Glaucoma is characterized by the progressive degeneration of retinal ganglion cells (RGCs), leading to blindness. The most prominent risk factor is elevated intraocular pressure (IOP), but an autoimmune component to disease pathology has long been suspected. Now, reporting in Nature Communications, Chen et al. show that a transient elevation in IOP can induce infiltration of autoreactive T cells into the retina and demonstrate that these T cells are pre-sensitized by the commensal microflora.
The authors used a mouse model in which glaucoma is induced by microbead injection into the eye, which induces a temporary elevation in IOP, as well as mice that develop glaucoma in response to a spontaneous elevation of their IOP. In both models, they found that the elevation of IOP was followed by degeneration of axons and RGCs and an infiltration of the RGC layer by interferon-γ-secreting CD4+ T cells.
Neurodegeneration appeared to occur in two stages: the acute initial phase (lasting approximately 2 weeks) during which the IOP is elevated and RGCs and axons are damaged, likely by physical stress, and a prolonged (progressive) phase during which the IOP is back to normal but loss of RGCs and axons continues (weeks 2-8).
In order to investigate the role of immune cells in this process, the authors subjected mice deficient in αβ T cells (TCRβ–/– mice), B cells (Igh6–/– mice) or both (Rag1–/– mice) to microbead injection. An initial phase of axon and RGC degeneration was observed in all mice, but mice lacking T cells did not experience the progressive phase of neurodegeneration. Adoptive transfer experiments confirmed a causal role of CD4+ T cells: microbead-treated Rag1–/– mice that received CD4+ cells from glaucomatous mice had progressive degeneration of their RGCs. CD4+ T cells from non-glaucomatous mice, or injection of total IgG from glaucomatous mice, did not have the same effect — indicating that the progressive phase of neurodegeneration is mediated by conditioned CD4+ T cells.
Next, the authors sought to identify the autoantigens recognized by the CD4+ T cells. Previous studies had implicated the heat shock proteins HSP27 and HSP60 as potential antigens. Indeed, these proteins were found to be upregulated on RGCs in response to elevated IOP, and significantly higher levels of serum HSP27-specific autoantibodies were found in mice that had experienced elevated IOP compared to mice that had not. Further assays confirmed increased levels of HSP27-specific CD4+ T cells in mice after IOP elevation. These cells appeared to accumulate in the retina and mediate the prolonged phase of neurodegeneration.
The authors then asked how T cell responses to HSPs are induced by IOP elevation. As HSPs are highly conserved from bacteria to humans, they hypothesized that mice may harbour HSP-specific memory T cells that were originally induced by commensal bacteria. Indeed, they found that mice housed under germ-free conditions do not experience any neurodegeneration after microbead injection into the eye or in response to a spontaneous elevation of IOP.
“glaucoma is caused by bacteria-primed CD4+ T cells that enter the eyes after the blood–retina barrier is compromised through pressure”
Collectively, these results suggest that glaucoma is caused by bacteria-primed CD4+ T cells that enter the eyes after the blood–retina barrier is compromised through pressure and cause neurodegeneration by cross-reacting with HSP-expressing RGCs. The authors found that patients with open-angle or normal tension glaucoma also have increased frequencies of HSP27-specific and HSP60-specific T cells, indicating that these findings are likely to be of human relevance.
Chen, H. et al. Commensal microflora-induced T cell responses mediate progressive neurodegeneration in glaucoma. Nat. Commun. 9, 3209 (2018)
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Flemming, A. Bacteria-primed T cells identified as culprit in glaucoma. Nat Rev Immunol 18, 603 (2018). https://doi.org/10.1038/s41577-018-0063-x