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Kazuhiko Namekata, Xiaoli Guo, Atsuko Kimura, Chikako Harada, Takayuki Harada; Dock8 and Dock10 regulate severity of inflammatory demyelination disorders.. Invest. Ophthalmol. Vis. Sci. 2014;55(13):5770. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Dock8, an atypical guanine nucleotide exchange factor (GEF) for Rho-family of small GTPases, has gained much attention since the discovery of Dock8 mutations in a combined immunodeficiency syndrome in humans. However, it is unknown whether Dock8 deficiency may be effective in inflammatory demyelinating disorders including optic neuritis. Therefore, we investigated roles of Dock8 and Dock10, a homologue of Dock8, in inflammatory demyelination.
Three transgenic mouse lines were generated: Dock8 deficient (Dock8 KO); Dock8 overexpressing (Dock8 Tg); and Dock10 deficient (Dock10 KO) mice. We induced experimental autoimmune encephalomyelitis (EAE) by myelin oligodendrocyte glycoprotein (MOG) immunization in these transgenic mice. T-cell activations and proliferations were measured using FACS. Clinical signs were scored daily and visual function was assessed by multifocal electroretinograms. Histopathological analysis of optic nerves and spinal cords was performed.
T-cell numbers in spleen were significantly reduced in Dock8 KO mice, but not in Dock8 Tg and Dock10 KO mice. Dock8 deficiency absolutely protected the optic nerve and spinal cord from inflammatory demyelination indicating that Dock8 is required to elicit autoimmune T-cell responses. The disease incidence was nearly halved in Dock8 Tg mice, and diseased EAE mice showed markedly decreased clinical signs, in which recovery was observed at later timepoints. In addition, a similar amelioration of inflammatory demyelination was observed in Dock10 KO mice; this resulted from suppression of cytokine production, namely, MIP-1α and MCP-1, in glial innate immunity.
Our findings suggest that manipulation of Dock8 and Dock10 signaling may serve as a novel therapeutic strategy against inflammatory demyelinating disorders.
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