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Clare L C Corbett, Lucia Kuffova, Yoshinori Fukui, John V Forrester; Disruption of DOCK2 expression significantly reduces retinal inflammation in a spontaneous mouse model of EAU: a pilot study. Invest. Ophthalmol. Vis. Sci. 2014;55(13):95.
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© ARVO (1962-2015); The Authors (2016-present)
Spontaneous experimental autoimmune uveoretinitis (EAU) develops in double transgenic (dTg) mice generated by crossing IRBP-Helhi single transgenic (sTg) mice on a B10.BR background, which express the protein hen egg lysozyme (HEL) as a novel self-antigen in the retina, with the 3A9 strain of mice that express HEL-specific T-cell receptors. Rac is a ubiquitously expressed small GTPase that is responsible for actin cytoskeleton remodeling, an essential process for many cellular functions including cellular migration. Rac function is regulated in part by Dedicator Of Cytokinesis 2 (DOCK2), a guanidine exchange factor (GEF) that is highly expressed by lymphocytes, neutrophils and plasmacytoid dendritic cells. DOCK2 deficient T-cells demonstrate defective TCR-mediated activation and chemokine-stimulated migration. This study investigates the role of DOCK2 in non-infectious ocular inflammation.
To study the effect of DOCK2 deficiency on EAU development DOCK2 heterozygous knockout mice were backcrossed to IRBP-Helhi: TCR dTg mice over more than 12 generations. Mice with genotypes DOCK2+/+ IRBP-Hel:TCR dTg and DOCK2-/+ IRBP-Hel:TCR dTg were sacrificed at age 30 days (n=3). Eyes were enucleated and fixed in 2.5% glutaraldehyde, sections were stained with haematoxylin and eosin and EAU severity was graded histologically. Eyes were also SNAP frozen in OCT and 6-8μm sections stained for the presence of macrophages, dendritic cells, B-cells and CD4+ T-cells.
EAU histology scores at 30 days were significantly lower in the DOCK2-/+ IRBP-Hel dTg mice than those of the DOCK2+/+ IRBP-Hel:TCR dTg mice (p< 0.05). There was a reduction in retinal infiltration by macrophages, dendritic cells, B-cells and CD4+ cells in the DOCK2-/+ IRBP-Hel:TCR dTg mice compared to the DOCK2+/+ IRBP-Hel dbl Tg mice.
DOCK2 heterozygosity was associated with reduced severity of ocular inflammation, evident at 30 days, in the spontaneous model of EAU. As DOCK2 expression is restricted to a limited number of immune cells it represents a promising therapeutic target for the treatment of uveitis.
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