膜联蛋白A自身抗体在儿童肾病综合征中的重要作用及分子机制
The important roles and molecular mechanisms of annexin A autoantibody in children with nephrotic syndrome.
作者信息
Ye Qing, Zhang Yingying, Zhuang Jieqiu, Bi Ye, Xu Hong, Shen Qian, Liu Jialu, Fu Haidong, Wang Jingjing, Feng Chunyue, Tang Xiaoxiao, Liu Fei, Gu Weizhong, Zhao Fei, Zhang Jianjiang, Qin Yuanhan, Shang Shiqiang, Shen Hongqiang, Chen Xuejun, Shen Huijun, Liu Aimin, Xia Yonghui, Lu Zhihong, Shu Qiang, Mao Jianhua
机构信息
Department of Clinical Laboratory, The Children's Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China.
Department of Nephrology, The Children's Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China.
出版信息
Ann Transl Med. 2021 Sep;9(18):1452. doi: 10.21037/atm-21-3988.
BACKGROUND
In recent years, B-cell dysfunction has been found to play an important role in the pathogenesis of primary nephrotic syndrome (PNS). B cells play a pathogenic role by secreting antibodies against their target antigens after transforming into plasma cells. Therefore, this study aimed to screen the autoantibodies that cause PNS and explore their pathogenic mechanisms.
METHODS
Western blotting and mass spectrometry were employed to screen and identify autoantibodies against podocytes in children with PNS. Both and experiments were used to study the pathogenic mechanism of PNS. The results were confirmed in a large multicenter clinical study in children.
RESULTS
Annexin A autoantibody was highly expressed in children with PNS with a pathological type of minimal change disease (MCD) or focal segmental glomerulosclerosis without genetic factors. The mouse model showed that anti-Annexin A antibody could induce proteinuria . Mechanistically, the effect of Annexin A antibody on the Rho signaling pathway was realized through promoting the phosphorylation of Annexin A at Tyr24 on podocytes by reducing its binding to PTP1B, which led to the cytoskeletal rearrangement and damage of podocytes, eventually causing proteinuria and PNS.
CONCLUSIONS
Annexin A autoantibody may be responsible for some cases of PNS with MCD/FSGS in children.
背景
近年来，已发现B细胞功能障碍在原发性肾病综合征（PNS）的发病机制中起重要作用。B细胞转化为浆细胞后通过分泌针对其靶抗原的抗体发挥致病作用。因此，本研究旨在筛选导致PNS的自身抗体并探讨其致病机制。
方法
采用蛋白质印迹法和质谱法筛选和鉴定PNS患儿中针对足细胞的自身抗体。采用体内和体外实验研究PNS的致病机制。研究结果在一项针对儿童的大型多中心临床研究中得到证实。
结果
膜联蛋白A自身抗体在病理类型为微小病变病（MCD）或无遗传因素的局灶节段性肾小球硬化的PNS患儿中高表达。小鼠模型显示抗膜联蛋白A抗体可诱导蛋白尿。机制上，膜联蛋白A抗体对Rho信号通路的作用是通过减少其与蛋白酪氨酸磷酸酶1B（PTP1B）的结合，促进膜联蛋白A在足细胞上Tyr24位点的磷酸化来实现的，这导致足细胞细胞骨架重排和损伤，最终导致蛋白尿和PNS。
结论
膜联蛋白A自身抗体可能是部分儿童MCD/FSGS型PNS病例的病因。
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