Endocrine Abstracts (2007) 13 P292

The calcium-sensing receptor is a target of autoantibodies in patients with autoimmune polyendocrine syndrome type 1

Nikos Gavalas1, Elizabeth Kemp1, Kai Krohn2, Edward Brown3, Philip Watson1 & Anthony Weetman1

1University of Sheffield, Sheffield, United Kingdom; 2University of Tampere, Tampere, Finland; 3Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, United States.

Autoimmune polyendocrine syndrome type 1 (APS1) is a rare autosomal recessive disorder caused by mutations in the autoimmune regulator gene. Major disease components include mucocutaneous candidiasis, hypoparathyroidism and Addison’s disease. Acquired hypoparathyroidism (AH) occurs in 80% of APS1 patients and is associated with hypocalcaemia, hyperphosphataemia and low serum levels of parathyroid hormone (PTH). Reports suggest that these clinical symptoms are initiated by the inhibition of PTH secretion due to the binding of autoantibodies to parathyroid cells. One targeted autoantigen was initially identified as the G-coupled calcium-sensing receptor (CaSR) which plays a pivotal role in maintaining calcium homeostasis by sensing circulating calcium levels and regulating PTH synthesis and release. However, controversy surrounds the detection of CaSR autoantibodies in APS1 patients. The aim of the present work was to analyse a defined set of APS1 patient sera for the presence of CaSR antibodies using different assay systems.

In the immunoprecipitation assay with the CaSR expressed in human embryonic kidney 293 cells, 12/14 (85.7%) APS1 patients, 2/10 (20%) GD patients but no AD patients or healthy controls were positive for CaSR antibodies. The frequency of receptor antibodies in the APS1 patient group was significantly greater than that in the cohort of healthy individuals (P< 0.0001 and P=0.103, respectively). In a flow cytometry assay, 5/10 (50%) APS1 patient sera showed binding to the extracellular domain of the CaSR. The frequency of receptor antibodies in the APS1 patient group was again significantly greater than that in the group of healthy controls (P=0.036). No CaSR antibodies could be detected in patients or controls using a radiobinding assay with in vitro translated CaSR as the ligand. The CaSR is an in APS1 but detection of antibodies against the receptor appears to be influenced by the assay system used.

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