被认为是一种胶原蛋白疾病，但这是迄今为止最有力的证据，证明胶原蛋白是葡萄膜炎的靶自身抗原。本建议的具体目的是：1。CI-alpha2 （22 kDa）在大鼠和人眼中的表达和定位-在眼组织中的表达。2. 眼内液中CI-alpha2 （22 kDa）的存在。3. 诱导对CI-alpha2 （22 kDa）的耐受性抑制EAAU。4. 人类特发性AAU靶抗原CI-alpha2 （22 kDa）的鉴定——即特发性AAU与牛CI-alpha2 （22 kDa）免疫应答的相关性。我们认为，这些研究对于明确证明EAAU是对眼CI-alpha2 （22 kDa）的自身免疫反应以及它是特发性人类AAU的自身抗原至关重要。这些观察结果也应该允许在这种疾病的治疗中基于选择性抗原特异性调节免疫反应的有效疗法的发展。

DESCRIPTION (provided by applicant): Idiopathic acute anterior uveitis (AAU) is the most common form of intraocular inflammation in humans. The recurrent nature of the disease can lead to permanent visual loss from the secondary complications of cystoid macular edema, posterior subcapsular cataract and glaucoma. Experimental autoimmune anterior uveitis (EAAU) is an organ specific autoimmune disease of the eye and serves as a model of idiopathic human AAU. It is produced in Lewis rats by an antigen specific CD4+ T cell response to an antigen derived from bovine iris and ciliary body. We have purified the uveitogenic antigen to homogeneity and recent results from our laboratory suggest that the uveitogenic antigen is a 22 kDa fragment of bovine type I collagen alpha-2 chain and we refer it to as CI-alpha2 (22 kDa). Our results further suggest that the pathogenic antigen in EAAU is tissue specific, being localized solely to the eye. Although human AAU has been historically characterized as a collagen disease, this is the strongest evidence to date that collagen is the target autoantigen in uveitis. The specific aims of this proposal are: 1. Expression and localization of CI-alpha2 (22 kDa) within the rat and human eye - expression within the ocular tissue. 2. Presence of CI-alpha2 (22 kDa) in intraocular fluid. 3. Induction of tolerance to CI-alpha2 (22 kDa) to inhibit EAAU. 4. Identification of CI-alpha2 (22 kDa) as the target antigen in idiopathic human AAU - i.e. correlation of idiopathic AAU with the immune response to bovine CI-alpha2 (22 kDa). We believe that these studies are essential to definitely prove that EAAU is an autoimmune response to ocular CI-alpha2 (22 kDa) and that it is the autoantigen responsible for idiopathic human AAU. These observations should also allow the development of effective therapy based on selective antigen specific modulation of the immune response in the treatment of this disease.