Fungal‐derived cues promote ocular autoimmunity through a Dectin‐2/Card9‐mediated mechanism

• Published in: Clinical and experimental immunology Vol. 190; no. 3; pp. 293 - 303
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.12.2017; John Wiley and Sons Inc
• Subjects: Animals; Antigens; Autoimmune Diseases - chemically induced; Autoimmune Diseases - immunology; Autoimmune Diseases - pathology; Autoimmunity; Candida albicans - immunology; Candidiasis - chemically induced; Candidiasis - immunology; Candidiasis - pathology; CARD Signaling Adaptor Proteins - genetics; CARD Signaling Adaptor Proteins - immunology; CD4 antigen; Cues; Experimental autoimmune uveitis; Experimental autoimmune uveoretinitis; Eye; Eye Proteins - toxicity; Freund's adjuvant; Fungi; Helper cells; Immunization; Immunological tolerance; inflammation; Interphotoreceptor retinoid-binding protein; Lectins, C-Type - genetics; Lectins, C-Type - immunology; Lymphocytes; Lymphocytes T; Mannan; Mice; Mice, Mutant Strains; Original; Retinol-Binding Proteins - toxicity; rodent; Saccharomyces cerevisiae - immunology; Signal transduction; Th17 Cells - immunology; Th17 Cells - pathology; Uveitis; Uveitis - chemically induced; Uveitis - genetics; Uveitis - immunology; Uveitis - pathology; eye; autoimmunity; uveitis; inflammation; rodent
• ISSN: 0009-9104; 1365-2249
• DOI: 10.1111/cei.13021

Summary Uveitis (intraocular inflammation) is a leading cause of loss of vision. Although its aetiology 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, interphotoreceptor retinoid binding protein (IRBP), in combination with mycobacteria‐containing complete Freund's adjuvant (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 T helper type 17 (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 Candida albicans or Saccharomyces cerevisae to promote IRBP‐triggered EAU was mediated by Card9. Because Card9 is an essential signalling molecule of a subgroup of C‐type lectin receptors (CLRs) important in host defence, we evaluated further 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 reproduced the uveitic phenotype of EAU sufficiently, in a process mediated by the Card9‐coupled signalling axis and interleukin (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. Intra‐ocular autoimmune disease (termed uveitis) presents a considerable medical challenge; yet the underlying mechanisms that mediate the eye's susceptibility to disease remain poorly understood. Even less is understood of the innate receptor pathways that are responsible for orchestration of T cell‐mediated autoimmunity targeted to the eye. This report reveals the inductive potential of fungal‐derived cues in autoimmunity with Dectin‐2/Card9‐mediated signaling axis as a mechanism.