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Activating Antibodies to the Calcium-Sensing Receptor in Two Patients with Autoimmune Hypoparathyroidism

Division of Endocrinology (O.K., M.S.L., R.B., I.K., E.M.B.), Diabetes and Hypertension, and Membrane Biology Program, and Department of Surgery (F.D.M.), Brigham and Women’s Hospital, and Harvard Medical School (O.K., M.S.L., R.B., I.K., E.M.B., F.D.M.), Boston, Massachusetts 02115; Department of Endocrinology (A.M.), Royal North Shore Hospital, Sydney, Australia 2065; and Scantibodies Laboratories (P.G., T.L.C.), Santee, California 92071-2861

Address all correspondence and requests for reprints to: Edward M. Brown, M.D., Endocrine-Hypertension Division, Department of Medicine, Brigham and Women’s Hospital, 221 Longwood Avenue, Boston, Massachusetts 02115. E-mail: embrown{at}rics.bwh.harvard.edu.

Autoimmune hypoparathyroidism is thought to result from immune-mediated destruction of the parathyroid glands. We encountered two patients with hypoparathyroidism and other autoimmune conditions (Graves’ disease and Addison’s disease, respectively) in whom autoimmune destruction of the parathyroid glands had not taken place. In the first, a histologically normal parathyroid gland was observed at the time of subtotal thyroidectomy; and in the second, the hypoparathyroidism remitted spontaneously. Both patients had antibodies that reacted with the cell surface of bovine parathyroid cells and human embryonic kidney (HEK293) cells transfected with the extracellular calcium-sensing receptor (CaR) but not with nontransfected HEK293 cells. The antibodies also reacted with the same bands on Western analysis of extracts of bovine parathyroid tissue and CaR-transfected HEK293 cells that were identified by an authentic, polyclonal, anti-CaR antiserum and reacted with several peptides with sequences from the CaR’s extracellular domain. These anti-CaR antibodies activated the receptor based on their ability to increase inositol phosphate accumulation, activate MAPK, and inhibit PTH secretion. These results, therefore, demonstrate that patients with the biochemical findings of primary hypoparathyroidism can harbor activating antibodies to the CaR, which, in the two cases studied here, did not produce irreversible destruction of the parathyroid glands.

This work was supported by the NIH (DK41415, DK48330, and DK52005) and The St. Giles Foundation.

Abbreviations: APS, Autoimmune polyendocrinopathy syndrome; Ca²⁺_i, cytosolic calcium concentration; Ca²⁺_o, extracellular calcium; CaR, calcium-sensing receptor; GF, glomerular filtrate; GFR, glomerular filtration rate; nl., normal; pERK, phospho-ERK; SDS, sodium dodecyl sulfate.

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