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Principal Investigator: Dong Feng Chen
Organization: SCHEPENS EYE RESEARCH INSTITUTE
Fiscal Year: 2024
Award: $717,827
Funding agency: National Eye Institute
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.
Terms: <Affect><Age><Antigens><Attenuated><Automobile Driving><Axon><Biological Markers><Blindness><Brain><Brain Nervous System><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CNS Nervous System><Cell Body><Cell Communication and Signaling><Cell Count><Cell Number><Cell Signaling><Cells><Cellular injury><Central Nervous System><Clinical><Collaborations><Cranial Nerve II><Degenerative Neurologic Disorders><Deterioration><Development><Diagnosis><Diagnostic><Disease><Disorder><Ear><Encephalon><Event><Exhibits><Eye><Eye diseases><Eyeball><Frequencies><Germ-Free><Glaucoma><HSP27><HSPB1><HSPB1 gene><Heat Shock 27 kD Protein 1><Heat Shock 27kD Protein 1 Gene><Heat Shock Protein 27><Heat shock proteins><Heat-Shock Protein 27 Gene><Hereditary><History><Hortega cell><Human><IFN-Gamma><IFN-g><IFN-γ><IFNG><IFNγ><Immune><Immune Interferon><Immune Markers><Immune Tolerance><Immune response><Immunes><Immunologic Markers><Immunologic Tolerance><Immunological response><Individual><Inflammation><Inflammatory><Inflammatory Response><Inherited><Innate Immune Response><Innate Immunity><Interferon Gamma><Interferon Type II><Intracellular Communication and Signaling><Intraocular Pressure><Investigators><Link><MHC Receptor><Major Histocompatibility Complex Receptor><Massachusetts><Mediating><Medical><Medulla Spinalis><Mice><Mice Mammals><Microglia><Modeling><Modern Man><Molecular><Murine><Mus><Native Immunity><Natural Immunity><Nerve Cells><Nerve Degeneration><Nerve Unit><Nervous System Degenerative Diseases><Neural Cell><Neural Degenerative Diseases><Neural degenerative Disorders><Neuraxis><Neurocyte><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurologic Degenerative Conditions><Neuron Degeneration><Neurons><Non-Specific Immunity><Nonspecific Immunity><Ocular Tension><Optic Nerve><POAG><Pathogenesis><Pathogenicity><Patients><Persons><Phase><Physiologic Intraocular Pressure><Pilot Projects><Prevention><Primary Open Angle Glaucoma><Productivity><Recording of previous events><Regulatory T-Lymphocyte><Reporting><Research Personnel><Research Proposals><Researchers><Retina><Retinal Ganglion Cells><Risk Factors><Second Cranial Nerve><Sight><Signal Induction><Signal Transduction><Signal Transduction Systems><Signaling><Signaling Factor Proto-Oncogene><Signaling Pathway Gene><Signaling Protein><Specialist><Spinal Cord><Stress><T cell infiltration><T cell response><T-Cell Antigen Receptors><T-Cell Receptor><T-Cells><T-Lymphocyte><T4 Cells><T4 Lymphocytes><Techniques><Technology><Testing><Treg><Up-Regulation><Upregulation><Vision><Visual Fields><adaptive immune response><adaptive immunity><ages><attenuate><attenuates><axon damage><axon injury><axonal damage><axonal degeneration><axonal injury><bio-markers><biologic marker><biological signal transduction><biomarker><cell damage><cell injury><cell type><cellular damage><commensal flora><commensal microbes><commensal microbiota><commensal microflora><damage to cells><damage to retina><degenerative axon><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><developmental><driving><driving force><extracellular><eye disorder><eye field><gitter cell><glaucomatous><glial activation><glial cell activation><histories><host response><immune system response><immune system tolerance><immune unresponsiveness><immune-based biomarkers><immunogen><immunogenic><immunological biomarkers><immunological markers><immunological paralysis><immunoresponse><injury to cells><intra-ocular pressure><intravitreal injection><lFN-Gamma><mesoglia><microglial cell><microgliocyte><mouse model><murine model><neural><neural degeneration><neural inflammation><neurodegeneration><neurodegenerative><neurodegenerative illness><neuroinflammation><neuroinflammatory><neurological degeneration><neuronal><neuronal degeneration><novel><ocular disease><ocular disorder><ophthalmopathy><peripheral blood><perivascular glial cell><pilot study><progressive neurodegeneration><protein expression><regulatory T-cells><response><retinal damage><retinal ganglion><retinal ganglion cell degeneration><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><stress protein><thymus derived lymphocyte><vision loss><visual function><visual loss>