Search Results (8)

Autoimmune polyglandular syndrome (APS) comprises a complex association of autoimmune pathological conditions. APS Type 1 originates from loss-of-function mutations in the autoimmune regulator (AIRE) gene. APS2, APS3 and APS4 are linked to specific HLA alleles within the major histocompatibility complex, with single-nucleotide polymorphisms (SNPs) in non-HLA genes also contributing to disease. In general, variability in the AIRE locus and the presence of heterozygous loss-of-function mutations can impact self-antigen presentation in the thymus. In this study, whole-exome sequencing (WES) was performed on a sixteen-year-old female APS3A/B patient to investigate the genetic basis of her complex phenotype. The analysis identified two variants (p.Arg111Trp and p.Thr101Ile) of the hepatitis A virus cell receptor 2 gene (HAVCR2) encoding for the TIM-3 (T cell immunoglobulin and mucin domain 3) protein. These variants were predicted, through in silico analysis, to impact protein structure and stability, potentially influencing the patient’s autoimmune phenotype. While confocal microscopy analysis revealed no alteration in TIM-3 fluorescence intensity between the PBMCs isolated from the patient and those of a healthy donor, RT-qPCR showed reduced TIM-3 expression in the patient’s unfractionated PBMCs. A screening conducted on a cohort of thirty APS patients indicated that the p.Thr101Ile and p.Arg111Trp mutations were unique to the proband. This study opens the pathway for the search of TIM-3 variants possibly linked to complex autoimmune phenotypes, highlighting the potential of novel variant discovery in contributing to APS classification and diagnosis. Full article

Hypocalcemia is a common occurrence in pediatric patients, attributed to various causes and presenting with diverse clinical manifestations. A prompt evaluation is necessary to determine its underlying cause, whether it presents acutely or chronically, and to tailor treatment based on its severity. Among the potential causes of chronic hypocalcemia, primary hypoparathyroidism stands out. The case of a seven-year-old male patient with hypocalcemia reported in this article serves as an illustration, wherein targeted next-generation sequencing revealed a homozygous p.R257X mutation in the AIRE gene, indicative of autoimmune polyendocrine syndrome type 1 (APS-1). It poses challenges due to its multisystemic nature and involvement of specific autoantibodies, often leading to underdiagnosis, owing to its rarity, varied manifestations, and incomplete penetrance. A comprehensive review of the APS-1 literature was conducted to provide insights into the clinical manifestations, genetic spectrum, potential immunological mechanisms, and current medical strategies. Additionally, the recognition of AIRE gene mutations is crucial for facilitating genetic diagnosis, prognosis, and potential treatment strategies for APS-1. The management of such cases involves individualized approaches to treatment, regular monitoring, medication adjustments, and the early identification of associated conditions. Full article

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), or polyglandular autoimmune syndrome type 1 (PAS-1/APS-1), is a rare autosomal recessive disorder linked to mutations in the autoimmune regulator (AIRE) gene. This review provides a detailed analysis of cutaneous manifestations in APECED, focusing on chronic mucocutaneous candidiasis (CMC), alopecia areata (AA), and vitiligo. The classic triad of hypoparathyroidism, adrenal insufficiency, and CMC serves as a diagnostic cornerstone. However, the varied clinical spectrum of APECED, particularly its cutaneous presentations, poses a diagnostic challenge. CMC, often an early sign, varies in prevalence across populations, including Finnish (100%), Irish (100%), Saudi Arabian (80%), Italian (60–74.7%), North American (51–86%), and Croatian (57.1%) populations. Similarly, AA prevalence varies in different populations. Vitiligo also exhibits variable prevalence across regions. The review synthesizes the current knowledge arising from a narrative analysis of 14 significant human studies published in English up to October 2023. Moreover, this paper underscores the importance of early detection and monitoring, emphasizing cutaneous manifestations as key diagnostic indicators. Ongoing research and clinical vigilance are crucial for unraveling the complexities of this rare autoimmune syndrome and enhancing patient care. Full article

