Abstract
Ocular antigens are sequestered behind the blood-retina barrier and the ocular environment protects ocular tissues from autoimmune attack. The signals required to activate autoreactive T cells and allow them to cause disease in the eye remain in part unclear. In particular, the consequences of peripheral presentation of ocular antigens are not fully understood. We examined peripheral expression and presentation of ocular neo-self-antigen in transgenic mice expressing hen egg lysozyme (HEL) under a retina-specific promoter. High levels of HEL were expressed in the eye compared to low expression throughout the lymphoid system. Adoptively transferred naïve HEL-specific CD4+ T cells proliferated in the eye draining lymph nodes, but did not induce uveitis. By contrast, systemic infection with a murine cytomegalovirus (MCMV) engineered to express HEL induced extensive proliferation of transferred naïve CD4+ T cells, and significant uveoretinitis. In this model, wild-type MCMV, lacking HEL, did not induce overt uveitis, suggesting that disease is mediated by antigen-specific peripherally activated CD4+ T cells that infiltrate the retina. Our results demonstrate that retinal antigen is presented to T cells in the periphery under physiological conditions. However, when the same antigen is presented during viral infection, antigen-specific T cells access the retina and autoimmune uveitis ensues.
Highlights
Sight-threatening intraocular inflammation is the fourth most common cause of blindness, equivalent in frequency to that of diabetic retinopathy[1,2,3], yet it is a relatively neglected disease
We previously demonstrated that IRBP:HELhi mice spontaneously develop autoimmune uveitis (EAU) when crossed with hen egg lysozyme (HEL)-TCR transgenic mice[30]
experimental autoimmune uveitis (EAU) occurs in 100% of dTg-IRBP:HELhi mice derived by crossing single transgenic (sTg)-IRBP:HELhi mice with HEL-TCR mice, despite the retinal thinning, indicating that in this mouse strain the level of retinal HEL antigen expression is sufficient to consistently induce EAU
Summary
Sight-threatening intraocular inflammation (uveitis) is the fourth most common cause of blindness, equivalent in frequency to that of diabetic retinopathy[1,2,3], yet it is a relatively neglected disease. This is partly due to the large number of uveitis entities[4] broadly grouped (a) anatomically, as anterior and intermediate/posterior; and (b) etiologically, as infectious or non-infectious[5]. (B–D) Adult non-Tg, sTg-IRBP:HELlo and sTg-IRBP:HELhi mice were administered CFSE-labelled lymph node cells from HEL-TCR donors.
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