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

B. R. Brown, Ellen Lee, P. E. Snow, E. E. Vance, Y. Iwakura, N. Ohno, N. Miura, Xin Lin, G. D. Brown, C. A. Wells, J. R. Smith, R. R. Caspi, Holly Rosenzweig

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
JournalClinical and Experimental Immunology
DOIs
StateAccepted/In press - 2017

Fingerprint

Uveitis
Autoimmunity
Cues
C-Type Lectins
Freund's Adjuvant
T-Lymphocytes
Fungal Antigens
Posterior Uveitis
Mannans
Th17 Cells
Immune Tolerance
Saccharomyces
Interleukin-17
mouse dectin-2
Mycobacterium
T-Cell Antigen Receptor
Candida albicans
Immunization
Fungi
Inflammation

Keywords

  • Autoimmunity
  • Eye
  • Inflammation
  • Rodent
  • Uveitis

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Fungal-derived cues promote ocular autoimmunity through a Dectin-2/Card9-mediated mechanism. / Brown, B. R.; Lee, Ellen; Snow, P. E.; Vance, E. E.; Iwakura, Y.; Ohno, N.; Miura, N.; Lin, Xin; Brown, G. D.; Wells, C. A.; Smith, J. R.; Caspi, R. R.; Rosenzweig, Holly.

In: Clinical and Experimental Immunology, 2017.

Research output: Contribution to journalArticle

Brown, BR, Lee, E, Snow, PE, Vance, EE, Iwakura, Y, Ohno, N, Miura, N, Lin, X, Brown, GD, Wells, CA, Smith, JR, Caspi, RR & Rosenzweig, H 2017, 'Fungal-derived cues promote ocular autoimmunity through a Dectin-2/Card9-mediated mechanism', Clinical and Experimental Immunology. https://doi.org/10.1111/cei.13021
Brown, B. R. ; Lee, Ellen ; Snow, P. E. ; Vance, E. E. ; Iwakura, Y. ; Ohno, N. ; Miura, N. ; Lin, Xin ; Brown, G. D. ; Wells, C. A. ; Smith, J. R. ; Caspi, R. R. ; Rosenzweig, Holly. / Fungal-derived cues promote ocular autoimmunity through a Dectin-2/Card9-mediated mechanism. In: Clinical and Experimental Immunology. 2017.
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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.",
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