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Sarah B Dale, Rose Mathew, Nancy Reyes, Tomas Blanco, Virginia L Calder, Daniel R Saban; A novel contribution for dendritic cells in fibrosis pathobiology as revealed in a mouse model of severe ocular allergy. Invest. Ophthalmol. Vis. Sci. 2014;55(13):4603. doi: https://doi.org/.
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The pathobiology underlying conjunctival fibrosis, such as evidenced in vision-threatening forms of severe ocular allergy (e.g. vernal/atopic keratoconjunctivitis) is poorly understood. Dendritic cells (DC) and fibroblasts both reside in the conjunctiva, and furthermore DCs exhibit enhanced aldehyde dehydrogenase (ALDH) activity. Interestingly ALDH has pro-fibrotic functions and led us to examine a potentially novel role for DCs in pro-fibrotic processes that occur in severe ocular allergy.
ALDH expression in allergy conjunctiva was investigated via immunohistochemistry. ALDH activity of CD11b bone marrow derived DCs (BMDCs) was measured with ALDEFLOUR kit. CD11b BMDCs treated with ALDH inhibitor, DEAB, were co-cultured with T cells from spleens of allergen-immunized C57BL/6 mice (i.e. 14 days after intraperitoneal immunization with ovalbumin in aluminium hydroxide and pertussis toxin). T cells were analysed for CFSE proliferation and Th1, Th2, Th17 frequencies by FACS. Fibroblasts explanted from conjunctiva of ocular allergy-induced (i.e. immunized and topical ovalbumin challenged) versus normal C57BL/6 mice were assessed for collagen secretion and proliferation via Sircol and CyQuant assays respectively.
There is enhanced ALDH expression in conjunctivae and DCs of ocular allergy-induced mice. In vitro stimulation of BMDCs by LPS (2ng/ml) or histamine (10-5M) increased ALDH activity. Interestingly, inhibition of DC derived ALDH decreased T cell proliferation—mainly in IL-13 producing CD4+ T cells (3.5 fold lower proliferation, p<0.05) and not IL-17 and IFN-γ producing T cells. Fibroblasts from ocular allergy-induced mice showed pro-fibrotic levels of collagen production (1.75 fold higher than normal fibroblasts, p<0.05) and proliferation. Strikingly, ALDH inhibition reversed these levels back to those seen in fibroblasts from normal conjunctivae.
Allergic provocation of DCs increases their ALDH activity, which appears to be important in activating Th2 responses relevant in a mouse model of severe ocular allergy. Interestingly, ALDH activity also has a profound pro-fibrotic effect on conjunctival fibroblasts, and thus establishes a possible pathobiological link for DCs in fibrosis. Ultimately this is a novel pro-fibrotic mechanism that may be contributing to scarring in severe ocular allergy patients.
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