Alimohammadi Mohammad, Björklund Peyman, Hallgren Asa, Pöntynen Nora, Szinnai Gabor, Shikama Noriko, Keller Marcel P, Ekwall Olov, Kinkel Sarah A, Husebye Eystein S, Gustafsson Jan, Rorsman Fredrik, Peltonen Leena, Betterle Corrado, Perheentupa Jaakko, Akerström Göran, Westin Gunnar, Scott Hamish S, Holländer Georg A, Kämpe Olle
University Hospital, Uppsala University, Uppsala, Sweden.
N Engl J Med. 2008 Mar 6;358(10):1018-28. doi: 10.1056/NEJMoa0706487.
Autoimmune polyendocrine syndrome type 1 (APS-1) is a multiorgan autoimmune disorder caused by mutations in AIRE, the autoimmune regulator gene. Though recent studies concerning AIRE deficiency have begun to elucidate the molecular pathogenesis of organ-specific autoimmunity in patients with APS-1, the autoantigen responsible for hypoparathyroidism, a hallmark of APS-1 and its most common autoimmune endocrinopathy, has not yet been identified.
We performed immunoscreening of a human parathyroid complementary DNA library, using serum samples from patients with APS-1 and hypoparathyroidism, to identify patients with reactivity to the NACHT leucine-rich-repeat protein 5 (NALP5). Subsequently, serum samples from 87 patients with APS-1 and 293 controls, including patients with other autoimmune disorders, were used to determine the frequency and specificity of autoantibodies against NALP5. In addition, the expression of NALP5 was investigated in various tissues.
NALP5-specific autoantibodies were detected in 49% of the patients with APS-1 and hypoparathyroidism but were absent in all patients with APS-1 but without hypoparathyroidism, in all patients with other autoimmune endocrine disorders, and in all healthy controls. NALP5 was predominantly expressed in the cytoplasm of parathyroid chief cells.
NALP5 appears to be a tissue-specific autoantigen involved in hypoparathyroidism in patients with APS-1. Autoantibodies against NALP5 appear to be highly specific and may be diagnostic for this prominent component of APS-1.
1型自身免疫性多内分泌腺综合征（APS-1）是一种多器官自身免疫性疾病，由自身免疫调节基因AIRE突变引起。尽管最近有关AIRE缺陷的研究已开始阐明APS-1患者器官特异性自身免疫的分子发病机制，但导致甲状旁腺功能减退（APS-1的一个标志及其最常见的自身免疫性内分泌病）的自身抗原尚未确定。
我们使用APS-1和甲状旁腺功能减退患者的血清样本对人甲状旁腺互补DNA文库进行免疫筛选，以鉴定对NACHT富含亮氨酸重复蛋白5（NALP5）有反应性的患者。随后，使用来自87例APS-1患者和293例对照（包括其他自身免疫性疾病患者）的血清样本，来确定抗NALP5自身抗体的频率和特异性。此外，还研究了NALP5在各种组织中的表达情况。
在49%的APS-1和甲状旁腺功能减退患者中检测到了NALP5特异性自身抗体，但在所有无甲状旁腺功能减退的APS-1患者、所有其他自身免疫性内分泌疾病患者以及所有健康对照中均未检测到。NALP5主要在甲状旁腺主细胞的细胞质中表达。
NALP5似乎是参与APS-1患者甲状旁腺功能减退的组织特异性自身抗原。抗NALP5自身抗体似乎具有高度特异性，可能对APS-1的这一突出组成部分具有诊断价值。
