Alterations of the autoimmune regulator transcription factor and failure of central tolerance: APECED as a model

Abstract

Self-nonself discrimination plays a key role in inducing a productive immunity and in preventing autoimmune reactions. Central tolerance within the thymus and peripheral tolerance in peripheral lymphoid organs lead to immunologic nonresponsiveness against self-components. The central tolerance represents the mechanism by which T cells binding with high avidity to self-antigens are eliminated through the so-called negative selection. Thymic medullary epithelial cells and medullary dendritic cells play a key role in this process, through the expression of a large number of tissue-specific self-antigens involving the transcription factor autoimmune regulator (AIRE). Mutations of AIRE result in autoimmune polyendocrinopathy candidiasis ectodermal dystrophy, a rare autosomal recessive disease (OMIM 240300), which is the paradigm of a genetically determined failure of central tolerance and autoimmunity. This review focuses on recent advances in the molecular mechanisms of central tolerance, their alterations and clinical implication.

AIRE expressing marginal zone dendritic cells balances adaptive immunity and T-follicular helper cell recruitment

“…An HLA association is not found in APS I. However specific HLA haplotypes are associated with alopecia and Addison's disease in APS I patients, although HLA does not have any influence on the autoantibody formation characteristically seen in APS I (Gallo et al, 2013).…”

“…Individuals with APS I display a high variability in their clinical features both among the patient group and also between family members and, thus, hint that despite the monogenic inheritance of the disease other genetic and non-genetic factors influence its clinical expression (Gallo et al, 2013). A prominent example of an intrafamilial variability was recently seen in two siblings carrying the same mutation but with strikingly different disease manifestations.…”

Non-autoimmune subclinical hypothyroidism due to a mutation in TSH receptor: report on two brothers

“…The recent finding that TSH-R, like other G protein-coupled receptors, can oligomerize in living cells led to the hypothesis that the formation of complexes between wild-type and mutant receptors may be responsible for partial TSH resistance in patients with heterozygous TSH-R mutations [31]. The clinical heterogeneity in our 2 patients carrying the same mutation, is not surprising as other monogenic diseases have been already shown to have a different phenotype despite the same causing mutation [32-36]. For most of these conditions, molecular basis of this heterogeneity are not well delineated.…”

APECED: A Paradigm of Complex Interactions between Genetic Background and Susceptibility Factors

“…In addition, Aire may also play a role in the proper differentiation of the thymic medullary epithelium, in the induction of apoptosis in end-stage terminally differentiated mTECs (39) as well as in mTECs’ differentiation program. In particular, evidence suggests that lack of Aire in mTECs results in an arrest of the differentiation program, with the cells remaining at the premature stage just before terminal differentiation (45, 46). …”

“…Mutations in AIRE gene result in development of APECED, which represents the paradigm of a genetically determined failure of central tolerance leading to autoimmunity (46). APECED is a rare autoimmune syndrome, but it has been reported worldwide showing a relatively higher prevalence in genetically isolated populations such as Iranian Jews (1:9,000) (47), Finns (1:25,000) (48, 49), and Sardinians (1:14,400) (50).…”