Commensal microflora-induced T cell responses mediate progressive neurodegeneration in glaucoma

Abstract

Glaucoma is the most prevalent neurodegenerative disease and a leading cause of blindness worldwide. The mechanisms causing glaucomatous neurodegeneration are not fully understood. Here we show, using mice deficient in T and/or B cells and adoptive cell transfer, that transient elevation of intraocular pressure (IOP) is sufficient to induce T-cell infiltration into the retina. This T-cell infiltration leads to a prolonged phase of retinal ganglion cell degeneration that persists after IOP returns to a normal level. Heat shock proteins (HSP) are identified as target antigens of T-cell responses in glaucomatous mice and human glaucoma patients. Furthermore, retina-infiltrating T cells cross-react with human and bacterial HSPs; mice raised in the absence of commensal microflora do not develop glaucomatous T-cell responses or the associated neurodegeneration. These results provide compelling evidence that glaucomatous neurodegeneration is mediated in part by T cells that are pre-sensitized by exposure to commensal microflora.

The interplay between inflammation, immunity and commensal microflora in glaucomatous neurodegeneration

“…Induction of HSP specific T cells and glaucomatous neurodegeneration by elevated IOP require exposure to commensal microflora. Elevated IOP induced retinal T cell infiltration, HSP-27 and HSP-60 specific T cell responses were detected in normally colonised mice but not detected in germ-free mice (7).…”

“…CD4+ T cells were transferred from B6 mice into Rag1 −/− mice via the tail vein to assess if CD4 + T cells had a causal role in the progression of the glaucomatous neurodegeneration. Rag1 −/− mice which received T cells from glaucomatous B6 mice showed a T cell infiltration and a significant further decrease in RGC density and axon numbers (7).…”

“…Chen et al showed short (3 weeks) elevation of IOP using microbead injection B6 mouse model and progressive elevation of IOP using genetic (DBA/2J) mice model, induces infiltration of IFN-γ-secreting T cells resulting in the reduction of RGC density and axonal loss (7). For retinal T cell infiltration to occur local inflammation is required.…”

“…Gut microbiome dysbiosis has been associated with gastrointestinal inflammatory conditions and extra-intestinal disorders; such as stroke, depression, neurodegenerative, cardiovascular and metabolic disorders (2)(3)(4)(5)(6). In the September 2018 issue of nature communications, Chen and colleagues report the findings from a study that found commensal microflora-induced T cell responses mediate progressive neurodegeneration in glaucoma, in mouse glaucoma models (7).…”

“…It is this autoimmune response to commensal microflora that is thought to mediate neurodegeneration through the production of activated retinal T cells. Chen et al showed elevated IOP induces two phases of retinal damage; the acute phase likely mediated by mechanical stress; the prolonged retinal degeneration, which continues after IOP has returned to normal, mediated by T cells (7).…”