Abstract
Abstract The ocular surface has an associated microbiome that contributes to maintenance of local immune homeostasis and protects the ocular surface from fungal and bacterial infections. However, in individuals with a dysregulated immune response, commensal flora could cause pathology. In this study, we seek to understand how an ocular commensal colonizing humans and mice, C. mastitidis (C. mast), stimulates immunity in the immunologically perturbed host. Cryopyrin Associated Periodic Syndrome (CAPS) patients suffer from systemic and ocular autoinflammatory disease caused by a hyperactive NLRP3 inflammasome. Knock-in mice bearing a mutated NLRP3 gene cloned from a CAPS patient responded to ocular colonization with C. mast by increased conjunctival neutrophilia, which progressed to overt ocular surface disease. Compared to wild type (WT) controls, their BM dendritic cells produced elevated IL-1 in response to C. mast. Additionally, gd T cells, which were primarily the Vg4 subset, isolated from eye-draining lymph nodes of C. mast-associated mutant mice were more activated and produced more IL-17, suggesting a qualitatively analogous but quantitatively amplified response compared to WT. Importantly, the same commensal elicited strongly elevated IL-17 production from leukocytes of inflammasome disease patients when compared with healthy controls. Our results suggest that C. mast induces an abnormal immune response in the NLRP3 mutant and acts as a pathobiont, in contrast to its behavior in the immunologically normal host. Based on these data, we hypothesize that the recurrent non-infectious conjunctivitis observed in CAPS patients may be driven by a hyperactive immune response to their own ocular surface bacteria.
Published Version
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call