Defining the interplay of interferon-gamma and cathepsin S in age-related dry eye

随着预期寿命的延长，与衰老相关的衰弱疾病预计也会增加， 其中之一就是干眼症。年龄的增长一再被认为与干眼有关， 尽管衰老导致干眼病的确切机制仍不清楚。 衰老伴随着眼部的临床慢性炎症，有时甚至亚临床慢性炎症。 表面和泪腺(Lg)。年龄相关的干眼症的影响是显著的，因为它 影响功能性视力，以及行动能力、独立性和执行日常任务的能力。 组织蛋白酶S是一种高效的半胱氨酸/蛋白水解酶，表达于两种树突状细胞的溶酶体室中 细胞和LG腺泡上皮细胞。组织蛋白酶S参与MHC II类抗原的生理性递呈。 组织蛋白酶S水平升高在动物模型和干燥症患者中已被描述 综合征和其他自身免疫的动物模型中也是如此，在这些动物模型中，它被认为有助于 自身反应性的CD4T细胞。我们的初步数据表明，组织蛋白酶S随着年龄的增长而升高。 然而，组织蛋白酶S在老年眼表和LG中的具体作用尚未阐明。 我们假设，与年龄相关的眼表和LG的炎症变化导致 腺泡上皮细胞和树突状细胞增加组织蛋白酶S的活性和产量。这增加了 组织蛋白酶S可能1)以旁分泌方式放大局部炎症和细胞因子的分泌 由上皮细胞可进一步增加组织蛋白酶S，造成恶性循环；2)增加MHC 老化树突状细胞提呈抗原，使其偏向致病的CD4IFN-γ(Th1) 促进与年龄相关的干眼病发生的细胞。为了研究我们的假设，我们 提出三个具体目标：具体目标1：如何在眼表和年龄相关性炎症 LG刺激组织蛋白酶S产生促进干眼发育？具体目标2：多大年龄-- 组织蛋白酶S调节树突状细胞功能促进血管生成 自身反应性致病的Th1细胞？具体目标3：组织蛋白酶S抑制能否调节年龄相关 干眼症？这些实验的结果将提高我们对基本原理的理解 老年性干眼病的发病机制。此外，它将改变我们对眼睛老化的看法 表面从不可避免的被动、退化过程转变为主动、炎症和免疫- 调节状态，可以有针对性，从而打开场地，防止有害的年龄相关性干眼。

With increased life expectancy, debilitating diseases that accompany aging are also expected to rise, and one of them is dry eye disease. Increased age has repeatedly been associated with dry eye, although the precise mechanisms by which aging predisposes to dry eye disease remain unknown. Aging is accompanied by clinical, and sometimes sub-clinical chronic inflammation on the ocular surface and lacrimal gland (LG). The impact of age related dry eye disease is significant because it affects functional vision, as well as mobility, independence and the ability to perform daily tasks. Cathepsin S is a potent cysteine/protease expressed in the lysosomal compartments of both dendritic cells and LG acinar epithelia. Cathepsin S participates in physiological MHC II antigen presentation. Elevated levels of cathepsin S have been described in animal models and patients with Sjögren Syndrome and also in other animal models of autoimmunity, where it is thought to facilitate generation of autoreactive CD4+ T cells. Our preliminary data suggests that Cathepsin S is elevated in aging. However, the specific role of cathepsin S in the aged ocular surface and LG has not been elucidated. We hypothesize that age-related inflammatory changes in the ocular surface and LG lead to increased activity and production of cathepsin S by acinar epithelia and dendritic cells. This increased cathepsin S may 1) act in a paracrine fashion to amplify local inflammation and secretion of cytokines by the epithelium that can further increase cathepsin S creating a vicious circle; and 2) increase MHC II antigen presentation by aged dendritic cells, skewing them to prime pathogenic CD4+IFN-γ+ (Th1) cells that promote development of age-related dry eye disease. To investigate our hypothesis, we propose three specific aims: Specific Aim 1: how age-related inflammation in the ocular surface and LG stimulates cathepsin S production that promotes development of dry eye? Specific Aim 2: how age- related increase of cathepsin S modulates dendritic cell function and promotes the generation of autoreactive, pathogenic Th1 cells? Specific Aim 3: can cathepsin S inhibition modulate age-related dry eye? Results from these proposed experiments will improve our understanding of the fundamental mechanisms of age-related dry eye disease. Furthermore, it will change our view of aging on the ocular surface from an inevitable passive, degenerative process to an active, inflammatory and immune- mediated status that can be targeted, thus opening venues to prevent deleterious age-related dry eye.