{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T16:06:33Z","timestamp":1769789193200,"version":"3.49.0"},"reference-count":42,"publisher":"The Endocrine Society","issue":"10","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2003,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>In autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, hypoparathyroidism (HP) is the most common endocrine component. It occurs in most (but not all) patients. Determinants of its occurrence are unknown, and there is no proof for its autoimmune nature. Recently, the Ca2+-sensing receptor (CaSR) was reported to be an autoantigen in HP. With our group of 90 patients, we aimed at identifying the determinants and pathomechanism of HP. For the determinants, we evaluated gender and the HLA class II. For the pathomechanism, we searched for parathyroid autoantibodies, including antibodies against CaSR and PTH. Also, we studied whether AIRE is expressed in the human parathyroid, because its absence could be a pathogenetic factor. We found a clear gender linkage with lower and later incidence in males. Of the 14 patients who had escaped HP, 13 were males. This was associated with adrenal failure, which was the first or only endocrinopathy in 47% of males vs. 7% of females. In contrast, we found no linkage to the HLA class II. By immunofluorescence, 19% of the patients had antibodies to parathyroid epithelia. By immunoblotting, these recognized several parathyroid proteins. No antibodies were observed against the CaSR or PTH. By RT-PCR, AIRE mRNA was not found in the parathyroid.<\/jats:p>","DOI":"10.1210\/jc.2003-030700","type":"journal-article","created":{"date-parts":[[2003,10,13]],"date-time":"2003-10-13T17:42:51Z","timestamp":1066066971000},"page":"4602-4608","source":"Crossref","is-referenced-by-count":56,"title":["The Hypoparathyroidism of Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy Protective Effect of Male Sex"],"prefix":"10.1210","volume":"88","author":[{"given":"Mikhail","family":"Gylling","sequence":"first","affiliation":[{"name":"Department of Bacteriology and Immunology (M.G., E.K., L.K., A.M.), University of Helsinki, FIN-00014 Helsinki, Finland"},{"name":"Department of Immunology (M.G., R.V., L.K., M.-L.S., A.M.), Helsinki University Central Hospital Laboratory Diagnostics, FIN-00290 Helsinki, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Essi","family":"Ka\u0308a\u0308ria\u0308inen","sequence":"additional","affiliation":[{"name":"Department of Bacteriology and Immunology (M.G., E.K., L.K., A.M.), University of Helsinki, FIN-00014 Helsinki, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Riitta","family":"Va\u0308isa\u0308nen","sequence":"additional","affiliation":[{"name":"Department of Immunology (M.G., R.V., L.K., M.-L.S., A.M.), Helsinki University Central Hospital Laboratory Diagnostics, FIN-00290 Helsinki, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Kerosuo","sequence":"additional","affiliation":[{"name":"Department of Bacteriology and Immunology (M.G., E.K., L.K., A.M.), University of Helsinki, FIN-00014 Helsinki, Finland"},{"name":"Department of Immunology (M.G., R.V., L.K., M.-L.S., A.M.), Helsinki University Central Hospital Laboratory Diagnostics, FIN-00290 Helsinki, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marja-Liisa","family":"Solin","sequence":"additional","affiliation":[{"name":"Department of Immunology (M.G., R.V., L.K., M.-L.S., A.M.), Helsinki University Central Hospital Laboratory Diagnostics, FIN-00290 Helsinki, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leena","family":"Halme","sequence":"additional","affiliation":[{"name":"Department of Surgery (L.H.), Helsinki University Hospital, FIN-00014 Helsinki, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seppo","family":"Saari","sequence":"additional","affiliation":[{"name":"National Veterinary and Food Research Institute (S.S.), FIN-00581 Helsinki, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Halonen","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine (M.H.), National Public Health Institute, FIN-00300 Helsinki, Finland"},{"name":"The Hospital for Children and Adolescents (M.H., J.P.), University of Helsinki, FIN-00290 Helsinki, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Olle","family":"Ka\u0308mpe","sequence":"additional","affiliation":[{"name":"Department of Medical Science (O.K.), University Hospital, SE-75185, Uppsala, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jaakko","family":"Perheentupa","sequence":"additional","affiliation":[{"name":"The Hospital for Children and Adolescents (M.H., J.P.), University of Helsinki, FIN-00290 Helsinki, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aaro","family":"Miettinen","sequence":"additional","affiliation":[{"name":"Department of Bacteriology and Immunology (M.G., E.K., L.K., A.M.), University of Helsinki, FIN-00014 Helsinki, Finland"},{"name":"Department of Immunology (M.G., R.V., L.K., M.