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

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

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.

MeSH terms

  • Animals
  • Autoimmune Diseases / chemically induced
  • Autoimmune Diseases / immunology*
  • Autoimmune Diseases / pathology
  • CARD Signaling Adaptor Proteins / genetics
  • CARD Signaling Adaptor Proteins / immunology*
  • Candida albicans / immunology*
  • Candidiasis / chemically induced
  • Candidiasis / immunology*
  • Candidiasis / pathology
  • Eye Proteins / toxicity
  • Lectins, C-Type / genetics
  • Lectins, C-Type / immunology*
  • Mice
  • Mice, Mutant Strains
  • Retinol-Binding Proteins / toxicity
  • Saccharomyces cerevisiae / immunology*
  • Th17 Cells / immunology
  • Th17 Cells / pathology
  • Uveitis / chemically induced
  • Uveitis / genetics
  • Uveitis / immunology*
  • Uveitis / pathology

Substances

  • CARD Signaling Adaptor Proteins
  • Card9 protein, mouse
  • Eye Proteins
  • Lectins, C-Type
  • Retinol-Binding Proteins
  • dectin-2, mouse
  • interstitial retinol-binding protein