AUTOIMMUNITY ASSOCIATED WITH PIGMENT DISPERSION GLAUCOMA

描述(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，其发病机制不明，治疗措施充其量也是令人满意的。在DBA/2J小鼠身上描述了一种新的小鼠模型，它与人类疾病有一种遥远但有趣的相似之处。在这个模型中，随着色素扩散的加剧，导致虹膜萎缩，随后眼压升高，导致视神经萎缩和视力障碍。令人惊讶的是，导致这种疾病的两个突变基因中的一个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到了作用。该基因突变导致的表型包括色素分散、裂隙状放射状透照缺陷和虹膜色素上皮的恶化。最近的实验已经确定，受影响的DBA/2 J小鼠的眼部房水缺乏抑制T细胞激活的能力，这种异常实际上在色素弥散的临床证据出现之前就已经出现了，并且在4个月大的时候就已经出现了炎症的证据，这意味着炎症在疾病中起到了致病作用。此外，发展为青光眼的DBA/2J眼缺乏促进前房相关免疫偏离的能力，并表现出眼睛免疫赦免受损。基于这些发现，以及虹膜和睫状体色素上皮细胞退化是该病的重要表现这一知识，我们制定了一项实验计划，将DBA/2J眼调节炎症和免疫反应的能力异常与色素弥散和虹膜萎缩的发病机制联系起来。我们假设DBA/2J小鼠的眼部免疫异常易于发展针对黑色素相关抗原的自身免疫，这种自身免疫启动和/或放大虹膜色素上皮的退化和基质萎缩。因此，前房的继发性结构改变，特别是房角和小梁网状结构的改变，导致眼压升高，最终导致视神经病变。

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.