Editorial: Functional Autoantibodies Cause Hypoparathyroidism

Hypoparathyroidism is a rare disease most commonly seen as a complication to thyroid surgery ( 1). Other causes are divided between a range of hereditary and acquired diseases such as DiGeorge syndrome ( 2), autoimmunity, and increased function of the calcium-sensing receptor (CaSR) by either activating mutations ( 3) or stimulatory antibodies ( 4). The parathyroid gland is rarely targeted by the immune system, but when it happens, it is often an early sign of autoimmune polyendocrine syndrome type I (APS-I) ( 5, 6). The pathogenesis of autoimmune hypoparathyroidism has long remained an enigma, but recent studies indicate that two complementary mechanisms are operational: one comprising a putative T cell-mediated destruction involving the parathyroid-specific protein nacht-leucine-rich protein 5 (NALP5) ( 7) and one mediated by antibodies modulating the activity of the CaSR ( 8). APS-I APS-I (OMIM 20400) is a recessive autosomal dominant disease caused by mutations in the autoimmune regulator ( AIRE) ( 9). The AIRE gene is mainly expressed in thymic medullary epithelial cells where it acts as a transcriptional regulator, driving the expression of tissue-specific proteins ( 10). This ectopic expression is instrumental in purging autoreactive T cells from the immunological repertoire in a process called negative selection as immature T cells percolate through the thymic medulla ( 11). The main clinical components of APS-I are hypoparathyroidism, adrenal insufficiency, and chronic mucocutaneous candida infections ( 6). The diagnosis can be made when two of these three manifestations ..