# Innate and Adaptive Immunity in the Pathogenesis of Glaucoma

> **NIH NIH R01** · SCHEPENS EYE RESEARCH INSTITUTE · 2024 · $140,834

## Abstract

Project Summary
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 neurodegen...

## Key facts

- **NIH application ID:** 11076039
- **Project number:** 3R01EY031696-03S2
- **Recipient organization:** SCHEPENS EYE RESEARCH INSTITUTE
- **Principal Investigator:** Dong Feng Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $140,834
- **Award type:** 3
- **Project period:** 2021-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11076039

## Citation

> US National Institutes of Health, RePORTER application 11076039, Innate and Adaptive Immunity in the Pathogenesis of Glaucoma (3R01EY031696-03S2). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11076039. Licensed CC0.

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