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- W2523979844 abstract "Author(s): Proekt, Irina | Advisor(s): DeFranco, Anthony L | Abstract: Studies of genetic factors associated with human autoimmune disease suggest a multigenic origin of susceptibility, however, how these factors interact and through which tolerance pathways they operate generally remain to be defined. One key checkpoint occurs through the activity of the Aire gene which promotes central T cell tolerance. Recently, a variety of dominant-negative human AIRE mutations have been described which likely contribute to human autoimmunity more so than previously thought. The penetrance of autoimmunity is incomplete in these families suggesting that other checkpoints are playing a role in preventing autoimmunity. In Chapter two of this thesis, I describe studies testing if a defect in Lyn, an inhibitory protein tyrosine kinase implicated in systemic autoimmunity, could combine with an Aire mutation to provoke organ-specific autoimmunity. Indeed, mice with a dominant-negative allele of Aire and deficiency in Lyn spontaneously developed organ-specific autoimmunity in the eye. I further show that a small pool of retinal protein-specific T cells escaped thymic deletion due to the hypomorphic Aire function and escaped peripheral tolerance in the presence of Lyn-deficient dendritic cells, leading to highly destructive autoimmune attack. These findings demonstrate how two distinct tolerance pathways can synergize to unleash autoimmunity and have implications for the determinism of autoimmune disease." @default.
- W2523979844 created "2016-10-07" @default.
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- W2523979844 date "2015-01-01" @default.
- W2523979844 modified "2023-09-27" @default.
- W2523979844 title "Organ-specific autoimmunity resulting from combined defects in two tolerance checkpoints" @default.
- W2523979844 hasPublicationYear "2015" @default.
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