Paradigms of maintaining anterior segment homeostasis

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Project Summary/Abstract Inflammatory responses in the eye, such as following corneal wounding, and in autoimmune-mediated uveitis, must be controlled and resolved to preserve homeostasis and prevent damage. In all these conditions, we discovered that immune cells are recruited to the surface of the lens, many with characteristics associated with immunomodulation. The central location of the lens and its interface with most eye tissues via the adjacent aqueous and vitreous humors places it in the perfect position for these Lens Capsule Associated Immune Cells (LC-AICs) to present antigens and produce proteins that can exert immunosuppressive functions across the eye. In addition, we found that there are resident immune cells, the sentinels of the immune system, that become integrated within the lens during development. We now build on these findings with studies aimed at understanding the lineage and functions of lens resident immune cells and LC-AICs recruited from other ocular sites, their roles in maintaining homeostasis, and whether their long-term persistence is linked to pathogenic outcomes. In Aim 1, we will perform lineage tracing studies to determine their ontogeny. These studies will reveal whether these immune cell populations are long-lived, self-renewing and embryonic yolk-sac derived, or short-lived, bone marrow-derived typical of those recruited to tissues in response to injury and pathogenesis. Since tissue resident immune cells are immediate responders to injury and pathogenesis, we will investigate whether their activation in response to corneal wounding is linked to LC-AIC recruitment and regenerative repair of the cornea. In Aim 2, we will perform a detailed analysis of the immunomodulatory properties of the LC-AICs recruited to the lens post-corneal wounding and in uveitis. These studies will include a functional analysis to directly link the LC-AICs to the suppression of T-cell activation. We also examine the anti- inflammatory and anti-angiogenic properties of the bioactive matrix-derived molecules proteolytically released by LC-AICs as they migrate within the lens capsule. Our studies of the LC-AICs strongly support their important functions as immunomodulators in the eye, including our discovery that they persist integrated with the lens surface during the resolution of inflammation in uveitic eyes. However, their long-term persistence at the lens capsule surface beyond this time, and the ability of a subset to abrogate lens immune privilege and infiltrate the lens, suggests that their prolonged presence could lead to pathological outcomes. In Aim 3, we will determine the mechanisms by which LC-AICs cross the lens capsule to infiltrate the lens and their fate, including whether they can be agents of cataractogenesis by becoming collagen I-producing myofibroblasts. In addition, we will investigate the properties of the fibrillar network with which the LC-AICs maintained on the surface of the lens become entwined, and to which the iris becomes attached at late stages of uveitis, which could be linked to pathological outcomes of uveitis. Understanding these links could lead to new treatment options for patients with ocular pathologies associated with chronic inflammation.