[Optic neuritis--immunological approach to elucidate pathogenesis and develop innovative therapy].

The pathogenesis of optic neuritis developed rapidly from the end of the 19th century to the beginning of the 20th century accompanying progress in morpho-anatomy and physiology. Thereafter, the pathology of the disease continues to be clarified with the advances in medicine and clinical peripheral devices. The analysis of optic neuritis is about to enter a new phase, triggered by the advent of molecular immunology and genetic engineering. This article describes the results of recent studies on the pathogenetic mechanism of optic neuritis and the potential of utilizing these new findings in the development of novel therapies. Studies revealed that optic neuritis associated with anti-aquaporin(AQP) 4 antibodies is refractory to steroid therapy and causes injuries to the optic nerve-optic chiasma-optic tract, resulting in a broad array of visual field abnormalities. Especially, the disease becomes severe in individuals who possess anti-AQP4 antibodies that target astrocytes, together with anti-myelin oligodendrocyte glycoprotein (MOG) antibodies that target myelin oligodendrocytes. Furthermore, measurement of glial fibrillary acidic protein (GFAP) levels in cerebrospinal fluid may be useful in the diagnosis of anti-AQP4 antibody positive optic neuritis. Studies using experimental autoimmune optic neuritis (EAON) models demonstrate two patterns: a pattern of myelin oligodendrocyte damage as in optic neuritis associated with multiple sclerosis, and a pattern of astrocyte damage as in anti-AQP4 antibody positive optic neuritis, which in optic neuritis associated with anti-AQP4 antibodies, incites IgG deposits in the optic nerve to damage astrocytes. In multiple sclerosis-associated optic neuritis models, visual acuity decreases first, followed by deposition of complements in the optic nerve and infiltration of microglia and inflammatory cells. Thereafter, the number of axons decreases and latency of visually evoked potential (VEP) is prolonged. The implication of these findings to treatment is that appropriate treatment should be started at the stage when visual acuity has decreased but before VEP latency is prolonged; that is, at the time when cells start to infiltrate the optic nerve. Evaluations of various immunotherapies in the EAON model, considered to be a model of optic neuritis associated with multiple sclerosis, suggest that optic neuritis may be suppressed by inducing anterior chamber-associated immune deviation (ACAID). Applying this phenomenon, cell therapy using dendritic cells transfected with CGRP or dendritic cells transfected with IL-10 was attempted, and was found to be effective in suppressing optic neuritis. At the same time, as a more practical therapy, administration of the new multiple sclerosis drug FTY720 (fingolimod) suggests suppression of cell infiltration into the optic nerve. The results of these studies show that therapies that suppress cell infiltration of the optic nerve at the early stage after onset is important to maintain visual function.