Aire-Deficient C57BL/6 Mice Mimicking the Common Human 13-Base Pair Deletion Mutation Present with Only a Mild Autoimmune Phenotype

Abstract

Autoimmune regulator (AIRE) is an important transcription regulator that mediates a role in central tolerance via promoting the “promiscuous” expression of tissue-specific Ags in the thymus. Although several mouse models of Aire deficiency have been described, none has analyzed the phenotype induced by a mutation that emulates the common 13-bp deletion in human APECED (autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy) by disrupting the first plant homeodomain in exon 8. Aire-deficient mice with a corresponding mutation showed some disturbance of the medullary epithelial compartment, but at the phenotypic level their T cell compartment appeared relatively normal in the thymus and periphery. An increase in the number of activated T cells was evident, and autoantibodies against several organs were detected. At the histological level, lymphocytic infiltration of several organs indicated the development of autoimmunity, although symptoms were mild and the quality of life for Aire-deficient mice appeared equivalent to wild-type littermates, with the exception of male infertility. Vβ and CDR3 length analysis suggested that each Aire-deficient mouse developed its own polyclonal autoimmune repertoire. Finally, given the prevalence of candidiasis in APECED patients, we examined the control of infection with Candida albicans in Aire-deficient mice. No increase in disease susceptibility was found for either oral or systemic infection. These observations support the view that additional genetic and/or environmental factors contribute substantially to the overt nature of autoimmunity associated with Aire mutations, even for mutations identical to those found in humans with APECED.

Diversity and clonotypic composition of influenza‐specific CD8+ TCR repertoires remain unaltered in the absence of Aire

“…This does not indicate that the naive T-cell repertoires are identical in wt and Aire-deficient mice, as the development of autoimmunity suggests the presence of self-reactive clones in the latter. Four Aire-deficient mouse models have been reported [3,14,16,34,35]. The similar phenotype shared by these models is less severe than that of APECED patients [16,[35][36][37].…”

“…An early study [15] comparing the features of TCRb repertoires between wt and Aire-deficient mice found differences in the immunoscopes of three of the 24 Vb families, suggesting that Aire may significantly perturb the repertoire. A more recent study [16] of the Vb gene usage and CDR3b lengths of naive CD4…”

Autoimmune regulator (AIRE)-deficient CD8+CD28lowregulatory T lymphocytes fail to control experimental colitis

“…We embarked on a study of the influence of AIRE on the in vitro and in vivo suppressor activity of CD8 + CD28 low Treg. Mice carrying a 13-bp mutation in the AIRE gene that disrupts the PHD1 domain in exon 8 were previously discussed (21). It was demonstrated that these mice developed mild symptoms of autoimmune pathology, similar to other AIRE-deficient mice on the C57BL/6 background.…”

“…In AIRE°mice, marginally reduced numbers of CD4 + Foxp3 + Treg may develop. However, molecular analysis of the TCR repertoire of WT and AIRE°CD4 + Foxp3 + Treg failed to detect any difference, and these cells have unaltered in vitro and in vivo suppressive activity (20,21,30,32,33). In APECED patients, decreased expression of Foxp3 and impaired suppressive function of Treg were observed (34).…”

“…This disease is mainly characterized by chronic mucocutaneous candidiasis, hypoparathyroidism, and adrenocortical insufficiency. Also, AIRE-deficient (AIRE°) mice develop an autoimmune pathology similar to APECED (18)(19)(20)(21)(22). Interestingly, it was recently shown that also candidiasis is probably due to an autoimmune disorder: APECED patients had neutralizing antibodies to Th17-associated cytokines known to be involved in immunity to fungi (23,24).…”