The AIRE -230Y Polymorphism Affects AIRE Transcriptional Activity: Potential Influence on AIRE Function in the Thymus

Area of Science:

• Immunology
• Genetics

Background:

• The autoimmune regulator (AIRE) protein is crucial for T-cell development in the thymus.
• AIRE facilitates negative selection of self-reactive T-cells by enabling the expression of peripheral tissue antigens in medullary epithelial cells.
• AIRE activity variations can influence the expression profile of these antigens.

Purpose of the Study:

• To investigate the impact of single nucleotide polymorphisms (SNPs) in the AIRE promoter on its transcriptional activity.
• To identify specific AIRE promoter variants and their functional consequences.

Main Methods:

• Screening of the AIRE promoter region for SNPs, identifying rs117557896 (-655R) and rs751032 (-230Y).
• Generation of a stable cell line for reporter gene assays to measure promoter activity.
• Luciferase assays were performed on constructs with different AIRE promoter haplotypes (AIRE-655G AIRE-230C, AIRE-655G AIRE-230T, AIRE-655A AIRE-230C).
• CpG methylation analysis of polymorphic sites.

Main Results:

• The common haplotype AIRE-655G AIRE-230C exhibited the highest promoter activity (p<0.001).
• The AIRE-655G AIRE-230T haplotype showed near-null promoter activity.
• Both polymorphic sites contain alleles capable of CpG methylation.

Conclusions:

• The AIRE-230Y SNP is in a conserved promoter region near a WT1 transcription factor binding site, suggesting it may affect factor binding and AIRE expression.
• The AIRE-655G AIRE-230T haplotype can significantly alter AIRE transcription.
• These alterations may impact T-cell negative selection and susceptibility to autoimmune diseases.