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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.

Author information

1
VA Portland Health Care System, Portland, OR, USA.
2
School of Medicine, Oregon Health and Science University, Portland, OR, USA.
3
Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, OR, USA.
4
Research Institute for Biomedical Sciences, Tokyo University of Science, Tokyo, Japan.
5
Tokyo University of Pharmacy and Life Science, Tokyo, Japan.
6
Department of Molecular and Cellular Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
7
Aberdeen Fungal Group, MRC Centre for Medical Mycology, Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK.
8
The University of Melbourne Centre for Stem Cell Systems, University of Melbourne, Parkville, Victoria, Australia.
9
Eye and Vision Health, Flinders University School of Medicine, Adelaide, Australia.
10
Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD, USA.

Abstract

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.

KEYWORDS:

autoimmunity; eye; inflammation; rodent; uveitis

PMID:
28763100
PMCID:
PMC5680064
[Available on 2018-12-01]
DOI:
10.1111/cei.13021
[Indexed for MEDLINE]

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