The NCF1 variant p.R90H aggravates autoimmunity by facilitating the activation of plasmacytoid dendritic cells.
The NCF1 variant p.R90H aggravates autoimmunity by facilitating the activation of plasmacytoid dendritic cells.
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DOI：
10.1172/jci153619
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发表时间：
2022-08-15
影响因子：
15.9
通讯作者：
Shen, Nan
中科院分区：
文献类型：
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作者：
Meng, Yao;Ma, Jianyang;Yao, Chao;Ye, Zhizhong;Ding, Huihua;Liu, Can;Li, Jun;Li, Guanhua;He, Yuke;Li, Jia;Yin, Zhihua;Wen, Li;Zhou, Haibo;Shen, Nan
浆细胞样树突状细胞(PDCs)是一种产生I型干扰素的专业性细胞，在自身免疫性疾病的发病机制中发挥重要作用。然而，PDCs功能的遗传调控及其与自身免疫的关系在很大程度上还不确定。在这里，我们调查了中性粒细胞胞浆因子1(NCF1)错义变体的因果关系，它是狼疮最重要的相关危险变量之一，并发现NCF1蛋白(NCF1p.R90H)第90位的精氨酸(R)替代组氨酸(H)导致pDC过度激活。一项机制研究表明，p.R90H降低了NCF1对磷脂的亲和力，从而损害了NCF1的内体定位。由于NCF1是NADPH氧化酶2(NOX2)复合体的一个亚单位，这种损伤导致内体pH酸化，并促进下游TLR信号转导。一致地，在PDC依赖的狼疮模型中，纯合子敲门小鼠表现出狼疮进展的加重。更重要的是，药物干预显示，在狼疮模型和系统性红斑狼疮标本中，羟基氯喹(HCQ)可以拮抗NCF1 p.R90H的有害功能，支持NCF1 p.R90H可以被确定为HCQ应用的遗传生物标志物的观点。因此，我们的研究为PDC功能的遗传控制提供了洞察力，并为应用遗传变异来改进自身免疫性疾病的靶向治疗提供了范例。
Plasmacytoid dendritic cells (pDCs) are a professional type I IFN producer that play critical roles in the pathogenesis of autoimmune diseases. However, both genetic regulation of the function of pDCs and their relationships with autoimmunity are largely undetermined. Here, we investigated the causality of the neutrophil cytosolic factor 1 (NCF1) missense variant, which is one of the most significant associated risk variants for lupus, and found that the substitution of arginine (R) for histidine (H) at position 90 in the NCF1 protein (NCF1 p.R90H) led to excessive activation of pDCs. A mechanism study demonstrated that p.R90H reduced the affinity of NCF1 for phospholipids, thereby impairing endosomal localization of NCF1. As NCF1 is a subunit of the NADPH oxidase 2 (NOX2) complex, this impairment led to an acidified endosomal pH and facilitated downstream TLR signaling. Consistently, the homozygous knockin mice manifested aggravated lupus progression in a pDC-dependent lupus model. More important, pharmaceutical intervention revealed that hydroxychloroquine (HCQ) could antagonize the detrimental function of NCF1 p.R90H in the lupus model and systemic lupus erythematosus samples, supporting the idea that NCF1 p.R90H could be identified as a genetic biomarker for HCQ application. Therefore, our study provides insights into the genetic control of pDC function and a paradigm for applying genetic variants to improve targeted therapy for autoimmune diseases.