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Ellen Lee, Joao Furtado, Brieanna Brown, Emily Vance, John Paul Sacdal, Varunika Bhargava, Justine Smith, Phyllis Silver, Rachel Caspi, Holly Rosenzweig; An unexpected role for the innate immune receptor NOD2 in suppression of experimental autoimmune uveitis. Invest. Ophthalmol. Vis. Sci. 2013;54(15):2523.
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© ARVO (1962-2015); The Authors (2016-present)
A recently identified gene NOD2 is genetically associated with Blau syndrome, a granulomatous uveitis that is accompanied by arthritis and dermatitis. NOD2 belongs to a family of innate immune receptors that normally function in host defense against microbial pathogens. Here, we sought to explore the role for NOD2 in an adaptive, T cell-dependent model of intraocular inflammation, experimental autoimmune uveitis (EAU).
The contribution of NOD2 was investigated using Nod2 knockout (KO) mice and C57BL/6J congenic wild-type (WT) controls, immunized for EAU with interphotoreceptor retinoid-binding protein (IRBP). Disease was followed clinically by topical endoscopic fundus imaging (TEFI) on d14 and d21 post-immunization and confirmed by histopathology (d21). IRBP-specific cytokine production by splenocytes was measured by ELISA. To determine the cellular compartment associated with uveitis susceptibility in the Nod2 KO animals, bone marrow (BM) chimeras of WT and Nod2 KO mice were subjected to EAU induction.
IRBP-immunized Nod2 KO mice developed significantly more severe EAU than their WT controls (p<0.01, n=13-14 mice/group). TEFI revealed NOD2-associated retinal damage in IRBP-immunized mice that was manifest by severe papillary and peripapillary inflammation, extensive retinal vascular cuffing, and florid retinitis. Eyes of mice injected with adjuvant alone (Nod2 KO and WT) mice did not exhibit any signs of inflammation. Histology in Nod2 KO mice revealed marked increase in severity of uveitis (p<0.01 vs. WT, n=13-14 mice/group) characterized by increased retinal hemorrhages, folding, detachment, and structural damage that were accompanied by perivascular, optic disc, and vitreous infiltration. Notably, granulomatous inflammation was a predominant immunopathological feature of Nod2 KO mice. Interestingly, although IL-17A rather than IFN-γ was shown to be critical for IRBP-EAU development, the deleterious effects of NOD2 deficiency were associated with augmented IRBP-specific T cell production of IFN-γ and diminished IL-17A production. BM chimera studies suggested that NOD2 expression in the hematopoietic compartment predominately contributed to inflammation protection.
These data reveal an unexpected and critical role for NOD2 in the hematopoietic cell compartment to dampen uveitogenic T cell responses.
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