Innate and Adaptive Immunity in the Pathogenesis of Glaucoma

Innate and Adaptive Immune Responses in the Pathogenesis of Glaucoma
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.

Grant Number: 5R01EY031696-05
NIH Institute/Center: NIH
Principal Investigator: Dong Feng Chen