-L.S., A.M.), Helsinki University Central Hospital Laboratory Diagnostics, FIN-00290 Helsinki, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"80","reference":[{"key":"2020071617261663400_R1","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1038\/ng1297-399","article-title":"An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domain.","volume":"17","year":"1997","journal-title":"Nat Genet"},{"key":"2020071617261663400_R2","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1038\/ng1297-393","article-title":"Positional cloning of the APECED gene.","volume":"17","author":"Nagamine","year":"1997","journal-title":"Nat Genet"},{"key":"2020071617261663400_R3","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.1126\/science.1075958","article-title":"Projection of immunological self-shadow within the thymus by the AIRE protein.","volume":"298","author":"Anderson","year":"2002","journal-title":"Science"},{"key":"2020071617261663400_R4","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1038\/ni906","article-title":"AIRE regulates negative selection of organ-specific T cells.","volume":"4","author":"Liston","year":"2003","journal-title":"Nat Immunol"},{"key":"2020071617261663400_R5","doi-asserted-by":"crossref","first-page":"1829","DOI":"10.1056\/NEJM199006283222601","article-title":"Clinical variation of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) in a series of 68 patients.","volume":"322","author":"Ahonen","year":"1990","journal-title":"N Engl J Med"},{"key":"2020071617261663400_R6","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1016\/S0889-8529(01)00013-5","article-title":"APS-I\/APECED: the clinical disease and therapy.","volume":"31","author":"Perheentupa","year":"2002","journal-title":"Endocrinol Metab Clin North Am"},{"key":"2020071617261663400_R7","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1210\/jcem-64-3-494","article-title":"Adrenal and steroidal cell antibodies in patients with autoimmune polyglandular disease type I and risk of adrenocortical and ovarian failure.","volume":"64","author":"Ahonen","year":"1987","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071617261663400_R8","first-page":"1488","article-title":"Antibodies to glutamic acid decarboxylase and insulin-dependent diabetes in patients with autoimmune polyendocrine syndrome type I.","volume":"81","author":"Tuomi","year":"1996","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071617261663400_R9","first-page":"119","article-title":"The incidence of parathyroid and other antibodies in the sera of patients with idiopathic hypoparathyroidism.","volume":"1","author":"Blizzard","year":"1966","journal-title":"Clin Exp Immunol"},{"key":"2020071617261663400_R10","first-page":"505","article-title":"Antibody to the oxyphil cells of the human parathyroid in idiopathic hypoparathyroidism.","volume":"4","author":"Irvine","year":"1969","journal-title":"Clin Exp Immunol"},{"key":"2020071617261663400_R11","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/S0140-6736(75)90004-5","article-title":"Autoantibodies to prolactin-secreting cells of human pituitary.","volume":"1","author":"Bottazzo","year":"1975","journal-title":"Lancet"},{"key":"2020071617261663400_R12","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1002\/jbmr.5650010512","article-title":"Parathyroid cell surface autoantibodies that inhibit parathyroid hormone secretion from dispersed human parathyroid cells.","volume":"1","author":"Posillico","year":"1986","journal-title":"J Bone Miner Res"},{"key":"2020071617261663400_R13","first-page":"889","article-title":"Parathyroid and other autoantibodies in patients with autoimmune polyendocrinopathy-candidosis-ectodermal dystrophy (APECED).","volume":"16","author":"Miettinen","year":"1982","journal-title":"Pediatr Res"},{"key":"2020071617261663400_R14","doi-asserted-by":"crossref","first-page":"8366","DOI":"10.1073\/pnas.83.21.8366","article-title":"Antibodies cytotoxic to bovine parathyroid cells in autoimmune hypoparathyroidism.","volume":"83","author":"Brandi","year":"1986","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071617261663400_R15","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1530\/eje.0.1430497","article-title":"Organ-specific