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.

中文翻译：

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NCF1 变体 p.R90H 通过促进浆细胞样树突状细胞的活化来加重自身免疫

浆细胞样树突状细胞 (pDC) 是一种专业的 I 型 IFN 产生者，在自身免疫性疾病的发病机制中起关键作用。然而，pDC 功能的遗传调控及其与自身免疫的关系在很大程度上尚未确定。在这里，我们调查了中性粒细胞溶质因子 1（NCF1) 错义变体，这是狼疮最重要的相关风险变体之一，并发现 NCF1 蛋白 (NCF1 p.R90H) 中第 90 位的精氨酸 (R) 取代组氨酸 (H) 导致过度激活pDC。一项机制研究表明，p.R90H 降低了 NCF1 对磷脂的亲和力，从而削弱了 NCF1 的内体定位。由于 NCF1 是 NADPH 氧化酶 2 (NOX2) 复合物的亚基，这种损伤导致内体 pH 值酸化并促进下游 TLR 信号传导。一致地，纯合敲入小鼠在pDC依赖性狼疮模型中表现出加重的狼疮进展。更重要的是，药物干预显示羟氯喹（HCQ）可以拮抗狼疮模型和系统性红斑狼疮样本中 NCF1 p.R90H 的有害功能，支持 NCF1 p.R90H 可以被鉴定为 HCQ 应用的遗传生物标志物的想法。因此，我们的研究提供了对 pDC 功能的遗传控制的见解，以及应用遗传变异改进自身免疫性疾病靶向治疗的范例。