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

Abstract

BackgroundThe autoimmune regulator (AIRE) is expressed in the thymus, particularly in thymic medullary epithelial cells (mTECs), and is required for the ectopic expression of a diverse range of peripheral tissue antigens by mTECs, facilitating their ability to perform negative selection of auto-reactive immature T-cells. The expression profile of peripheral tissue antigens is affected not only by AIRE deficiency but also with variation of AIRE activity in the thymus.Method and ResultsTherefore we screened 591bp upstream of the AIRE transcription start site including AIRE minimal promoter for single nucleotide polymorphism (SNPs) and identified two SNPs -655R (rs117557896) and -230Y (rs751032) respectively. To study the effect of these variations on AIRE promoter activity we generated a Flp-In host cell line which was stably transfected with a single copy of the reporter vector. Relative promoter activity was estimated by comparing the luciferase specific activity for lysates of the different reporter AIRE promoter-reporter gene constructs including AIRE-655G AIRE-230C, AIRE-655G AIRE-230T and AIRE-655A AIRE-230C. The analysis showed that the commonest haplotype AIRE-655G AIRE-230C has the highest luciferase specific activity (p<0.001). Whereas AIRE-655G AIRE-230T has a luciferase specific activity value that approaches null. Both AIRE promoter polymorphic sites have one allele that forms a CpG methylation site which we determined can be methylated in methylation assays using the M.SssI CpG methyltransferase.Conclusion AIRE-230Y is in a conserved region of the promoter and is adjacent to a predicted WT1 transcription factor binding site, suggesting that AIRE-230Y affects AIRE expression by influencing the binding of biochemical factors to this region. Our findings show that AIRE-655GAIRE-230T haplotype could dramatically alter AIRE transcription and so have an effect on the process of negative selection and affect susceptibility to autoimmune conditions.

Alopecia areata: a review of disease pathogenesis

“…AIRE dysfunction allows a range of naive autoreactive T cells (possibly against HFs) to go on unrecognized, increasing the possibility for autoimmune diseases . Several studies have revealed the association of AIRE gene polymorphisms with non‐APECED AA …”

“…115,116 Several studies have revealed the association of AIRE gene polymorphisms with non-APECED AA. [116][117][118][119] From immune privilege collapse to actual immune response As mentioned above, IFN-c and tumour necrosis factor-a are the first cytokines produced and released around HFs by either NK cells or activated T cells. IFN-c induces expression of MHC-I, NKG2D and chemokines such as CXCLs, all of which could perpetuate a vicious cycle of inflammation.…”

Syndrome APECED et lichen plan atrophique : un cas

“…Ce gène code pour la protéine AIRE 1, facteur de transcription [8], qui joue un rôle sur la tolérance centrale thymique du soi et en périphérie sur la régulation de l'activation des lymphocytes T par des cellules dendritiques [2,9]. Le diagnostic du syndrome APECED a été confirmé dans le cas décrit par la mutation du gène AIRE qui a été recherché devant les signes cliniques évocateurs du syndrome, notamment une candidose chronique cutanéo-muqueuse.…”

Update on Aire and thymic negative selection

“…Depending on the localization of mutations along the human Aire gene and the AIRE protein domain affected, the clinical manifestation can be different. For example, dominant mutations in the PHD1–2 and SAND domain affect the protein structure and correlate with the presence of organ‐specific autoimmune diseases . In addition, mutations in the promoter region impair the transcriptional activity of Aire or mutations in the CARD/HSR domain affect the localization and export of AIRE protein from cytoplasm to the nucleus and mutations in intronic regions can alter the splicing of Aire mRNA …”