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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.
Historical Perspective and Rationale of HSCT for Autoimmune Diseases
Published in Richard K. Burt, Alberto M. Marmont, Stem Cell Therapy for Autoimmune Disease, 2019
Firstly, a distinction must be made between autoimmune conditions produced by lymphoproliferative diseases which may be overt but also occult (autoimmune MGUS) and include paraproteinemic (IgM) polyneuropathy and chronic cold agglutinin disease (CAD), where autoantibodies display a monoclonal pattern (monoclonal autoimmunity),4 and where successful HSCT may be clearly curative, and the more common organ-specific and systemic autoimmune diseases, which generally follow the pattern of antigen-driven immune reactions.5,6 Another distinction must be made between autoimmune diseases (ADs) with a postulated impaired immune system7 and diseases which are believed to be antigen-driven, this last being a subcellular particle or a multimolecular complex involved in important cellular functions.5,8 A bias has also been suggested in the development of the immunoglobulin (Ig) repertoire, which might play a role in the tendency to autoimmunity.8,9 Perhaps the single autoimmune human disease arising from a one gene mutation is APECED (autoimmune polyendocrinopathy candidiasis ectodermal dystrophy), where the gene encodes an autoimmune regulator gene (AIRE).10
Organ-specific autoimmune diseases
Published in Gabriel Virella, Medical Immunology, 2019
Gabriel Virella, George C. Tsokos
Autoimmune polyglandular syndrome I (APS-I) is a rare childhood disease with Mendelian recessive inheritance mode. The three major components are chronic mucocutaneous candidiasis, hypoparathyroidism, and autoimmune Addison's disease. Other endocrine glands may be involved. The entity is also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). The molecular basis for this entity has been established. These patients lack autoimmune regulator (AIRE), a transcriptional regulator that is believed to control the expression of tissue-specific genes in the thymus. Therefore, autoreactive T cells do not see self-antigens in the thymus, and they are not deleted during the negative selection process in the thymus. The second variant of APS, APS-II, is more common than APS-I and afflicts young adults. Main features include diabetes and Addison's disease. Some patients may have vitiligo, pernicious anemia, celiac disease, and other autoimmune diseases. It is proper, therefore, that patients presenting with diabetes or Addison's disease be screened for other autoimmune diseases.
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.
How do nuclear factor kappa B (NF-κB)1 and NF-κB2 defects lead to the incidence of clinical and immunological manifestations of inborn errors of immunity?
Published in Expert Review of Clinical Immunology, 2023
Nazanin Fathi, Hanieh Mojtahedi, Marzieh Nasiri, Hassan Abolhassani, Mahsa Yousefpour Marzbali, Marzie Esmaeili, Fereshte Salami, Furozan Biglari, Nima Rezaei
The NF-κB pathway may be activated by TCRs, costimulatory CD28, TNF-like receptor signals, and different stimuli during T cell development and activity. The different effector subsets of activated CD4 + T cells such as type 1 T helper (Th1), Th2, Th9, Th17, Tfh, and Treg cells each have distinctive functions that are depending on TCR signaling. TCR stimulation is also necessary for the proliferation and differentiation of activated naïve CD8 + T cells into effector and memory cells. TCR activates the canonical NF-κB pathway. The non-canonical NF-κB2 pathway is crucial for controlling differentiation but not for the initial activation of T cells through TCR signaling. The majority of T cell-autonomous effects via CD28 signaling are tightly controlled by NF-κB. In particular, the NF-κB p65/p52-dependent upregulation of Bcl-xL is one survival function of CD28 [50]. Treg cells are an essential subgroup of lymphocytes that suppress self-reactive T cells so escape negative selection. They limit the immunological responses relying on T cells and preventing autoimmune diseases. Treg development depends on the TCR and CD28 signaling by stimulating the NF-κB1 pathway [51]. Autoimmune regulator (AIRE) is an essential transcriptional regulator, expression in the medullary thymic epithelial cells (mTECs). AIRE induces developing Tregs to establish central immune tolerance and eliminates autoreactive T cells by managing the expression of several tissue-specific antigens in mTECs [52].
Systemic lupus erythematosus and immunodeficiency
Published in Immunological Medicine, 2019
Tetsuji Sawada, Daiki Fujimori, Yusuke Yamamoto
With regard to the mechanisms responsible for the autoimmune manifestations observed in PID, it has been demonstrated that in certain PIDs the mutation responsible for PID affects the checkpoints that govern T-cell tolerance [23]. For example, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, also known as autoimmune polyglandular syndrome type 1, is an autosomal recessive disorder with a mutation of the autoimmune regulator (AIRE) gene that causes antigen-specific T-cells for the endocrine glands to escape central tolerance in the thymus [24]. Another example is the syndrome of immune dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance, that is, X-linked IPEX, which is caused by genetic mutations in the FoxP3 transcription factor that is essential for development of CD25+ regulatory T-cells [25].