Innate and Adaptive Immunity in the Pathogenesis of Glaucoma

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Glaucoma is a globally unmet medical challenge and a leading cause of irreversible blindness. Elevated intraocular pressure (IOP) is a major risk factor of glaucoma; yet, clinically it is neither required nor sufficient to cause neuronal damage. The mechanisms underlying glaucomatous neurodegeneration are not fully understood. Recently, we have provided the first convincing evidence demonstrating an immune mechanism underlying neurodegeneration in glaucoma. We showed in both the inducible and inherited glaucomatous mouse models that elevated IOP induced upregulation of heat shock proteins (HSPs), retinal microglial activation and T cell infiltration/HSP-specific CD4+ T cell responses and that retinal immune responses are the driving force for progressive RGC and axon degeneration in glaucoma. Remarkably, in germ free mice, which are deficient in HSP-specific T cells, IOP elevation failed to induce microglial activation, HSP-specific T cell responses, and glaucomatous neurodegeneration. These results strongly support that elevated IOP presents a physical stress rather than direct damage to RGCs and axons; it is the stress-evoked events, likely involving both innate and adaptive immune responses that cause glaucomatous neurodegeneration. The key unanswered questions are how elevated IOP activates microglia and T cell responses to induce RGC and axon damage and what are the molecular signals that induce microglial and T cell responses in glaucoma. HSP expression, especially when released from the cell, is known to induce both innate and adaptive immune responses. We hypothesize that elevated IOP induces HSP signaling, leading to microglial activation and HSP- specific T cell responses, which in turn cause RGC degeneration in glaucoma. In the present application, we propose to critically test this hypothesis from three complementary angles: 1) to determine if HSP signaling is responsible for initiating both innate and adaptive immune responses in the retina and inducing glaucomatous neurodegeneration; 2) to investigate if HSPs are key pathogenic antigens driving T cell responses in glaucoma; and 3) to test if levels of HSP-specific T cells in the peripheral blood of patients with glaucoma can serve as biomarkers for diagnosis or predication of glaucoma progression. The proposed studies will be carried out as a collaborative effort among investigators and glaucoma specialist at the Massachusetts Eye and Ear and Massachusetts Institute of Technology, who have complementary expertise and a long history of productive collaboration. Elucidation of the immune mechanisms in glaucomatous neurodegeneration would lead to a paradigm shift in the understanding of the disease pathogenesis and provide a basis for the development of mechanism-based diagnosis, prevention and treatments. Given that the retina has long been served as a model for the central nervous system, the proposed studies may also shed light on the pathogenesis of other neurodegenerative disorders afflicting the brain and spinal cord.