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Stephen C. Pflugfelder, Michael E. Stern, Jerry Y. Niederkorn, John D. Pitcher, III, Eugene Volpe, Niral Gandhi, William J. Farley, De-Quan Li, Cintia S. De Paiva; Spontaneous Autoimmune Inflammation of the Ocular Surface Mucosa in Aged CD4-DNTGFβRII Mice. Invest. Ophthalmol. Vis. Sci. 2011;52(14):2095.
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To investigate if defective TGF-β signaling in CD4+ T cells promotes development of autoimmune inflammation in ocular surface tissues.
The ocular surface of 8- and 14-week old mice transgenic for directed expression of a dominant-negative form of TGF-receptor II (dnTGFRII), under the influence of the CD4 promoter (CD4-DNTGFβRII) was evaluated and compared to wild-type littermates of the same age. Corneal smoothness was assessed by reflection of a ring light. Corneal barrier function was assessed using fluorescent Oregon-Green Dextran (OGD). Conjunctival goblet cell density was counted in PAS stained sections. Immunohistochemistry evaluated CD4 and CD8 T cell infiltration of the cornea, conjunctiva and lacrimal gland. T helper (Th)-1, 2 and 17 associated cytokines were evaluated in cornea and conjunctiva by real time PCR.
14 week-old CD4-DNTGFβRII exhibited a spontaneous dry eye phenotype compared to littermates: they had greater OGD staining and cornea surface irregularity, lower conjunctival goblet cell density and higher CD4+T cell infiltration in cornea, conjunctiva and lacrimal gland than 8 week-old mice. At 14 weeks of age, DNTGFBRII mice showed higher levels of MMP-9, IL-6, IL-17A and IFN-γ mRNA transcripts in both cornea and conjunctiva compared to wild-type control mice.
Disruption of TGF-β signaling in CD4 T cells promotes spontaneous autoimmunity in cornea, conjunctiva and lacrimal gland that has features of dry eye disease. T cell infiltration of the cornea is rarely observed in other autoimmune mouse models of dry eye, suggesting that that functional TGF-β signaling prevents CD4+ T infiltration in the cornea.
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