Glaucoma, a leading cause of irreversible blindness worldwide, is often not diagnosed until many years after disease onset. Early and objective diagnostic measures are yet missing. Besides the main risk factor, an elevated intraocular pressure (IOP), age, sex, and ethnicity are known to affect disease progression and severity. Furthermore, oxidative stress, elevated glutamate concentrations, and an autoimmune component are considered possible risk factors. We could identify several potential proteomic biomarkers in glaucoma and examine distinct changes in the glaucomatous human retina proteome. Using an experimental autoimmune glaucoma animal (EAG) model we could demonstrate an IOP-independent loss of retinal ganglion cells (RGC), which is accompanied by antibody depositions and increased levels of microglia. In a different animal model we showed that intermittent IOP elevations provoke neurodegeneration in the optic nerve and the retina and elicit changes of IgG autoantibody reactivities. The correlation between neuronal damage and changes in autoantibody reactivity suggests that autoantibody profiling could be a useful biomarker for glaucoma. In vivo studies on neuroretinal cells and porcine retinal explants demonstrated a protective effect of antibodies (eg, anti-GFAP) on RGC, which seems to be the result of reduced stress levels in the retina. We conclude that the absence of some autoantibodies in glaucoma patients reflects a loss of the protective potential of natural autoimmunity and may thus encourage neurodegenerative processes. Concluding, autoantibody profiles resemble useful biomarkers for diagnosis, progression and severity of glaucoma. Future longitudinal studies will help to improve early detection and enable better monitoring of disease progression.