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Clin Exp Immunol. 2017 Dec;190(3):293-303. doi: 10.1111/cei.13021. Epub 2017 Aug 30.

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

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VA Portland Health Care System, Portland, OR, USA.
School of Medicine, Oregon Health and Science University, Portland, OR, USA.
Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, OR, USA.
Research Institute for Biomedical Sciences, Tokyo University of Science, Tokyo, Japan.
Tokyo University of Pharmacy and Life Science, Tokyo, Japan.
Department of Molecular and Cellular Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
Aberdeen Fungal Group, MRC Centre for Medical Mycology, Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK.
The University of Melbourne Centre for Stem Cell Systems, University of Melbourne, Parkville, Victoria, Australia.
Eye and Vision Health, Flinders University School of Medicine, Adelaide, Australia.
Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD, USA.


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.


autoimmunity; eye; inflammation; rodent; uveitis

[Available on 2018-12-01]
[Indexed for MEDLINE]

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