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

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.

Lessons from primary immunodeficiencies: Autoimmune regulator and autoimmune polyendocrinopathy‐candidiasis‐ectodermal dystrophy

“…Aire and the inhibitory protein tyrosine kinase Lyn, which developed autoimmune uveitis, underscoring the cooperation between central and peripheral tolerance checkpoints in the organ-specific phenotypic expression of autoimmune disease 129. Similarly, mice with deficiency in both Aire and the T cell peripheral tolerance checkpoint Cbl-b (Casitas B-lineage lymphoma), which modulates CD28 co-stimulation, developed lethal exocrine pancreatic autoimmune disease 130.…”

Commensal microbiota as a potential trigger of autoimmune uveitis

“…Using a short-term course of the same antibiotic mix, disease in the immunization-induced model was temporarily ameliorated, which the authors felt could be attributed at least in part by emergence of T regulatory cells in the intestine of antibiotic-treated mice, possibly as a result of the altered microflora. In contrast, broad-spectrum antibiotics did not affect progression of spontaneous uveitis in a recent report using the model of combined mutations in hypomorphic AIRE function and LYN deficiency [15]. The length of antibiotic treatment that was used in different studies (weeks vs. months) and/or the specific microbial environments in various facilities may underlie these differences.…”

Microbiome and Autoimmune Uveitis

“…More recently, Proekt et al (15) reported that a dominant-negative AIRE allele (G228W point mutation), with only partial penetrance, resulted in high incidence of uveitis when combined with LYN-deficiency (which by itself leads to a lupus-like disease). The findings support the notion of multiple gene defects combining for an overtly autoimmune phenotype.…”