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

B R Brown, E J Lee, P E Snow, E E Vance, Y Iwakura, N Ohno, N Miura, X Lin, G D Brown, C A Wells, J R Smith, R R Caspi, H L Rosenzweig (Corresponding Author)

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Abstract

Uveitis (intraocular inflammation) is a leading cause of vision loss. Although its etiology 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, interphotoceptor retinoid binding protein (IRBP), in combination with mycobacteria-containing 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 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 C. albicans or S. cerevisae to promote IRBP-triggered EAU was mediated by Card9. Since Card9 is an essential signaling molecule of a subgroup of C-type lectin receptors (CLRs) important in host defense, we further evaluated 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 sufficiently reproduced the uveitic phenotype of EAU, in a process mediated by the Card9- coupled signaling axis and 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
Pages (from-to)293-303
Number of pages11
JournalClinical and Experimental Immunology
Volume190
Issue number3
Early online date30 Aug 2017
DOIs
Publication statusPublished - Dec 2017

Fingerprint

Uveitis
Autoimmunity
Cues
C-Type Lectins
Retinol-Binding Proteins
T-Lymphocytes
Fungal Antigens
Posterior Uveitis
Mannans
Th17 Cells
Immune Tolerance
Interleukin-17
mouse dectin-2
Mycobacterium
T-Cell Antigen Receptor
Immunization
Fungi
Inflammation
Phenotype
Antigens

Keywords

  • Rodent
  • Autoimmunity
  • Eye
  • Uveitis
  • Inflammation

Cite this

Brown, B. R., Lee, E. J., Snow, P. E., Vance, E. E., Iwakura, Y., Ohno, N., ... Rosenzweig, H. L. (2017). Fungal-derived cues promote ocular autoimmunity through a Dectin-2/Card9-mediated mechanism. Clinical and Experimental Immunology, 190(3), 293-303. https://doi.org/10.1111/cei.13021

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

In: Clinical and Experimental Immunology, Vol. 190, No. 3, 12.2017, p. 293-303.

Research output: Contribution to journalArticle

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 2017, 'Fungal-derived cues promote ocular autoimmunity through a Dectin-2/Card9-mediated mechanism', Clinical and Experimental Immunology, vol. 190, no. 3, pp. 293-303. https://doi.org/10.1111/cei.13021
Brown, B R ; Lee, E J ; Snow, P E ; Vance, E E ; Iwakura, Y ; Ohno, N ; Miura, N ; Lin, X ; Brown, G D ; Wells, C A ; Smith, J R ; Caspi, R R ; Rosenzweig, H L. / Fungal-derived cues promote ocular autoimmunity through a Dectin-2/Card9-mediated mechanism. In: Clinical and Experimental Immunology. 2017 ; Vol. 190, No. 3. pp. 293-303.
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abstract = "Uveitis (intraocular inflammation) is a leading cause of vision loss. Although its etiology 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, interphotoceptor retinoid binding protein (IRBP), in combination with mycobacteria-containing 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 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 C. albicans or S. cerevisae to promote IRBP-triggered EAU was mediated by Card9. Since Card9 is an essential signaling molecule of a subgroup of C-type lectin receptors (CLRs) important in host defense, we further evaluated 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 sufficiently reproduced the uveitic phenotype of EAU, in a process mediated by the Card9- coupled signaling axis and 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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N2 - Uveitis (intraocular inflammation) is a leading cause of vision loss. Although its etiology 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, interphotoceptor retinoid binding protein (IRBP), in combination with mycobacteria-containing 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 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 C. albicans or S. cerevisae to promote IRBP-triggered EAU was mediated by Card9. Since Card9 is an essential signaling molecule of a subgroup of C-type lectin receptors (CLRs) important in host defense, we further evaluated 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 sufficiently reproduced the uveitic phenotype of EAU, in a process mediated by the Card9- coupled signaling axis and 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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