AIRE-1 (Autoimmune Regulator Type 1) as a Regulator of the Thymic Induction of Negative Selection
The monogenic autoimmune syndrome, APS-1 (autoimmune polyglandular syndrome type 1), is characterized by the loss of self-tolerance to multiple organs. Although mutations in the AIRE (autoimmune regulator) gene are responsible for the APS-1, the function of AIRE is not known. AIRE may determine thymic induction of tolerance to self-antigens in multiple organs. To study the function of AIRE in induction of self-tolerance, an in vitro negative selection system was made using 106 DO11.10 TCR transgenic thymocytes, 105 antigen-presenting cells (APC), and the different constructs of ovalbumin (OVA). In this system, the addition of the immunodominant epitopes of OVA peptide, the antigenic ligand for the DO11.10, made the thymocytes apoptotic and negatively selected. Overexpression of the AIRE gene in APC using retroviral transduction did not cause more thymocytes to become apoptotic. However, the suppression of the expression of AIRE in APC using the dominant-negative gene made the recovery rates of the thymocytes higher than those with the expression of LacZ as a control, and consequently inducing loss of self-tolerance. From these studies, it might be possible to suggest that the AIRE gene might regulate thymic induction of the negative selection process. The target genes for transcriptional regulation by AIRE have been investigated to study the influence of AIRE expression on other proteins in antigen presentation. The expression level of B7.1 was higher in APC expressing the dominant-negative form of AIRE. The target gene regulated by AIRE in transcription will be screened using cDNA microarray.
aire regulator negative selection