A partial form of AIRE deficiency underlies a mild form of autoimmune polyendocrine syndrome type 1
Bergithe Eikeland Oftedal, … , Jakub Abramson, Eystein Sverre Husebye
Bergithe Eikeland Oftedal, … , Jakub Abramson, Eystein Sverre Husebye
Published November 1, 2023
Citation Information: J Clin Invest. 2023;133(21):e169704. https://doi.org/10.1172/JCI169704.
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Research Article Autoimmunity Endocrinology

A partial form of AIRE deficiency underlies a mild form of autoimmune polyendocrine syndrome type 1

Abstract

Autoimmune polyendocrine syndrome type 1 (APS-1) is caused by mutations in the autoimmune regulator (AIRE) gene. Most patients present with severe chronic mucocutaneous candidiasis and organ-specific autoimmunity from early childhood, but the clinical picture is highly variable. AIRE is crucial for negative selection of T cells, and scrutiny of different patient mutations has previously highlighted many of its molecular mechanisms. In patients with a milder adult-onset phenotype sharing a mutation in the canonical donor splice site of intron 7 (c.879+1G>A), both the predicted altered splicing pattern with loss of exon 7 (AireEx7–/–) and normal full-length AIRE mRNA were found, indicating leaky rather than abolished mRNA splicing. Analysis of a corresponding mouse model demonstrated that the AireEx7–/– mutant had dramatically impaired transcriptional capacity of tissue-specific antigens in medullary thymic epithelial cells but still retained some ability to induce gene expression compared with the complete loss-of-function AireC313X–/– mutant. Our data illustrate an association between AIRE activity and the severity of autoimmune disease, with implications for more common autoimmune diseases associated with AIRE variants, such as primary adrenal insufficiency, pernicious anemia, type 1 diabetes, and rheumatoid arthritis.

Authors

Bergithe Eikeland Oftedal, Amund Holte Berger, Øyvind Bruserud, Yael Goldfarb, Andre Sulen, Lars Breivik, Alexander Hellesen, Shifra Ben-Dor, Rebecca Haffner-Krausz, Per M. Knappskog, Stefan Johansson, Anette S.B. Wolff, Eirik Bratland, Jakub Abramson, Eystein Sverre Husebye

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Figure 3

The AIRE splice mutation c.879+1G>A has less of an effect on T cells.

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The AIRE splice mutation c.879+1G>A has less of an effect on T cells....
(A) Thymic Tregs were found to be reduced in AireC313X–/– and AireEx7–/– mice compared with Aire+/+ mice. (B) Recirculating Tregs were reduced in the thymic compartment only in AireC313X–/– mice. (C) For SPCD4 T cell development, the effect of AIRE loss was greater in AireC313X–/– mice than in AireEx7–/– mice, with a decrease in cells destined for apoptosis, (D) as determined by cleaved caspase 3 expression. (E) In the spleen, no differences were found within the Treg (CD4+FoxP3+CD25+) compartment. (F) Anergic T cells in the spleen, as determined by CD73 and FR3 expression in CD4+FoxP3–CD44+ cells, were increased in the AireC313X–/– mice. Error bars in A–F represent SD in 1 of 3 individual experiments (n = 3–6 mice in each group). *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001, and ****P ≤ 0.0001, by 1-way ANOVA with multiple comparisons between AireC313X–/– and AireEx7–/– versus Aire+/+.