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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 4

AireGW/+ Lyn-DC–/– mice develop uveitis that is accompanied by an anti-IRBP immune response.

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AireGW/+ Lyn-DC–/– mice develop uveitis that is accompanied by an anti-...
(A) Representative funduscopic images of 3- to 6-month-old mice of indicated genotypes showing retinal disease in a subset of the AireGW/+ Lyn-DC–/– mice. (B) Time course of funduscopic changes in an AireGW/+ Lyn-DC–/– mouse with uveitis (representative of n = 3 mice with uveitis analyzed longitudinally). (C) Anti-IRBP antibody levels in the serum of 2- to 6-month-old AireGW/+ Lyn-DC–/– mice with (n = 5) and without uveitis (n = 7) were measured. Control mice analyzed consisted of Lynfl/fl (n = 8), AireGW/+ Lynfl/fl (n = 15), and Cd11c-Cre Lynfl/fl (n = 10). Each dot represents an individual mouse; the horizontal lines show mean ± SD; the dashed line represents the limit of detection. (D) Left set of panels: Plots of retinal cell populations from AireGW/+ Lyn-DC–/– mice with or without uveitis. Single-cell suspensions from retinas of individual mice were analyzed for CD45+TCRβ+ T cells (top) and P2 tetramer–specific CD4 T cells (bottom). Numbers shown indicate percentage of cells in gate. Right set of panels: Calculated total numbers of the indicated cells per retina. Each dot represents an individual mouse, and the horizontal lines show mean. The dashed line represents the limit of detection, calculated as in Figure 2. Data are representative of at least 3 independent experiments. (E) Confocal imaging of retinal sections of AireGW/+ Lyn-DC–/– mice with or without uveitis showing infiltration of TCRβ+ T cells (red) in mice with disease (original magnification, ×40; scale bars: 50 μm). Data are representative of 2 independent experiments.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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