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LYN- and AIRE-mediated tolerance checkpoint defects synergize to trigger organ-specific autoimmunity
Irina Proekt, … , Mark S. Anderson, Anthony L. DeFranco
Irina Proekt, … , Mark S. Anderson, Anthony L. DeFranco
Published August 29, 2016
Citation Information: J Clin Invest. 2016;126(10):3758-3771. https://doi.org/10.1172/JCI84440.
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Research Article Autoimmunity

LYN- and AIRE-mediated tolerance checkpoint defects synergize to trigger organ-specific autoimmunity

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Abstract

Studies of the 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 autoimmune regulator AIRE, which promotes central T cell tolerance. Recent reports have described a variety of dominant-negative AIRE mutations that likely contribute to human autoimmunity to a greater extent than previously thought. In families with these mutations, the penetrance of autoimmunity is incomplete, suggesting that other checkpoints play a role in preventing autoimmunity. Here, we tested whether a defect in LYN, an inhibitory protein tyrosine kinase that is 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. We further determined that a small pool of retinal protein–specific T cells escaped thymic deletion as a result of the hypomorphic Aire function and that these cells also escaped peripheral tolerance in the presence of LYN-deficient dendritic cells, leading to highly destructive autoimmune attack. These findings demonstrate how 2 distinct tolerance pathways can synergize to unleash autoimmunity and have implications for the genetic susceptibility of autoimmune disease.

Authors

Irina Proekt, Corey N. Miller, Marion Jeanne, Kayla J. Fasano, James J. Moon, Clifford A. Lowell, Douglas B. Gould, Mark S. Anderson, Anthony L. DeFranco

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Figure 2

Presence of anti-IRBP antibodies and IRBP-reactive T cells in AireGW/+ Lyn–/– mice with uveitis.

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Presence of anti-IRBP antibodies and IRBP-reactive T cells in AireGW/+ L...
(A) The sera of 2- to 6-month-old AireGW/+ Lyn–/– mice with (n = 14) and without (n = 9) uveitis, or of WT (n = 8), AireGW/+ (n = 36), or Lyn–/– (n = 31) mice, were analyzed for the presence of anti-IRBP antibodies with a radioligand binding assay and normalized to a commercially available anti-IRBP antibody to determine autoantibody index (AI). Each dot represents an individual mouse, and the horizontal lines show mean ± SD. The dashed line represents the limit of detection, calculated as an average of AI values for all WT samples plus 3 SDs. (B) Representative flow cytometric analysis of IRBP P2 tetramer–binding CD4 T cells in pooled spleen and cervical lymph nodes (top) and funduscopy (bottom) from 2- to 5-month-old AireGW/+ Lyn–/– mice with and without uveitis. Plots were pregated for CD4+ T cells as described in Methods. The calculated total number of tetramer-positive cells in the whole sample is shown on the plot. (C) Numbers of P2-specific CD3+ CD4 T cells gated as in B from individual AireGW/+ Lyn–/– mice with and without uveitis, and from WT and single-mutant control mice. Each dot represents an individual mouse, and the horizontal lines show mean ± SD. The dashed line represents the limit of detection, calculated as average number of P2-binding CD3+CD8+ T cells plus 3 SDs. Data are pooled from 3 to 5 independent experiments. ***P < 0.001, 1-way ANOVA.

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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