and non-organ-specific autoantibodies in children and young adults with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED).","volume":"143","author":"Perniola","year":"2000","journal-title":"Eur J Endocrinol"},{"key":"2020071617261663400_R16","doi-asserted-by":"crossref","first-page":"4015","DOI":"10.1073\/pnas.85.11.4015","article-title":"Anti-endothelial cell antibodies: detection and characterization in sera from patients with autoimmune hypoparathyroidism.","volume":"85","author":"Fattorossi","year":"1988","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071617261663400_R17","first-page":"353","article-title":"Demonstration and characterization of anti-human mitochondria autoantibodies in idiopathic hypoparathyroidism and in other conditions.","volume":"62","author":"Betterle","year":"1985","journal-title":"Clin Exp Immunol"},{"key":"2020071617261663400_R18","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1007\/BF03343654","article-title":"Spontaneously occurring anti-PTH autoantibodies must be considered in the differential diagnosis of patients with elevated serum PTH levels.","volume":"22","author":"Cavaco","year":"1999","journal-title":"J Endocrinol Invest"},{"key":"2020071617261663400_R19","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1172\/JCI118513","article-title":"Autoantibodies to the extracellular domain of the calcium sensing receptor in patients with acquired hypoparathyroidism.","volume":"97","author":"Li","year":"1996","journal-title":"J Clin Invest"},{"key":"2020071617261663400_R20","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1006\/bbrc.1999.0308","article-title":"Autoimmune regulator is expressed in the cells regulating immune tolerance in thymus medulla.","volume":"257","author":"Heino","year":"1999","journal-title":"Biochem Biophys Res Commun"},{"key":"2020071617261663400_R21","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1006\/dbio.2001.0342","article-title":"Hoxa3 and Pax1 transcription factors regulate epithelial cells death and proliferation during thymus and parathyroid organogenesis.","volume":"236","author":"Su","year":"2001","journal-title":"Dev Biol"},{"key":"2020071617261663400_R22","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1242\/dev.129.13.3033","article-title":"Eya1 is required for the morphogenesis of mammalian thymus, parathyroid and thyroid.","volume":"129","author":"Xu","year":"2002","journal-title":"Development"},{"key":"2020071617261663400_R23","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1038\/85845","article-title":"DiGeorge syndrome phenotype in mice mutant for the T-box gene, Tbx1.","volume":"27","author":"Jerome","year":"2001","journal-title":"Nat Genet"},{"key":"2020071617261663400_R24","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1038\/85855","article-title":"Mice lacking the homologue of the human 22q11.2 gene CRKL phenocopy neurocristopathies of DiGeorge syndrome.","volume":"27","author":"Guris","year":"2001","journal-title":"Nat Genet"},{"key":"2020071617261663400_R25","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1038\/35018111","article-title":"Genetic ablation of parathyroid glands reveals another source of parathyroid hormone.","volume":"406","author":"Gu\u0308nther","year":"2000","journal-title":"Nature"},{"key":"2020071617261663400_R26","first-page":"912","article-title":"A thymoma as a cause of true ectopic hyperparathyroidism","volume":"79","author":"Rizzoli","year":"1994","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071617261663400_R27","first-page":"4434","article-title":"\u03b2-cell autoantibodies, human leukocyte antigen II alleles, and type 1 diabetes in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.","volume":"85","author":"Gylling","year":"2000","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071617261663400_R28","doi-asserted-by":"crossref","first-page":"3842","DOI":"10.1210\/endo.137.9.8756555","article-title":"Expression of a calcium-sensing receptor in a human medullary thyroid carcinoma cell line and its contribution to calcitonin secretion.","volume":"137","author":"Freichel","year":"1996","journal-title":"Endocrinology"},{"key":"2020071617261663400_R29","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1006\/jaut.1997.0154","article-title":"A novel micro-assay for insulin autoantibodies.","volume":"10","author":"Williams","year":"1997","journal-title":"J