22 - Autoimmune Polyglandular Syndromes

Abstract

The loss of immune tolerance to self-antigens is key to the development of autoimmune disorders. This process is influenced by multiple factors, including the complex interaction between genes and the environment. At least three genes play a critical role in maintaining self-tolerance. These are the autoimmune regulatory gene (AIRE), the forkhead transcription factor gene (FOXP3), and the human leukocyte antigen gene (HLA). Mutations in AIRE lead to autoimmune polyglandular syndrome type 1 (APS I), characterized by chronic mucocutaneous candidiasis, autoimmune hypoparathyroidism, and autoimmune adrenalitis. Patients’ sera are often positive for organ-specific autoantibodies before the development of clinical signs and symptoms, and these can be used to assess the risk of development, or monitor specific organ dysfunction. Mutations in FOXP3 lead to IPEX (immune dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance) syndrome. IPEX syndrome is characterized by multiorgan autoimmunity and includes the triad of neonatal onset type 1 diabetes, eczematous dermatitis, and enteropathy (watery diarrhea). In addition to the single gene defects associated with APS I and IPEX, polygenic disorders, such as APS II, have been described. APS II, characterized by patients with autoimmune adrenalitis, thyroid, and islet autoimmunity is associated with HLA DR/DQ subtypes. Herein, we will review the pathways associated with normal central and peripheral tolerance, as well as the defects and clinical manifestations associated with the autoimmune polyglandular syndromes.