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Nancy A. McNamara, Ying-Ting Chen, Feeling Chen, Ahmad F. Bahrami, Lisa B. Noble, Marianne Gallup, Delu Zhou; Essential Role of CD4+ T Cell-Dependent Macrophage Infiltration in the Pathogenesis of Sjögren’s Syndrome-Associated Dry Eye. Invest. Ophthalmol. Vis. Sci. 2012;53(14):1282. doi: https://doi.org/.
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Lymphocytic infiltration of the lacrimal gland and ocular surface in autoimmune diseases like Sjögren’s syndrome (SS) provokes an aqueous-deficient dry eye. Desiccating stress coupled with chronic inflammation alters the integrity of the corneal epithelium and, in severe disease, promotes fibrosis of the underlying stroma. Previous studies have established autoimmune regulator (Aire) knock out (KO) mice as a useful model to study SS-associated dry eye where CD4+ T cells play an indispensable role in disease development. We hypothesized that macrophages serve as cellular intermediates linking CD4+ T cells to local tissue damage in Aire KO mice.
We examined macrophage infiltration of the ocular surface in Aire KO mice and in immunodeficient recipients following adoptive transfer of autoreactive CD4+ T cells. We depleted macrophages using clodronate liposome and examined lacrimal gland histopathology by H&E staining, tear secretion by phenol red cotton thread test and ocular epithelial integrity by lissamine green staining. We used immunofluorescent microscopy to examine immune cell infiltration (using antibodies directed against F4/80 and CD4) and stromal fibrosis (using antibodies directed against vimentin and alpha smooth muscle actin).
Large numbers of F4/80-positive macrophages and CD4+ T cells infiltrated the corneal stroma, limbus and lacrimal glands of Aire KO mice. Adoptive transfer of autoreactive CD4+ T cells from Aire KO mice promoted macrophage infiltration and ocular surface damage in immunodeficient recipients. Depletion of local macrophages through subconjunctival injection of clodronate liposome attenuated lissamine green staining and subepithelial fibrosis while systemic depletion of macrophages through intraperitoneal injection promoted significant improvement in lacrimal gland exocrinopathy and tear secretion.
Autoreactive CD4+ T cells provoked macrophage infiltration of the eyes and lacrimal glands in Aire KO mice. In turn, macrophages functioned systemically to promote exocrinopathy and locally to direct the development of ocular surface disease.
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