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Hypoparathyroidism in pediatric patients
Published in Pallavi Iyer, Herbert Chen, Thyroid and Parathyroid Disorders in Children, 2020
Andrew C. Calabria, Michael A. Levine
Hypoparathyroidism can arise due to the development of anti-parathyroid antibodies, so-called “autoimmune hypoparathyroidism.” Autoimmune hypoparathyroidism may be isolated or occur in the context of a complex autoimmune syndrome, most commonly the autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome (APS-1). The molecular defect in APS-1 occurs in the autoimmune regulator (AIRE) gene at 21q22.3 (7), which encodes a transcription factor that regulates thymic epithelial cells through the transcription of diverse proteins that result in their presentation as self-antigens to developing T cells, with subsequent elimination of autoreactive T cells. Autoantibodies against type 1 interferon are typically present in affected subjects. Most patients have biallelic mutations, but in some patients a non-classical form of APS-1 has been associated with dominant mutations. APECED is an uncommon disorder in most populations (approximately 1:90,000–3:100,000), but it occurs with greater frequency (1:9000 to 1:25,000) in genetically isolated groups such as Finns, Sardinians, and Iranian Jews.
Special Groups
Published in Vineet Relhan, Vijay Kumar Garg, Sneha Ghunawat, Khushbu Mahajan, Comprehensive Textbook on Vitiligo, 2020
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) syndrome is a rare autosomal recessive disease characterized classically by a triad of hypothyroidism, primary adrenocortical insufficiency, and chronic mucocutaneous candidiasis. According to the diagnostic criteria proposed by Husebye et al., the minor components include vitiligo, alopecia areata, chronic diarrhea, keratitis, periodic rash with fever, severe constipation, autoimmune hepatitis, and enamel hypoplasia. Vitiligo has been reported in up to one-third of these patients and generally forms a part of the initial manifestations of the disease; however, it is less commonly found than alopecia areata, another autoimmune condition. Vitiligo tends to be extensive in these patients [4,5].
Cronkhite−Canada Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
First, CCS polyps often contain elevated antinuclear antibody (ANA) and IgG4 levels. Some sporadic juvenile CCS polyps are infiltrated by IgG4 plasma cells, which are typically observed in autoimmune disorders such as autoimmune pancreatitis, sclerosing cholangitis, and retroperitoneal fibrosis. Therefore, a proportion of CCS can be attributed to innate immune response enhanced by B cell activating factor (BAFF) and IL-13 that leads to the infiltration of IgG4 producing B cells. In addition, there is a clear association between CCS and hypothyroidism and various other autoimmune diseases (e.g., membranous glomerulonephritis, systemic lupus erythematosus, rheumatoid arthritis, and scleroderma). Moreover, skin and nail changes in CCS resemble those in autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED) syndrome. The fact that CCS manifestations are notably alleviated or lessened by immunosuppression agents (e.g., corticosteroids or long-term azathioprine) provides further evidence of an inflammatory cause of CCS.
Cellular mechanisms and clinical applications for phenocopies of inborn errors of immunity: infectious susceptibility due to cytokine autoantibodies
Published in Expert Review of Clinical Immunology, 2023
Rui Sun, Yating Wang, Hassan Abolhassani
Autoimmune Regulator (AIRE) is thought to be responsible for turning on the expression of genes coding tissue-specific antigens in the thymus, thus playing an important role in shaping the T-cell repertoire through a negative selection of autoreactive T cells in the thymus [6]. This gene has also been shown to be expressed in secondary lymphoid organs and contributes to both central and peripheral tolerances [7,8]. The biallelic deleterious germline variants of the AIRE gene lead to a rare but severe inherited IEI known as Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). APECED leads to damage of multiple internal glands, mainly insulin-producing pancreatic islets, adrenals, thyroid, and parathyroid glands and shows susceptibility to fungal infections, particularly candidiasis [9–11]. The main pathogenic mechanisms are believed to be T cell-mediated, in which defective AIRE directly affects the deletion of autoreactive T cells in the thymus, and promotes a broad range of autoAbs against various self-antigens, targeting endocrine and other tissue antigens and cytokines, especially IFNs [12,13]. However, little is known about the role of T cell defects on B cell stimulation and autoAbs production in APECED patients.
Clinical, immunological, and genetic features in 938 patients with autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED): a systematic review
Published in Expert Review of Clinical Immunology, 2021
Niusha Sharifinejad, Majid Zaki-Dizaji, Shafi Tebyanian, Hamed Zainaldain, Mahnaz Jamee, Fatema Sadaat Rizvi, Soheila Hosseinzadeh, Farimah Fayyaz, Haleh Hamedifar, Araz Sabzevari, Mojdeh Matloubi, Edyta Heropolitańska-Pliszka, Fatemeh Aghamahdi, Hassan Abolhassani, Gholamreza Azizi
Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) also known as autoimmune polyendocrine syndrome type 1 (APS-1), is an inborn immune error associated with autosomal recessive or dominant mutations in the autoimmune regulator (AIRE) gene [1,2]. The AIRE protein is a transcriptional regulator that plays an important role in self-tolerance by promoting the expression of tissue-specific antigens (TSAs) in the thymus [3]. The human AIRE gene (OMIM: *607,358) is located on chromosome position 21q22.3 and consists of 14 coding exons that encode a transcription regulator of 545 amino acids with a molecular weight of 58 kDa. The most prominent domains in the AIRE protein are the caspase recruitment domain/homogeneously staining (CARD/HSR) region, a conserved nuclear localization signal (NLS), a SAND (SP100, AIRE, Nuc p41/75, DEAF) domain, four LXXLL (L is leucine and X is any amino acid) motifs, and two plant homeodomain (PHD) zinc fingers [4].
Diagnostic and therapeutic challenge of unclassifiable enteropathies with increased intraepithelial CD103+ CD8+ T lymphocytes: a single center case series
Published in Scandinavian Journal of Gastroenterology, 2021
Christina Hartl, Jürgen Finke, Peter Hasselblatt, Wolfgang Kreisel, Annette Schmitt-Graeff
Chronic enteropathy associated with intraepithelial lymphocytosis (IEL) and villous atrophy (VA) of the duodenal mucosa and persistent diarrhea may result from many pathologies with celiac disease (CD) being the most prevalent underlying cause. In the absence of CD auto-antibodies and after exclusion of the clinically challenging diagnosis of seronegative CD, e.g., by exposure to gluten-free diet and HLA testing [1], a plethora of differential diagnoses have to be considered in patients with VA and IEL. Gastrointestinal pathology frequently occurs in primary immunodeficiency disorders (PID) such as the IPEX (immune dysregulation polyendocrinopathy enteropathy X-linked) or APECED syndromes (autoimmune polyendocrinopathy candidiasis ectodermal dystrophy) and CVID (common variable immunodeficiency) [2,3]. Potential causes also include medications such as olmesartan or immune checkpoint inhibitors, Crohn’s disease, infections (in particular, HIV infection, mycobacteriosis, giardiasis, Whipple’s disease), food intolerances or autoimmune enteropathy (AIE) [4,5]. The diagnostic work-up should therefore include blood tests for assessing malnutrition, ruling out seropositive or seronegative CD and testing for anti-enterocyte antibodies. In addition, microbiological examinations and endoscopies with duodenal biopsies are mandatory during diagnostic work-up to rule out infections, inflammatory bowel disease or lymphoproliferative disorders (LPD) [6,7].