Abstract
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare primary immunodeficiency disorder typically caused by biallelic autoimmune regulator (AIRE) mutations that manifests with chronic mucocutaneous candidiasis (CMC) and autoimmunity. Patients with STAT1 gain-of-function (GOF) mutations also develop CMC and autoimmunity; they exhibit increased STAT1 protein levels at baseline and STAT1 phosphorylation (pSTAT1) upon interferon (IFN)-γ stimulation relative to healthy controls. AIRE interacts functionally with a protein that directly regulates STAT1, namely protein inhibitor of activated STAT1, which inhibits STAT1 activation. Given the common clinical features between patients with AIRE and STAT1 GOF mutations, we sought to determine whether APECED patients also exhibit increased levels of STAT1 protein and phosphorylation in CD14+ monocytes. We obtained peripheral blood mononuclear cells from 8 APECED patients and 13 healthy controls and assessed the levels of STAT1 protein and STAT1 tyrosine phosphorylation at rest and following IFN-γ stimulation, as well as the levels of STAT1 mRNA. The mean STAT1 protein levels in CD14+ monocytes exhibited a ~20% significant decrease in APECED patients both at rest and after IFN-γ stimulation relative to that of healthy donors. Similarly, the mean peak value of IFN-γ-induced pSTAT1 level was ~20% significantly lower in APECED patients compared to that in healthy controls. The decrease in STAT1 and peak pSTAT1 in APECED patients was not accompanied by decreased STAT1 mRNA or anti-IFN-γ autoantibodies; instead, it correlated with the presence of autoantibodies to type I IFN and decreased AIRE−/− monocyte surface expression of IFN-γ receptor 2. Our data show that, in contrast to patients with STAT1 GOF mutations, APECED patients show a moderate but consistent and significant decrease in total STAT1 protein levels, associated with lower peak levels of pSTAT1 molecules after IFN-γ stimulation.
Highlights
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystr ophy (APECED) or autoimmune polyglandular syndrome type-1 (APS-1; OMIM 240300) is a monogenic disorder caused by biallelic mutations in the autoimmune regulator (AIRE) gene, a thymus-enriched transcription regulator that promotes central immune tolerance via the expression of peripheral tissue selfantigens in medullary thymic epithelial cells [1, 2]
We focused on CD14+ monocytes because of their relatively high levels of IFN-γ receptors 1 and 2, which allows for detection of rapid activation of STAT1 [29]
Because of the similarities in clinical presentation of chronic mucocutaneous candidiasis (CMC) and autoimmunity and decreased peripheral blood Th17 frequencies between patients with APECED and STAT1 GOF mutations, our study examined STAT1 protein and phosphorylation levels in patients with APECED and shows that APECED patient monocytes do not share the same cell-intrinsic increase in STAT1 protein and phosphorylation levels as cells from patients with STAT1 GOF mutations
Summary
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystr ophy (APECED) or autoimmune polyglandular syndrome type-1 (APS-1; OMIM 240300) is a monogenic disorder caused by biallelic mutations in the autoimmune regulator (AIRE) gene, a thymus-enriched transcription regulator that promotes central immune tolerance via the expression of peripheral tissue selfantigens in medullary thymic epithelial cells [1, 2]. Heterozygous dominant-negative AIRE mutations in the plant homeodomain 1 domain have been described, associated with organ-specific APECED-associated autoimmune manifestations and/or chronic mucocutaneous candidiasis (CMC) [7,8,9]. In addition to the breakdown in mechanisms of T-cell tolerance, AIRE-deficient patients have high titers of neutralizing autoantibodies against Th17 cytokines and tissue-specific autoantigens, which have been shown to correlate with the development of CMC and organ-specific autoimmune manifestations, respectively [13,14,15]. APECED patients exhibit a decreased frequency of peripheral blood IL-17-producing CD4+ T cells following PMA/ionomycin stimulation [(3, 15), Lionakis, unpublished observations]
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