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- W4313385688 abstract "Abstract Studies of genetic factors associated with human autoimmunity suggest a multigenic origin of autoimmune susceptibility. To address how defects in different immune tolerance pathways cooperate to result in disease, we investigated whether genetic alterations in two such pathways might synergize to produce autoimmunity in mice. The intracellular protein tyrosine kinase Lyn is critical for inhibitory receptor function in innate immune cells and B cells. Lyn-deficient mice develop systemic but not organ-specific autoimmunity. In contrast, Autoimmune Regulator (Aire) promotes expression of tissue-specific antigens by thymic epithelial cells and T-cell negative selection. Aire-deficient mice develop multiorgan autoimmunity, including autoimmune uveitis, due to lack of thymic expression of the retina-specific interphotoreceptor retinoid binding protein (IRBP). AireGW/+ knockin mice express a dominant negative allele of Aire, have low but detectable thymic expression of IRBP and do not develop uveitis. To determine whether lack of Lyn inhibitory pathways could cooperate with a partial defect in T cell central tolerance, we generated AireGW/+ Lyn−/− double mutants. Remarkably, over 50% of these mice developed severe uveitis that was accompanied by a rise in anti-IRBP antibodies and an expansion of IRBP-specific CD4 T cells. To determine the contribution of different Lyn-expressing cell subsets to uveitis, we crossed AireGW/+ mice to a panel of Cre lines with an inducible Lyn knockout allele. Deletion of Lyn selectively in dendritic cells (DCs) was sufficient to drive disease, suggesting that Lyn-deficient DCs may have increased ability to prime IRBP-specific T cells that have escaped negative selection in the AireGW/+ thymus." @default.
- W4313385688 created "2023-01-06" @default.
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- W4313385688 date "2016-05-01" @default.
- W4313385688 modified "2023-09-26" @default.
- W4313385688 title "Triggering of organ-specific autoimmunity through synergy of defects in key tolerance checkpoints" @default.
- W4313385688 doi "https://doi.org/10.4049/jimmunol.196.supp.117.1" @default.
- W4313385688 hasPublicationYear "2016" @default.
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