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Fungal-derived cues promote ocular autoimmunity through a Dectin-2/Card9-mediated mechanism
- Source :
- Clinical and Experimental Immunology. 190:293-303
- Publication Year :
- 2017
- Publisher :
- Oxford University Press (OUP), 2017.
-
Abstract
- 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.
- Subjects :
- 0301 basic medicine
T cell
Immunology
Saccharomyces cerevisiae
Biology
medicine.disease_cause
Autoimmune Diseases
Immune tolerance
Autoimmunity
Uveitis
Mice
03 medical and health sciences
0302 clinical medicine
Antigen
Candida albicans
medicine
Animals
Immunology and Allergy
Lectins, C-Type
Eye Proteins
Receptor
Innate immune system
Effector
Candidiasis
Original Articles
medicine.disease
Mice, Mutant Strains
eye diseases
CARD Signaling Adaptor Proteins
Retinol-Binding Proteins
030104 developmental biology
medicine.anatomical_structure
Th17 Cells
030215 immunology
Subjects
Details
- ISSN :
- 13652249 and 00099104
- Volume :
- 190
- Database :
- OpenAIRE
- Journal :
- Clinical and Experimental Immunology
- Accession number :
- edsair.doi.dedup.....f418438c0caf981fd941f53f0fe27154