Identification of endothelin-converting enzyme-2 as an autoantigen in autoimmune polyendocrine syndrome type 1.

Autoimmune polyendocrine syndrome type 1 (APS1) is a rare monogenic autoimmune disorder caused by mutations in the autoimmune regulator (AIRE) gene. High titer autoantibodies are a characteristic feature of APS1 and are often associated with particular disease manifestations. Pituitary deficits are reported in up to 7% of all APS1 patients, with immunoreactivity to pituitary tissue frequently reported.

Autoantibodies Targeting a Collecting Duct-Specific Water Channel in Tubulointerstitial Nephritis.

Tubulointerstitial nephritis is a common cause of kidney failure and may have diverse etiologies. This form of nephritis is sometimes associated with autoimmune disease, but the role of autoimmune mechanisms in disease development is not well understood. Here, we present the cases of three patients with autoimmune polyendocrine syndrome type 1 who developed tubulointerstitial nephritis and ESRD in association with autoantibodies against kidney collecting duct cells.

Transglutaminase 4 as a prostate autoantigen in male subfertility.

Autoimmune polyendocrine syndrome type 1 (APS1), a monogenic disorder caused by AIRE gene mutations, features multiple autoimmune disease components. Infertility is common in both males and females with APS1. Although female infertility can be explained by autoimmune ovarian failure, the mechanisms underlying male infertility have remained poorly understood.

Dominant Mutations in the Autoimmune Regulator AIRE Are Associated with Common Organ-Specific Autoimmune Diseases.

The autoimmune regulator (AIRE) gene is crucial for establishing central immunological tolerance and preventing autoimmunity. Mutations in AIRE cause a rare autosomal-recessive disease, autoimmune polyendocrine syndrome type 1 (APS-1), distinguished by multi-organ autoimmunity. We have identified multiple cases and families with mono-allelic mutations in the first plant homeodomain (PHD1) zinc finger of AIRE that followed dominant inheritance, typically characterized by later onset, milder phenotypes, and reduced penetrance compared to classical APS-1.

BPIFB1 is a lung-specific autoantigen associated with interstitial lung disease.

Interstitial lung disease (ILD) is a complex and heterogeneous disorder that is often associated with autoimmune syndromes. Despite the connection between ILD and autoimmunity, it remains unclear whether ILD can develop from an autoimmune response that specifically targets the lung parenchyma. We examined a severe form of autoimmune disease, autoimmune polyglandular syndrome type 1 (APS1), and established a strong link between an autoimmune response to the lung-specific protein BPIFB1 (bactericidal/permeability-increasing fold-containing B1) and clinical ILD.

IL-7 dysregulation and loss of CD8+ T cell homeostasis in the monogenic human disease autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a monogenic autoimmune disease that is caused by mutations in the AIRE gene. Murine studies have linked AIRE to thymocyte selection and peripheral deletional tolerance, but the pathogenesis of the human disease remains unclear. In this study, we show that APECED patients have elevated IL-7 levels and a drastically decreased expression of IL-7R on CD8(+) T cells.

Increased IL-17A secretion in response to Candida albicans in autoimmune polyendocrine syndrome type 1 and its animal model.

Autoimmune polyendocrine syndrome type 1 (APS-1) is a multiorgan autoimmune disease caused by mutations in the autoimmune regulator (AIRE) gene. Chronic mucocutaneous candidiasis, hypoparathyroidism and adrenal failure are hallmarks of the disease. The critical mechanisms causing chronic mucocutaneous candidiasis in APS-1 patients have not been identified although autoantibodies to cytokines are implicated in the pathogenesis.

Regulatory T cell defect in APECED patients is associated with loss of naive FOXP3(+) precursors and impaired activated population.

The pathogenetic mechanisms of organ-specific autoimmune diseases remain obscured by the complexity of the genetic and environmental factors participating in the breakdown of tolerance. A unique opportunity to study the pathogenesis of human autoimmunity is provided by autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), a rare inherited autoimmune disease caused by mutations in Autoimmune Regulator (AIRE) gene. Loss of AIRE function disrupts the deletion of autoreactive T cells and impairs the suppressive function of regulatory T (Treg) cells.

Chronic mucocutaneous candidiasis in APECED or thymoma patients correlates with autoimmunity to Th17-associated cytokines.

Chronic mucocutaneous candidiasis (CMC) is frequently associated with T cell immunodeficiencies. Specifically, the proinflammatory IL-17A-producing Th17 subset is implicated in protection against fungi at epithelial surfaces. In autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED, or autoimmune polyendocrine syndrome 1), CMC is often the first sign, but the underlying immunodeficiency is a long-standing puzzle.

gammadelta T cells develop independently of Aire.

Mutations in the transcriptional regulator Aire disrupt thymic alphabeta T cell selection, causing in humans Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). However, it is not known whether Aire is needed for normal gammadelta T cell development. We show that Aire(-/-) mice have a normal frequency of gammadelta T cells, with TCR repertoire comparable to that of wild-type mice, and normal amount of TCR Cdelta mRNA in ileum and skin.

Pulmonary autoimmunity as a feature of autoimmune polyendocrine syndrome type 1 and identification of KCNRG as a bronchial autoantigen.

Patients with autoimmune polyendocrine syndrome type 1 (APS-1) suffer from multiple organ-specific autoimmunity with autoantibodies against target tissue-specific autoantigens. Endocrine and nonendocrine organs such as skin, hair follicles, and liver are targeted by the immune system. Despite sporadic observations of pulmonary symptoms among APS-1 patients, an autoimmune mechanism for pulmonary involvement has not been elucidated.

Autoantibodies in autoimmune polyglandular syndrome type I patients react with major brain neurotransmitter systems.

