Glaucoma and Autoimmunity: Immunopathogenic Mechanisms and Emerging Immunomodulatory Therapies

Glaucoma is a chronic progressive optic neuropathy and one of the leading causes of irreversible blindness worldwide. Although elevated intraocular pressure remains the most important modifiable risk factor, increasing evidence suggests that immune dysregulation and autoimmune responses also contribute substantially to disease onset and progression. Clinical studies across different glaucoma subtypes have identified subtype-dependent immune abnormalities, including altered serum autoantibody profiles, dysregulated cytokine and chemokine expression, and changes in peripheral immune cell subsets. Experimental and translational studies further indicate that multiple immunopathogenic mechanisms are involved in glaucomatous neurodegeneration, including glial cell-mediated immune responses, activation of pattern recognition receptor signalling pathways, adaptive immune responses, and complement cascade dysregulation. These processes may interact to sustain chronic neuroinflammation, promote retinal ganglion cell injury, and accelerate optic nerve degeneration. Importantly, a better understanding of immune involvement in glaucoma has generated growing interest in immunomodulatory therapy as a potential strategy beyond intraocular pressure lowering. Targeting microglial activation, inflammatory signalling pathways, adaptive immune imbalance, and complement-mediated injury has shown neuroprotective potential in animal or in vitro models, whereas clinical evidence in glaucoma patients remains limited. These findings may provide preliminary directions for future therapeutic development. In this review, we summarise the current clinical evidence linking glaucoma with autoimmunity, discuss the major immune mechanisms implicated in disease pathogenesis, and highlight recent advances in immunomodulatory therapeutic strategies. Elucidating the immune basis of glaucoma may help pave the way for more precise and effective treatments for this complex optic neuropathy. We believe that immune dysregulation in glaucoma functions as a context-dependent amplifier of retinal ganglion cell injury rather than a uniform primary driver, with innate (microglia/astrocytes), adaptive (T/B cells, HSP-specific immunity), and complement pathways interacting to sustain neuroinflammation and neurodegeneration. This integrated immune response contributes to subtype- and stage-specific vulnerability, and targeting these maladaptive immune mechanisms represents a promising, precision-guided strategy for neuroprotection beyond intraocular pressure lowering.