Müller cells and retinal axons can be primary targets in experimental neuromyelitis optica spectrum disorder

Recent work from our laboratory, using different models of experimental neuromyelitis optica spectrum disorder ( NMOSD ), has led to a number of observations that might be highly relevant for NMOSD patients. For example: (i) in the presence of neuromyelitis optica immunoglobulin G, astrocyte‐destructive lesions can be initiated by CD 4+ T cells when these cells recognize aquaporin 4 ( AQP 4), but also when they recognize other antigens of the central nervous system. The only important prerequisite is that the T cells have to be activated within the central nervous system by “their” specific antigen. Recently activated CD 4+ T cells with yet unknown antigen specificity are also found in human NMOSD lesions. (ii) The normal immune repertoire might contain AQP 4‐specific T cells, which are highly encephalitogenic on activation. (iii) The retina might be a primary target of AQP 4‐specific T cells and neuromyelitis optica immunoglobulin G: AQP 4‐specific T cells alone are sufficient to cause retinitis with low‐grade axonal pathology in the retinal nerve fiber/ganglionic cell layer. A thinning of these layers is also observed in NMOSD patients, where it is thought to be a consequence of optic neuritis. Neuromyelitis optica immunoglobulin G might target cellular processes of Müller cells and cause their loss of AQP 4 reactivity, when AQP 4‐specific T cells open the blood–retina barrier in the outer plexiform layer. Patchy loss of AQP 4 reactivity on Müller cells of NMOSD patients has been recently described. Cumulatively, our findings in experimental NMOSD suggest that both CD 4+ T cell and antibody responses directed against AQP 4 might play an important role in the pathogenesis of tissue destruction seen in NMOSD .