Calcium-Sensing Receptor Autoantibodies in Patients with Autoimmune Polyendocrine Syndrome Type 1 : Epitopes, Specificity, Functional Affinity, IgG Subclass, and Effects on Receptor Activity

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Habibullah , M , Porter , J A , Kluger , N , Ranki , A , Krohn , K J E , Brandi , M L , Brown , E M , Weetman , A P & Kemp , E H 2018 , ' Calcium-Sensing Receptor Autoantibodies in Patients with Autoimmune Polyendocrine Syndrome Type 1 : Epitopes, Specificity, Functional Affinity, IgG Subclass, and Effects on Receptor Activity ' , Journal of Immunology , vol. 201 , no. 11 , pp. 3175-3183 . https://doi.org/10.4049/jimmunol.1701527

Title: Calcium-Sensing Receptor Autoantibodies in Patients with Autoimmune Polyendocrine Syndrome Type 1 : Epitopes, Specificity, Functional Affinity, IgG Subclass, and Effects on Receptor Activity
Author: Habibullah, Mahmoud; Porter, Julie A.; Kluger, Nicolas; Ranki, Annamari; Krohn, Kai J. E.; Brandi, Maria L.; Brown, Edward M.; Weetman, Anthony P.; Kemp, E. Helen
Contributor: University of Helsinki, Department of Dermatology, Allergology and Venereology
University of Helsinki, Department of Dermatology, Allergology and Venereology
Date: 2018-12-01
Language: eng
Number of pages: 9
Belongs to series: Journal of Immunology
ISSN: 0022-1767
URI: http://hdl.handle.net/10138/275493
Abstract: A major manifestation of autoimmune polyendocrine syndrome type 1 (APS1) is hypoparathyroidism, which is suggested to result from aberrant immune responses against the parathyroid glands. The calcium-sensing receptor (CaSR), which plays a pivotal role in maintaining calcium homeostasis by sensing blood calcium levels and regulating release of parathyroid hormone (PTH), is an autoantibody target in APS1. In this study, the aim was to characterize the binding sites, specificity, functional affinity, IgG subclass, and functional effects of CaSR autoantibodies using phage-display technology, ELISA, and bioassays. The results indicated that CaSR autoantibody binding sites were at aa 41-69, 114-126, 171-195, and 260-340 in the extracellular domain of the receptor. Autoantibodies against CaSR epitopes 41-69, 171-195, and 260-340 were exclusively of the IgG1 subclass. Autoantibody responses against CaSR epitope 114-126 were predominantly of the IgG1 with a minority of the IgG3 subclass. Only autoantibodies recognizing CaSR epitopes 114-126 and 171-195 affected receptor activity; inositol-phosphate accumulation was increased significantly in HEK293-CaSR cells, and PTH secretion from PTH-C1 cells was reduced significantly when either were incubated with purified Ab and Ca2+ compared with Ca2+ alone. In conclusion, although the majority of APS1 patients do not have CaSR-stimulating autoantibodies, the hypoparathyroid state in a small minority of patients is the result of functional suppression of the parathyroid glands.
Subject: ACQUIRED HYPOCALCIURIC HYPERCALCEMIA
HUMAN CA2+ RECEPTOR
EXTRACELLULAR DOMAIN
ADDISONS-DISEASE
BINDING-SITES
HYPOPARATHYROIDISM
ANTIBODIES
MUTATIONS
MARKERS
3121 General medicine, internal medicine and other clinical medicine
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