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Kumarkrishna Raychaudhuri, Anthony St. Leger, Fatimah Almaghrabi, Ivan J Fuss, Warren Strober, Rachel R Caspi; An aberrant immune response to an ocular commensal results in disease in a mouse model of Muckle-Wells Syndrome. Invest. Ophthalmol. Vis. Sci. 2018;59(9):720. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Recent data suggest that Corynebacterium mastitidis (=C. mast), an ocular commensal, elicits production of protective IL-17 from conjunctival T cells (PMID: 28709803). Muckle-Wells Syndrome (MWS) is a human autoinflammatory disease that results in spontaneous arthritis, dermatitis and conjunctivitis. Pathology is at least in part attributable to an overactive NLRP3 inflammasome that leads to production of multiple proinflammatory cytokines, including, most prominently, IL-1, due to a gain of function mutation in the NLRP3 gene (CIAS1). We hypothesized that an aberrant immune response to commensal microbes at the ocular surface may underlie the conjunctivitis that is characteristic of MWS
We used a mouse model of MWS, produced by a knock (KI) of the human mutated CIAS1 gene. The mice, initially negative for C. mast, were ocularly colonized with the bacterium. In vivo and in vitro responses to the commensal were assessed by changes in transcriptome, production of IL-1, neutrophil infiltration and clinical appearance
Ocular colonization with the commensal C. mast, induced conjunctival inflammation in MWS mice, but not in WT controls. This correlated with increased neutrophil infiltration observed in the conjunctiva of CIAS KI mice compared to WT. DCs from MWS mice produced increased amounts of IL-1b upon stimulation with C. mast lysates. DCs harvested from MWS mice more efficiently activated gd T cells (in particular, Vγ4+ cells) in co-culture experiments, compared to DCs from WT mice. Interestingly, our data suggest a BMDC independent role of inflammasome component in the gd T cells. We found that gd T cells isolated from CIAS KI mice showed increased caspase-1 activity compared to WT counterparts. We are currently investigating if C. mast can regulate the inflammasome function in gd T cells
Our results suggest that the commensal C. mast can act as a pathobiont to trigger ocular inflammation in mice with an overactive NLRP3 inflammasome. We suggest that an aberrant immune response to commensal microbes in humans with this mutation may underlie the recurrent conjunctivitis seen in patients with MWS or similar autoinflammatory diseases
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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