Patients with autoimmune polyglandular syndrome type I (APS1) often display high titers of autoantibodies (autoAbs) directed against aromatic L-amino acid decarboxylase (AADC), tyrosine hydroxylase (TH), tryptophan hydroxylase (TPH), and glutamic acid decarboxylase (GAD). Neurological symptoms, including stiff-man syndrome and cerebellar ataxia, can occur in subjects with high levels of GAD autoAbs, particularly when patient sera can immunohistochemically stain gamma-aminobutyric acid (GABA) neurons. However, it was not known if APS1 sera can also stain major monoamine systems in the brain.

Radioimmunoassay for autoantibodies against interferon omega; its use in the diagnosis of autoimmune polyendocrine syndrome type I.

Patients with the autoimmune polyendocrine syndrome I (APS I) have high titers of neutralizing IgG autoantibodies against type I interferons (IFNs), in particular IFN-omega. Until now, the most specific assay has been the antiviral interferon neutralizing assay (AVINA), which has the drawbacks of requiring a cytolytic virus, being cumbersome and difficult to standardise. We have developed a fast and reliable immunoassay based on radiolabelled IFN-omega for quantifying anti-IFN-omega antibodies.

Reduction of fluconazole susceptibility of Candida albicans in APECED patients due to long-term use of ketoconazole and miconazole.

We have analysed further the y of usage of antifungals in autoimmune polyendocrinopathy - candidiasis - ectodermal dystrophy (APECED) patients and its impact on the susceptibility to fluconazole in Candida albicans. Data were obtained from patient records up to 30 y earlier. Analysing the use of azoles preceding isolation of each isolate showed that significantly more y of azole usage preceded isolation of C.

Interferon autoantibodies associated with AIRE deficiency decrease the expression of IFN-stimulated genes.

Neutralizing autoantibodies to type I, but not type II, interferons (IFNs) are found at high titers in almost every patient with autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), a disease caused by AIRE gene mutations that lead to defects in thymic T-cell selection. Combining genome-wide expression array with real time RT-PCR assays, we here demonstrate that antibodies against IFN-alpha cause highly significant down-regulation of interferon-stimulated gene expression in cells from APECED patients' blood by blocking their highly dilute endogenous IFNs. This down-regulation was lost progressively as these APECED cells matured in cultures without neutralizing autoantibodies.

Activity of amphotericin B, anidulafungin, caspofungin, micafungin, posaconazole, and voriconazole against Candida albicans with decreased susceptibility to fluconazole from APECED patients on long-term azole treatment of chronic mucocutaneous candidiasis.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED, APS-I) is exceptionally common in Finland. Most patients have chronic oral candidiasis since childhood. Thus, most patients receive repeated courses of antifungals throughout their life.

Autoimmune polyendocrine syndrome type 1 and NALP5, a parathyroid autoantigen.

Background: Autoimmune polyendocrine syndrome type 1 (APS-1) is a multiorgan autoimmune disorder caused by mutations in AIRE, the autoimmune regulator gene. Though recent studies concerning AIRE deficiency have begun to elucidate the molecular pathogenesis of organ-specific autoimmunity in patients with APS-1, the autoantigen responsible for hypoparathyroidism, a hallmark of APS-1 and its most common autoimmune endocrinopathy, has not yet been identified.

Methods: We performed immunoscreening of a human parathyroid complementary DNA library, using serum samples from patients with APS-1 and hypoparathyroidism, to identify patients with reactivity to the NACHT leucine-rich-repeat protein 5 (NALP5).

Testis-expressed protein TSGA10 an auto-antigen in autoimmune polyendocrine syndrome type I.

Autoimmune polyendocrine syndrome type 1 (APS1) is a rare monogenic autosomal recessive disorder. Autoimmune gonadal failure is often one of its features. The aim of this study was to identify targets of immune reactions associated with male autoimmune hypogonadism in APS1.

Decreased susceptibility of Candida albicans to azole antifungals: a complication of long-term treatment in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) patients.

Background: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED, APS1) is an autosomal recessive disease exceptionally common in Finland. Most patients have chronic oral candidiasis from early childhood and this infection has been shown to be carcinogenic. Hence, patients receive repeated treatment and prophylactic courses of antifungals throughout life.

Pituitary autoantibodies in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED).

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is an autosomal recessive disease due to mutations in the AIRE (AutoImmune REgulator) gene. The role of pituitary autoimmunity in APECED is not known. We determined the prevalence of pituitary autoantibodies in a cohort of 67 Finnish patients with APECED from 217 serum samples collected over 26 years by one investigator.

Pituitary autoantibodies in autoimmune polyendocrine syndrome type 1.

Autoimmune polyendocrine syndrome type 1 (APS1) is a rare autosomal recessive disorder caused by mutations in the autoimmune regulator (AIRE) gene. High titer autoantibodies (Aabs) toward intracellular enzymes are a hallmark for APS1 and serve as diagnostic markers and predictors for disease manifestations. In this study, we aimed to identify pituitary autoantigens in patients with APS1.

A defect of regulatory T cells in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), a monogenic recessive disease characterized by autoimmunity against multiple tissues, offers a unique possibility to study the breakdown of self-tolerance in humans. It is caused by mutations in the autoimmune regulator gene (AIRE), which encodes a transcriptional regulator. Work using Aire(-/-) mice suggests that Aire induces ectopic expression of peripheral Ags and promotes their presentation in the thymus.

Epitope mapping of human aromatic L-amino acid decarboxylase.

Autoimmune polyendocrine syndrome type I (APS I) is a rare hereditary condition considered a model disease for organ specific autoimmunity. A wide range of autoantibodies targeting antigens present in the affected organs have been identified. Autoantibodies against aromatic L-amino acid decarboxylase (AADC) are present in about 50% of APS I patients.