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 4

Differential gene expression in mTEChi populations of Aire mutants versus WT.

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Differential gene expression in mTEChi populations of Aire mutants versu...
(A) PCA plots showing transcriptomes of mTEChi from AireEx7–/–, AireC313X–/–, and Aire+/+ mice. (B) Volcano and hexbin plots of the differential expression results using DESeq2, looking at each mutant versus Aire+/+ or AireEx7–/– compared with AireC313X–/–. Significance is shown on the y axis as log10 (FDR) and relative expression as log2 FC on the x axis. Hexes are colored according to the number of genes between 1 and 1,000 found within the hex area. Blue lines denote log2 FC cutoffs at 1 and –1, and red lines denote the FDR cutoff at 0.05. (C) Venn diagram of the overlap of genes expressed at significantly lower levels in AireEx7–/– and AireC313X–/– mice versus Aire+/+ mice. (D) Venn diagram of genes expressed at significantly lower levels in each mutant versus Aire+/+ mice and significantly differentially expressed genes in AireEx7–/– versus AireC313X–/– mice. (E) Combination violin and dot plots of absolute expression in transcripts per million (TPM) of the 6 most significantly expressed genes in AireEx7–/– versus WT mice. (F) TPM of known Aire-regulated genes. (G) TPM of the 6 most significantly expressed genes among the 118 genes with significantly lower expression in AireC313X–/– versus Aire+/+ mice and with significantly differential expression in AireEx7–/– versus AireC313X –/– mice. (H) TPM of the 3 genes with significantly lower expression in AireEx7–/– compared with WT mice and with significantly differential expression in AireEx7–/– compared with AireC313X–/– mice. (I) Expression of Aire in the 3 groups. (E–I) Black bars denote the median TPM in mice in each population for each gene.