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

Area of Science:

• Immunology
• Ocular immunology
• Autoimmunity

Background:

• Uveitis, a leading cause of vision loss, stems from immune system dysregulation targeting the eye.
• Experimental autoimmune uveitis (EAU) models human posterior uveitis, but innate receptor pathways driving autoreactive T cells are unclear.
• Current research on EAU pathogenesis primarily focuses on CD4+ T cell responses, neglecting innate immune triggers.

Purpose of the Study:

• To investigate the role of fungal-derived antigens in promoting autoimmune uveitis.
• To identify the specific innate immune receptors and signaling pathways involved in fungal-mediated EAU.
• To elucidate the contribution of the Dectin-2/Card9 axis in ocular autoimmunity.

Main Methods:

• Induction of EAU using interphotoreceptor retinoid binding protein (IRBP) and fungal antigens (e.g., Candida albicans, Saccharomyces cerevisae) in wild-type and gene-deficient mice.
• Assessment of uveitis development and severity.
• Analysis of the involvement of C-type lectin receptors (CLRs), specifically Dectin-2, Mincle, and Dectin-1, using single receptor-deficient mouse models.
• Investigation of the Card9 signaling pathway and interleukin-17 (IL-17) production.

Main Results:

• Fungal antigens were found to promote EAU, similar to complete Freund's adjuvant (CFA).
• The fungal promotion of EAU was critically dependent on the Card9 signaling molecule.
• Dectin-2 was identified as the predominant C-type lectin receptor mediating fungal-induced uveitis, while Mincle and Dectin-1 were less involved.
• Activation of Dectin-2 by α-mannan alone was sufficient to induce the uveitic phenotype, mediated by the Card9 pathway and IL-17 production.

Conclusions:

• The Dectin-2/Card9 signaling pathway plays a significant role in initiating and perpetuating ocular autoimmunity.
• Fungal-derived signals can act as potent inducers of autoimmune uveitis, highlighting an underappreciated role for commensal fungi in disease pathogenesis.
• This study provides novel insights into how innate immune receptors orchestrate T cell-mediated autoimmunity in the eye.