Idiopathic Anterior Uveitis and Type I Collagen

描述(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形式。由于黄斑囊样水肿、后囊下白内障和青光眼等继发性并发症，该病的反复发作可导致永久性视力丧失。实验性自身免疫性前葡萄膜炎(EAAU)是一种眼部器官特异性自身免疫性疾病，是特发性人类AAU的模型。在Lewis大鼠中，它是由抗原特异性的CD4T细胞对来自牛虹膜和睫状体的抗原产生的。我们已经纯化了葡萄膜生成抗原，最近的实验室结果表明，葡萄膜生成抗原是牛I型胶原α-2链的一个22 kDa的片段，我们称之为CI-α2(22 KDa)。我们的结果进一步表明，EAAU中的致病抗原是组织特异性的，仅定位于眼睛。尽管人类AAU历史上一直被描述为一种胶原病，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标自身抗原。这一建议的具体目的是：1.CI-α2(22 KDa)在大鼠体内的表达和定位，以及人眼在眼组织中的表达。2.眼内液中存在CI-α2(22 KDa)。3.诱导对CI-α2(22 KDa)的耐受以抑制EAAU。4.确定CI-α2(22 KDa)为特发性人AAU的靶抗原，即特发性AAU与牛CI-α2(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-α2(22 KDa)的自身免疫反应以及它是导致特发性人类AAU的自身抗原是至关重要的。这些观察还应该允许开发基于选择性抗原特异性调节免疫反应的有效治疗方法来治疗这种疾病。

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.