Autoimmune-Poly-Endocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED), caused by mutations in the Autoimmune Regulator (AIRE) gene, is an autosomal recessive multi-organ autoimmunity syndrome usually defined by high serum titers of type I Interferon Autoantibodies (Type 1 IFN-Abs). These antibodies have recently been found in individuals in the general population who develop life-threatening Coronavirus Disease 2019 (COVID-19), but the significance of pre-existing Type 1 IFN-Abs in APECED patients with COVID-19 remains unclear. Previous reports of COVID-19 outcomes in APECED patients have been divergent, and protective roles have been proposed for female sex, age <26 years, and immunomodulatory medications including intravenous immunoglobulin (IVIg). We report the case of a 30-year-old male APECED patient who experienced a Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection with mild symptoms of fatigue and headache without respiratory distress and did not require hospitalization. He received a stress dose of hydrocortisone for adrenal insufficiency and continued on his baseline medications, including subcutaneous administration of Immunoglobulins (SCIgs) for chronic inflammatory demyelinating polyneuropathy (CIDP). Mild COVID-19 in a 30-year-old male patient with APECED and pre-existing Type 1 IFN-Abs was unexpected. Younger age and management of autoimmunity may have played a role. Full article

Background: Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) is a rare monogenetic autosomal recessive disorder caused by a mutation in the autoimmune regulator (AIRE) gene characterized by complex phenotypic characteristics discovered over years of follow-up. Methods: 7 patients were recruited in this case series in a period of the last 37 years from Southern Croatia. All patients were screened for AIRE R257X mutations. Results: This study group had a mean current age of 25.3 years (age range from 5.4 to 40.2 years), while the mean age at the onset of the disease was 6.5 years (age range from 0.7 to 9.2 years) and with a mean follow-up period of 17.8 years. The overall prevalence of APECED syndrome is estimated to be 1 in 75,000. The most common initial manifestation of the disease was onychodystrophy, while the first major component of APECED syndrome was chronic mucocutaneous candidiasis. Conclusions: APECED is a ‘‘multi-faced’’ disease based on the very unpredictable and inconsistent onset of major components. Furthermore, based on our results, we suggest that onychodystrophy could be included as a warning sign of APECED syndrome. Full article

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare disorder caused by mutations in the autoimmune regulator (AIRE) gene, leading to defects in T cell selection. The disease manifestations include both autoimmune tissue destruction and immunodeficiency, with specific susceptibility to chronic mucocutaneous candidiasis. Studies have demonstrated a wide repertoire of high affinity tissue- and cytokine-specific antibodies in patients with APECED. Here, we review the antigenic targets and function of these disease-causing and disease-ameliorating antibodies. Full article

Autoimmune regulator (Aire) mutations result in autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), which manifests as multi-organ autoimmunity and chronic mucocutaneous candidiasis (CMC). Indendritic cells (DCs), pattern recognition receptors (PRR), such as Toll-like receptors (TLRs), are closely involved in the recognition of various pathogens, activating the intercellular signaling pathway, followed by the activation of transcription factors and the expression of downstream genes, which take part in mediating the immune response and maintaining immune tolerance. In this study, we found that Aire up-regulated TLR3 expression and modulated the downstream cytokine expression and nuclear factor-κB (NF-κB) of the TLR3 signaling pathway. Full article

Type 1 autoimmune polyglandular syndrome (APS1) is a rare autosomal recessive disease, caused by mutations in the autoimmune regulator gene (AIRE); the encoded Aire protein plays an important role in the establishment of the immunological tolerance acting as a transcriptional regulator of the expression of organ-specific antigens within the thymus in perinatal age. While a high prevalence for this rare syndrome is reported in Finland and Scandinavia (Norway), autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED) cohorts of patients are also detected in continental Italy and Sardinia, among Iranian Jews, as well as in other countries. The syndrome is diagnosed when patients present at least two out of the three fundamental disorders including chronic mucocutaneous candidiasis, hypoparathyroidism, and Addison’s disease. Among the associated conditions insulin-dependent diabetes mellitus (Type 1 diabetes) has been rarely reported in different series of patients and occurring more frequently in Finnish APECED patients. In this review, we analyze the incidence of Type 1 diabetes as a clinical manifestation of APECED in different populations highlighting the peculiar genetic and immunological features of the disease when occurring in the context of this syndrome. Full article