Uveitis (intraocular inflammation) is a leading cause of vision loss. Although its etiology is largely speculative, it is thought to arise from complex genetic-environmental interactions that break immune tolerance to generate eye-specific autoreactive T cells. Experimental autoimmune uveitis (EAU), induced by immunization with the ocular antigen, interphotoceptor retinoid binding protein (IRBP), in combination with mycobacteria-containing CFA, has many clinical and histopathological features of human posterior uveitis. Studies in EAU have focused on defining pathogenic CD4+ T cell effector responses, such as those of Th17 cells, but the innate receptor pathways precipitating development of autoreactive, eye-specific T cells remain poorly defined. In this study, we found that fungal-derived antigens possess autoimmune uveitis-promoting function akin to CFA in conventional EAU. The capacity of commensal fungi such as C. albicans or S. cerevisae to promote IRBP-triggered EAU was mediated by Card9. Since Card9 is an essential signaling molecule of a subgroup of C-type lectin receptors (CLRs) important in host defense, we further evaluated the proximal Card9-activating CLRs. Using single receptor-deficient mice, we identified Dectin-2, but not Mincle or Dectin-1, as a predominant mediator of fungal-promoted uveitis. Conversely, Dectin-2 activation by α-mannan sufficiently reproduced the uveitic phenotype of EAU, in a process mediated by the Card9- coupled signaling axis and IL-17 production. Taken together, this report relates the potential of the Dectin-2/Card9-coupled pathway in ocular autoimmunity. Not only does it contribute to understanding of how innate immune receptors orchestrate T cell-mediated autoimmunity, it also reveals a previously unappreciated ability of fungal-derived signals to promote autoimmunity.
Brown, B. R., Lee, E. J., Snow, P. E., Vance, E. E., Iwakura, Y., Ohno, N., Miura, N., Lin, X., Brown, G. D., Wells, C. A., Smith, J. R., Caspi, R. R., & Rosenzweig, H. L. (2017). Fungal-derived cues promote ocular autoimmunity through a Dectin-2/Card9-mediated mechanism. Clinical and Experimental Immunology, 190(3), 293-303. https://doi.org/10.1111/cei.13021