The autoimmune polyglandular syndromes—a group of syndromes comprising a combination of endocrine and nonendocrine autoimmune diseases—differ in their component diseases and in the immunologic features of their pathogenesis. One of the three main syndromes, type 1 autoimmune polyglandular syndrome (APS-1), has a unique pathogenic mechanism owing tomutations in the autoimmune regulator (AIRE) gene, which results in the loss of central tolerance—a process by which developing T cells with potential reactivity for self-antigens are eliminated during early differentiation in the thymus. Patients with IPEX (immune dysfunction, polyendocrinopathy, enteropathy, X-linked) syndrome harbor mutations in the forkhead box P3 (FOXP3) gene in regulatory Tcells, which leads to severe autoimmunity and immune deficiency. Although both of these disorders are rare, their well-defined mechanisms of disease provide a basis for the understanding of the more common condition, APS-2. In this syndrome, alleles of human leukocyte antigens (HLAs) determine the targeting of specific tissues by autoreactive T cells, which leads to organ-specific autoimmunity as aresult of this loss of tolerance. Non-HLA genes also contribute to autoimmunity in APS-2 and, depending on the polymorphism, potentially predispose to a loss of tolerance or influence which organ is specifically targeted. This Review discusses the genetic basis of APS-1, APS-2 and IPEX syndrome, with an emphasis on the mechanisms of autoimmunity and presents currently available therapies to treattheir underlying autoimmune disorders.
Immunological tolerance is necessary for cells to distinguish foreign proteins and molecules from self-antigens. Central tolerance occurs in the thymus as T cells mature and can result in the development of effector T cells needed for host defense, regulatory T cells that suppress activation of the immune system and autoreactive T cells thatreact to proteins and tissues of the host. Central tolerance is composed of two selection processes; positive selection produces effector T cells and regulatory T cells that enter the circulation, whereas negative selection removes T cells with a high affinity for self-antigens. Peripheral tolerance occurs outside the thymus and acts as a safeguard to control any autoreactive T cells that survivenegative selection in the thymus and reach the peripheral tissues. In healthy individuals, these autoreactive T cells are kept unresponsive by stimuli from regulatory T cells. Together, central and peripheral tolerance prevent the expansion and activation of autoreactive T cells and provide protection from autoimmune disease.
The autoimmune polyglandular syndromes (APS) are a group of disorderscharacterized by the presence of a combination of multiple autoimmune disorders and, in some cases, immunodeficiency. The syndromes include monogenic disorders such as APS-1 and IPEX (immune dysfunction, polyendocrinopathy, X-linked) syndrome, as well as complex genetic disorders, such as APS-2. Some of the underlying autoimmune disorders occur frequently in all syndromes, such as autoimmunethyroid disease and type 1A diabetes mellitus—the immune-mediated subtype of type 1 diabetes mellitus— whereas other components, for example, Addison disease and myasthenia gravis, are rare. Advances in the understanding of T cells and the process of tolerance to self-antigens have helped elucidate how certain individuals develop multiple autoimmune disorders.
Type 1 Autoimmune Polyglandular SyndromeAPS-1, also called autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), is a rare disorder, which generally manifests during infancy. The diagnosis is made when a child has at least two of the following pathologies: mucocutaneous candidiasis, hypoparathyroidism or Addison disease. Symptoms of mucocutaneous candidiasis—a recurring fungal infection that is limited to...