The gut-retina axis: Uncovering the role of autoimmunity in glaucoma development

Glaucoma, a leading cause of irreversible blindness worldwide, is characterized by progressive loss of retinal ganglion cells (RGCs) and optic nerve damage. While elevated intraocular pressure (IOP) is the only known modifiable risk factor, normal-tension glaucoma (NTG) challenges this notion, suggesting other mechanisms beyond IOP may contribute to its development. Emerging evidence support the hypothesis that glaucoma may be an autoimmune disease. This review summarizes evidence for this hypothesis, focusing on the gut-retina axis. We discuss how antigens of gut bacterial prime peripheral T cells to breach the blood-retina barrier (BRB) and initiate cross-reactivity with ocular tissues via molecular mimicry, resulting in autoimmune RGC damage. Understanding these mechanisms may uncover new diagnostic biomarkers and therapeutic strategies targeting immune pathways alongside conventional IOP-lowering treatments. Immunological insights into glaucoma. The main events are as follows. At the gut, peripheral T cells are primed by commensal microbial antigens. Primed peripheral T cells are enabled to cross the blood-retinal-barrier (BRB). Under stress conditions such as elevated intraocular pressure (IOP), glial cells are activated and release pro-inflammatory factors. The local inflammatory state facilitates peripheral primed T cells to cross the BRB. Infiltrating T cells in the retina provoke an immune response against ocular self-antigens through cross-immune reactions, resulting in apoptosis of retinal ganglion cells (RGCs). ①Antigen presenting cell; ②T cell; ③microglial cell; ④retinal ganglion cell; ⑤apoptotic retinal ganglion cell. [Display omitted] •The gut-retina axis is pivotal in glaucoma autoimmunity.•Patients with glaucoma show altered gut microbiota, activating peripheral immune responses.•Gut antigens prime T cells to cross the BRB via MAdCAM-1 interactions, mediating RGC apoptosis through the FasL/Fas pathway.•Persistent glial-driven eye inflammation sustains T cell infiltration and RGC damage despite normalized IOP.•Elevated ocular autoantibodies suggest humoral immunity involvoment in glaucoma, though their role remians debated.