Idiopathic Anterior Uveitis and Type I Collagen

描述（由申请方提供）：特发性急性前葡萄膜炎（AAU）是人类最常见的眼内炎症。该病的复发性可导致永久性视力丧失，继发性并发症包括黄斑囊样水肿、后囊下白内障和青光眼。实验性自身免疫性前葡萄膜炎（EAAU）是眼器官特异性自身免疫性疾病，可作为特发性人类AAU的模型。在刘易斯大鼠中，通过抗原特异性CD 4 + T细胞对牛虹膜和睫状体来源的抗原的应答产生。我们已经将致葡萄膜炎抗原纯化至同质，并且我们实验室的最近结果表明，致葡萄膜炎抗原是牛I型胶原α-2链的22 kDa片段，我们将其称为CI-α 2（22 kDa）。我们的研究结果进一步表明，EAAU的致病抗原是组织特异性的，仅局限于眼睛。尽管人类AAU在历史上被表征为胶原蛋白疾病，但这是迄今为止胶原蛋白是葡萄膜炎中的靶自身抗原的最有力证据。该提案的具体目标是：1.大鼠和人眼内CI-α 2（22 kDa）的表达和定位-眼组织内的表达。2.眼内液中存在CI-α 2（22 kDa）。 3.诱导对CI-α 2（22 kDa）的耐受性以抑制EAAU。 4.鉴定CI-α 2（22 kDa）作为特发性人AAU中的靶抗原-即特发性AAU与对牛CI-α 2（22 kDa）的免疫应答的相关性。 我们相信这些研究对于明确证明EAAU是对眼部CI-α 2（22 kDa）的自身免疫应答以及它是导致特发性人类AAU的自身抗原是必不可少的。这些观察结果还应允许在治疗这种疾病中基于免疫应答的选择性抗原特异性调节的有效疗法的开发。

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.