Autoimmune Polyglandular Syndromes

The autoimmune polyglandular syndromes (APS) are clusters of endocrine abnormalities that occur in discreet patterns in subjects with immune dysregulation and that permit treatment and anticipation of associated systemic or other hormonal deficiencies. Three major entities are recognized, APS1, APS2 and APS3; the rare X-linked syndrome of immune-dysregulation, poly-endocrinopathy, and enteropathy due to mutations in the gene also qualifies as an APS. An additional increasingly described category occurs in patients treated with immunoregulatory agents such as checkpoint inhibitors for cancer, so that tumor antigens that have evaded recognition can now be targeted, but at the expense of activating autoimmunity with adverse effects on various endocrine tissues. APS1 is a syndrome characterized by chronic muco-cutaneous candidiasis, hypoparathyroidism, primary adrenal insufficiency, as well as ectodermal dystrophy and a host of other endocrine and non-endocrine tissue involvement in autoimmune destructive processes. The underlying cause is a homozygous inactivating mutation in the autoimmune regulator gene which permits the intra-thymic expression of ectopic antigens normally expressed only in specific peripheral tissues (e.g. insulin), so that T-cells as they mature within the thymus and acquire a receptor for the self- antigen are eliminated (negative selection), thereby avoiding autoimmunity. Studies demonstrate that in addition to the classical homozygous mutations, single gene dominant mutations in play an important role in autoimmune regulation and its disorders. Recent studies demonstrate that tissue damage in APS1 due to AIRE mutations is mediated via the JAK-STAT signaling cascade and involves interferon gamma. Inhibiting the JAK-STAT signaling cascade via the monoclonal antibody, ruxolitinib, improves clinical and biochemical manifestations in both a murine model and human patients, offering promise for dramatic improvement in prognosis and clinical outcomes for affected patients. Larger studies in affected patients are awaited with interest. APS2 and APS3 are both due to mutations in the HLA DQ/DR regions which regulate antigen presentation to T-cell receptors; however, their genetic profile is more complex. APS2 is characterized by type 1 diabetes mellitus (T1DM), Addison Disease, and hypothyroidism, whereas APS3 is similar but without Addison disease. In keeping with other autoimmune disorders, these entities are more frequent in females, whereas APS1 has no sexual predominance. The recent emergence of autoimmune endocrinopathies in patients treated with checkpoint immunoregulatory agents for cancer add a new dimension to considerations of autoimmune polyendocrinopathy syndromes. Rapid progress in the immunology and genetics of these entities offers the promise of potential amelioration and eventual reversal via genetic manipulation before organ damage is established. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.