Chronic mucocutaneous candidiasis (CMC) is characterized by recurrent infections with Candida spp., often linked to primary immunodeficiencies. We report a case of two 8-year-old monozygotic twin brothers presenting with extensive dermatophytosis, later diagnosed with autoimmune polyendocrinopathy, candidiasis, and ectodermal dystrophy (APECED) syndrome due to a homozygous p.M1V mutation in the AIRE gene. The twins exhibited widespread skin and nail infection, along with malabsorption, dental caries, and other autoimmune manifestations. This case highlights the novel presentation of extensive dermatophytosis in APECED, underscoring the variability in clinical expression even within a single family.

Loss-of-function mutations of the Autoimmune Regulator (AIRE) gene results in organ-specific autoimmunity and disease Autoimmune Polyendocrinopathy type 1 (APS1)/Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dystrophy (APECED). The AIRE protein is crucial in the induction of central tolerance, promoting ectopic expression of tissue-specific antigens in medullary thymic epithelial cells and enabling removal of self-reactive T-cells. AIRE expression has recently been detected in myeloid dendritic cells (DC), suggesting AIRE may have a significant role in peripheral tolerance. DC stimulation of T-cells is critical in determining the initiation or lack of an immune response, depending on the pattern of costimulation and cytokine production by DCs, defining immunogenic/inflammatory (inflDC) and tolerogenic (tolDC) DC. In AIRE-deficient patients and healthy controls, we validated the role of AIRE in the generation and function of monocyte-derived inflDC and tolDCs by determining mRNA and protein expression of AIRE and comparing activation markers (HLA-DR/DP/DQ,CD83,CD86,CD274(PDL-1),TLR-2), cytokine production (IL-12p70,IL-10,IL-6,TNF-α,IFN-γ) and T-cell stimulatory capacity (mixed lymphocyte reaction) of AIRE+ and AIRE- DCs. We show for the first time that: (1) tolDCs from healthy individuals express AIRE; (2) AIRE expression is not significantly higher in tolDC compared to inflDC; (3) tolDC can be generated from APECED patient monocytes and (4) tolDCs lacking AIRE retain the same phenotype and reduced T-cell stimulatory function. Our findings suggest that AIRE does not have a role in the induction and function of monocyte-derived tolerogenic DC in humans, but these findings do not exclude a role for AIRE in peripheral tolerance mediated by other cell types.