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Brieanna Brown, Ellen J Lee, Paige Snow, Emily Vance, Rachel R Caspi, Holly Lallman Rosenzweig; Fungal components trigger induction of EAU through a Card9-dependent mechanism. Invest. Ophthalmol. Vis. Sci. 2016;57(12):502.
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© ARVO (1962-2015); The Authors (2016-present)
The signals that initiate autoreactive T cells to target the eye, which may be of infectious or non-infectious origin, are poorly understood. Our recent work identified Card9, a signaling molecule essential in defense against fungi, as an important determinant in susceptibility to uveitis. Here, we further investigated the ability of fungal triggers, which are commonly encountered in our environment, to induce uveitis and the role of Card9 in pathogenesis of experimental autoimmune uveitis (EAU).
EAU was induced in wild-type mice (WT, C57BL/6J strain) by immunization with interphotoreceptor retinoid-binding protein (IRBP) and the adjuvant CFA. Uveitis was evaluated with fundus imaging and histology. Adjuvant replacement studies were performed in which CFA was replaced with various mycobacterial cell wall components including trehalose-6,6-dibehenate (TDB, synthetic analog of mycobacterial cord factor), peptidoglycan (PGN), and muramyl dipeptide (MDP), or with heat-killed Candida albicans (HKCA) or its components curdlan, zymosan, or α-mannan. Negative controls using incomplete Freund’s adjuvant (IFA) were also included. To assess the contribution of Card9 in HKCA-induced EAU, uveitis was evaluated in mice sufficient or deficient in Card9.
EAU induced by whole HKCA resulted in robust uveitis that was comparable in severity and onset to EAU induced using CFA (n=10 mice/group). Subsequent adjuvant replacement studies with the fungal cell wall components curdlan, zymosan or α-mannan reproduced the phenotype of EAU with HKCA, while those with mycobacterial components (PGN and MDP) did not (n=8 mice/group). TDB however, did induce the full EAU phenotype and this was dependent on Card9. We found that HKCA-induced EAU was also significantly abrogated by Card9-deficiency (p<0.05; n=10 mice/group) as determined by both fundus imaging and histology.
These experiments serve as a proof-of-principle study to demonstrate the importance of the Card9-signaling pathway in orchestration of autoimmunity targeted to the eye, which can be initiated by either mycobacterial TDB or fungal triggers. Additional studies to elucidate the upstream innate immune receptors that respond to fungal triggers and that activate Card9 (e.g. C-type lectin receptors Dectin-1, Dectin-2, Mincle) are necessary to fully understand the role of fungal triggers in EAU.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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