AIRE Deficiency Exposes Inefficiencies of Peripheral Tolerance Leading to Variable APECED Phenotypes

show strong affinity for these self-peptide/MHC complexes are deleted by activation-induced apoptosis. The deletion of autoreactive T cell clones through thymic-expressed TSAs is known as central tolerance. The discrepancy between antigens expressed and presented by cortical thymic epithelial cells (cTECs) versus mTECs has been termed the alternate peptide hypothesis. This hypothesis can partially explain how autoreactive T cells survive positive selection in the cortex but fail to pass negative selection in the medulla (Marrack, McCormack, & Kappler, 1989). In order to express TSAs, mTECs must transactivate genes that are not normally expressed in the thymus through a process called promiscuous gene expression (PGE; De Martino et al., 2013; Kyewski & Derbinski, 2004; Laan & Peterson, 2013; Metzger & Anderson, 2011; Tykocinski, Sinemus, & Kyewski, 2008). PGE is dependent upon the transcription of DNA in chromatin states often associated with inhibited expression (Abramson, Giraud, Benoist, & Mathis, 2010; Tykocinski et al., 2010; Ucar & Rattay, 2015; Žumer, Saksela, & Peterlin, 2013). The autoimmune regulator (AIRE) protein expressed in mTECs is a transcription factor that facilitates this process. Loss of AIRE function limits TSA tolerance, leading to organspecific autoimmunity and autoantibody production (Kisand & Peterson, 2015; Laan & Peterson, 2013; Metzger & Anderson, 2011). Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) is the monogenic disorder caused by mutations at the AIRE locus. However, APECED may be considered a syndrome because symptoms can also stem from indirect disruptions of AIRE function (De Martino et al., 2013). While APECED cases may feature some similar symptoms such as mucocutaneous canIntroduction T cells provide capable, targeted defense against foreign antigens through their receptor specificity. The vast repertoire of T cell receptors allows the immune system to mount a response against most foreign invaders. Generation of receptor diversity is accomplished mainly through gene rearrangement at the alpha and beta chain loci. Positive selection in the thymic cortex is able to expand T cell clones with receptors that bind major histocompatibility complex (MHC)/self-peptide complexes with at least moderate affinity (De Martino et al., 2013). However, cells that pass positive selection may still have a strong affinity for self-peptides presented on MHC molecules. In order to eliminate these autoreactive T cells from escaping from the thymus into the periphery, T cell clones positively selected for in the thymic cortex undergo negative selection in the thymic medulla. During the negative selection process, T cells are presented with medullary thymic epithelial cell (mTEC)-expressed tissue-specific antigens (TSAs) in the medulla (Derbinski, Schulte, Kyewski, & Klein, 2001; Kyewski & Derbinski, 2004). T cells that AIRE Deficiency Exposes Inefficiencies of Peripheral Tolerance Leading to Variable APECED Phenotypes