Autoimmun"},{"key":"2020071617261663400_R30","doi-asserted-by":"crossref","first-page":"2568","DOI":"10.1210\/jcem.87.6.8564","article-title":"AIRE mutations and human leukocyte antigen genotypes as determinants of the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy phenotype.","volume":"87","author":"Halonen","year":"2002","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071617261663400_R31","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1016\/S1470-2045(02)00776-3","article-title":"An oncological view on the blood-testis barrier.","volume":"3","author":"Bart","year":"2002","journal-title":"Lancet Oncol"},{"key":"2020071617261663400_R32","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1038\/ni0901-777","article-title":"Sex differences in autoimmune disease.","volume":"2","author":"Whitacre","year":"2001","journal-title":"Nat Immunol"},{"key":"2020071617261663400_R33","doi-asserted-by":"crossref","first-page":"2060","DOI":"10.4049\/jimmunol.167.4.2060","article-title":"Testosterone acts directly on CD4+ T lymphocytes to increase IL-10 production.","volume":"167","author":"Liva","year":"2001","journal-title":"J Immunol"},{"key":"2020071617261663400_R34","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1016\/S1043-2760(01)00435-0","article-title":"Genetics and animal models of hypoparathyroidism.","volume":"12","author":"Garfield","year":"2001","journal-title":"Trends Endocrinol Metab"},{"key":"2020071617261663400_R35","first-page":"379","article-title":"Addison\u2019s disease, ovarian failure and hypoparathyroidism.","volume":"4","author":"Irvine","year":"1975","journal-title":"Clin Endocrinol (Oxf)"},{"key":"2020071617261663400_R36","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1111\/j.1939-1676.1988.tb01971.x","article-title":"Primary hypoparathyroidism in the dog. Report of 15 cases and review of 13 previously reported cases.","volume":"2","author":"Bruyette","year":"1988","journal-title":"J Vet Intern Med"},{"key":"2020071617261663400_R37","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1677\/joe.0.1310193","article-title":"Parathyroiditis in the non-obese diabetic mouse\u2014a new finding.","volume":"131","author":"Krug","year":"1991","journal-title":"J Endocrinol"},{"key":"2020071617261663400_R38","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1016\/S0140-6736(71)91750-8","article-title":"Hypoparathyroidism and cell-mediated immunity.","volume":"1","author":"Moulias","year":"1971","journal-title":"Lancet"},{"key":"2020071617261663400_R39","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1016\/0002-9343(92)90263-B","article-title":"T-lymphocyte activation in adult-onset idiopathic hypoparathyroidism","volume":"92","author":"Wortsman","year":"1992","journal-title":"Am J Med"},{"key":"2020071617261663400_R40","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1128\/CDLI.3.2.143-146.1996","article-title":"Celiac disease and hypoparathyroidism: cross-reaction of endomysial antibodies with parathyroid tissue.","volume":"3","author":"Kumar","year":"1996","journal-title":"Clin Diagn Lab Immunol"},{"key":"2020071617261663400_R41","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1210\/jc.2002-020249","article-title":"A syndrome of hypocalciuric hypercalcemia caused by autoantibodies directed at the calcium-sensing receptor.","volume":"88","author":"Kifor","year":"2003","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071617261663400_R42","doi-asserted-by":"crossref","first-page":"1032","DOI":"10.1038\/ni723","article-title":"Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self.","volume":"2","author":"Derbinski","year":"2001","journal-title":"Nat Immunol"}],"container-title":["The Journal of Clinical Endocrinology &amp; Metabolism"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/jcem\/article-pdf\/88\/10\/4602\/10402763\/jcem4602.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/jcem\/article-pdf\/88\/10\/4602\/10402763\/jcem4602.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,6,12]],"date-time":"2021-06-12T00:46:32Z","timestamp":1623458792000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jcem\/article\/88\/10\/4602\/2845715"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2003,10,1]]},"references-count":42,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2003,10,1]]}},"URL":"https:\/\/doi.org\/10.1210\/jc.2003-030700","relation":{},"ISSN":["0021-972X","1945-7197"],"issn-type":[{"value":"0021-972X","type":"print"},{"value":"1945-7197","type":"electronic"}],"subject":[],"published":{"date-parts":[[2003,10,1]]}}}