AUTOIMMUNITY ASSOCIATED WITH PIGMENT DISPERSION GLAUCOMA

描述（由申请人提供）：色素弥散综合征是人类继发性青光眼的重要原因，其发病机制尚不清楚，治疗措施充其量也是令人满意的。在DBA/2 J小鼠中描述了一种与人类疾病有着遥远但有趣的相似之处的新小鼠模型。在该模型中，随着色素分散升级，留下虹膜萎缩，眼内压升高，导致视神经萎缩和视力损害。 令人惊讶的是，引起该疾病的两个突变基因之一在骨髓来源的树突状细胞中表达，这意味着炎症/免疫在发病机制中可能起作用。 该基因突变导致的表型包括色素分散、裂隙样放射状透照缺陷和虹膜色素上皮退化。最近的实验已经确定，来自受影响的DBA/2 J小鼠的眼睛的房水缺乏抑制T细胞活化的能力，T细胞活化是实际上在色素分散的临床证据开始之前的异常，并且炎症的证据在4个月大时已经存在，这意味着炎症在疾病中的致病作用。 此外，注定发展成青光眼的DBA/2 J眼睛缺乏促进前房相关免疫偏离的能力，并且它们显示受损的眼免疫豁免。 基于这些发现，以及虹膜和睫状体色素上皮细胞变性是该疾病的重要表现的知识，我们已经开发了一个实验计划，该计划将DBA/2 J眼调节炎症和免疫反应的能力异常与色素分散和虹膜萎缩的发病机制联系起来。 我们假设DBA/2 J小鼠的眼部免疫异常易导致针对黑色素相关抗原的自身免疫的发展，并且这种自身免疫启动和/或放大虹膜色素上皮的变性和基质萎缩。因此，前房的继发性结构变化，特别是在房角和小梁网处，导致眼内压升高和最终的视神经病变。

DESCRIPTION (provided by applicant): Pigment dispersion syndrome is an important cause of secondary glaucoma in humans, its pathogenesis is obscure, and therapeutic measures are satisfactory at best. A new mouse model that bears a distant, but interesting, resemblance to the human disease has been described in DBA/2J mice. In this model, as pigment dispersion escalates leaving iris atrophy in its wake, elevated intraocular pressure ensues, leading to optic nerve atrophy and vision impairment. One of the two mutant genes that give rise to the disease is expressed, surprisingly, in dendritic cells of bone marrow origin, implying a possible role for inflammation/immunity in the pathogenesis. The phenotype resulting from mutation of this gene involves pigment dispersion, slit-like radial trans-illumination defects and deterioration of the iris pigment epithelium. Recent experiments have determined that aqueous humor from eyes of affected DBA/2 J mice lacks the capacity to suppress T cell activation, an abnormality that actually precedes the onset of clinical evidence of pigment dispersion, and evidence of inflammation is already present at 4 months of age, implying a pathogenic role for inflammation in the disease. Moreover, DBA/2J eyes destined to develop glaucoma lack the capacity to promote anterior chamber associated immune deviation and they display impaired ocular immune privilege. Based on these findings, and the knowledge that degeneration of pigment epithelial cells of iris and ciliary body is an important manifestation of the disease, we have developed an experimental plan that links abnormalities in the ability of the DBA/2J eye to regulate inflammation and immune responses to the pathogenesis of pigment dispersion and iris atrophy. We hypothesize that ocular immune abnormalities in DBA/2J mice predispose to the development of autoimmunity directed at melanin-associated antigens, and that this autoimmunity initiates and/or amplifies the degeneration of iris pigment epithelium and stromal atrophy. As a consequence, secondary structural changes in the anterior chamber, especially at the angle and trabecular meshwork, lead to increased intraocular pressure and eventual optic neuropathy.