Goswami Ravinder, Brown Edward M, Kochupillai Narayana, Gupta Nandita, Rani Rajni, Kifor Olga, Chattopadhyay Naibedya
Department of Endocrinology and Metabolism, All India Institute of Medical Sciences, New Delhi 110029, India.
Eur J Endocrinol. 2004 Jan;150(1):9-18. doi: 10.1530/eje.0.1500009.
The pathogenesis of sporadic idiopathic hypoparathyroidism is unclear. The calcium sensing receptor (CaSR) plays a pivotal role in extracellular calcium homeostasis and is the candidate autoantigen in hypoparathyroidism associated with autoimmune polyglandular endocrinopathy syndrome. We therefore looked for antibodies (Ab) against the CaSR in patients with sporadic idiopathic hypoparathyroidism and their association, if any, with the major histocompatibility complex (MHC) class II human leukocyte antigen (HLA)-DR haplotypes.
The subjects included 51 patients with sporadic idiopathic hypoparathyroidism and 45 healthy controls. Investigations included computerised tomography, serum calcium, phosphorus, thyroxine, TSH, cortisol, intact parathyroid hormone (iPTH), ACTH and thyroid peroxidase (TPO) and adrenal antibodies. The CaSRAb were assayed in patients' sera by Western blot. Genotyping of the HLA-DR locus was performed using PCR and sequence-specific oligonucleotide probes.
Intracranial calcification and cataract were present in 76.5% and 41.1% of the patients respectively and 62.7% had convulsions. Autoantibodies against the 168 kDa CaSR protein were demonstrated in the serum of 49.0% of the patients and in 13.3% of the controls (P<0.001). Pre-incubating serum samples from the CaSRAb-positive patients with parathyroid membrane produced a 90% decrease in the band intensity. HLA-DRB101 and DRB109 alleles were significantly associated with idiopathic hypoparathyroidism (relative risk of 7.8, P=0.001). The frequency of HLA-DRB109 and DRB110 alleles tended to be higher in patients positive for the CaSRAb. There was no significant difference in the frequency of occurrence of convulsions, cataract, intracranial calcification, calcium:phosphorus ratio, and iPTH levels between patients with and without CaSRAb.
49.0% of the patients studied had serological evidence of organ-specific autoimmunity against the CaSR protein. The occurrence of CaSRAb and the HLA-DR associations imply an autoimmune component to the disease, but the primary role of the CaSRAb in the pathogenesis of the disease needs to be assessed further.
散发性特发性甲状旁腺功能减退症的发病机制尚不清楚。钙敏感受体（CaSR）在细胞外钙稳态中起关键作用，是与自身免疫性多内分泌腺病综合征相关的甲状旁腺功能减退症的候选自身抗原。因此，我们在散发性特发性甲状旁腺功能减退症患者中寻找抗CaSR抗体（Ab），以及它们与主要组织相容性复合体（MHC）Ⅱ类人白细胞抗原（HLA）-DR单倍型的关联（若有）。
研究对象包括51例散发性特发性甲状旁腺功能减退症患者和45名健康对照者。检查项目包括计算机断层扫描、血清钙、磷、甲状腺素、促甲状腺激素、皮质醇、完整甲状旁腺激素（iPTH）、促肾上腺皮质激素（ACTH）以及甲状腺过氧化物酶（TPO）和肾上腺抗体。采用蛋白质印迹法检测患者血清中的CaSRAb。使用聚合酶链反应（PCR）和序列特异性寡核苷酸探针进行HLA-DR基因座的基因分型。
分别有76.5%和41.1%的患者存在颅内钙化和白内障，62.7%的患者有惊厥发作。49.0%的患者血清中检测到针对168 kDa CaSR蛋白的自身抗体，而对照组中这一比例为13.3%（P<0.001）。将CaSRAb阳性患者的血清样本与甲状旁腺膜预先孵育后，条带强度降低了90%。HLA-DRB101和DRB109等位基因与特发性甲状旁腺功能减退症显著相关（相对风险为7.8，P=0.001）。CaSRAb阳性患者中HLA-DRB109和DRB110等位基因的频率往往更高。有无CaSRAb的患者在惊厥发作、白内障、颅内钙化、钙磷比值和iPTH水平的发生率上无显著差异。
49.0%的研究患者有针对CaSR蛋白的器官特异性自身免疫的血清学证据。CaSRAb的出现以及与HLA-DR的关联提示该疾病存在自身免疫成分，但CaSRAb在疾病发病机制中的主要作用仍需进一步评估。
