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

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.

journal_name

Clin Exp Immunol

journal_title

Clinical and experimental immunology

authors

Brown BR,Lee EJ,Snow PE,Vance EE,Iwakura Y,Ohno N,Miura N,Lin X,Brown GD,Wells CA,Smith JR,Caspi RR,Rosenzweig HL

doi

10.1111/cei.13021

subject

Has Abstract

pub_date

2017-12-01 00:00:00

pages

293-303

issue

eissn

0009-9104

issn

1365-2249

journal_volume

190

pub_type

杂志文章

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