Mitochondrial oxidative stress initiates visual loss in sympathetic ophthalmia.

The visual loss that occurs with sympathetic ophthalmia (SO) in the absence of recognizable retinal damage and inflammatory cell infiltration is an enigma. Experimental autoimmune uveoretinitis (EAU) is an animal model used to study human endogenous uveitis. Both innate and adaptive immune responses have been well studied in the photoreceptor damage mechanism of EAU. In our studies, in the early phase of EAU, proinflammatory molecules such as tumor necrosis factor (TNF)-α and inducible nitric oxide synthase (iNOS) and the subsequent mitochondrial DNA damage, mitochondrial protein alteration, and mitochondrial dysfunction by oxidative stress were observed before retinal inflammatory cell infiltration. Our recent study shows the importance of Toll-like receptors (TLRs) in the production of proinflammatory molecules and the induction of mitochondrial oxidative stress. Thus, the innate immune responses occur first with the activation of TLRs; this activation upregulates proinflammatory molecules, leading to mitochondrial oxidative stress before retinal inflammatory cell infiltration and the subsequent adaptive immune responses. Like EAU, SO also results in photoreceptor mitochondrial oxidative damage without retinal inflammatory cell infiltration. Such damage was associated with TNF-α, TNF-α receptors, and iNOS expression in the photoreceptors, suggesting that this molecular mechanism without retinal inflammatory cell infiltration may initiate photoreceptor damage in SO.