ArticleThe Journal of clinical investigation2022
The NCF1 variant p.R90H aggravates autoimmunity by facilitating the activation of plasmacytoid dendritic cells.
Article in The Journal of clinical investigation, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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24 citing papers in PubMed, 29 citations in OpenAlex.
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- Mitochondrial dysfunction in myeloid cells: a central deficit in autoimmune diseases.Trends in immunology · 2025Review
- Whole Exome Sequencing for the Identification of Mutations in Bone Marrow CD34+Cells in Hodgkin Lymphoma.Current issues in molecular biology · 2025Article
- Recent insights into the role of innate immunity in lupus.Human molecular genetics · 2025Review
- Metabolomics and proteomics reveal blocking argininosuccinate synthetase 1 alleviates colitis in mice.Nature communications · 2025Article
- Immunometabolism in systemic lupus erythematosus.Nature reviews. Rheumatology · 2025Review
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- The systemic lupus erythematosus-associated NCF1Nature communications · 2025Article
- Human hypofunctional NCF1 variants promote pulmonary fibrosis in the bleomycin-induced mouse model and patients with systemic sclerosis via expansion of SPP1Annals of the rheumatic diseases · 2025Article
- Whole-Exome Sequencing: Discovering Genetic Causes of Granulomatous Mastitis.International journal of molecular sciences · 2025Article
- Reliable genetic diagnosis ofFrontiers in immunology · 2025Article
- NADPH oxidase in B cells and macrophages protects against murine lupus by regulation of TLR7.JCI insight · 2024Article
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- NADPH oxidase exerts a B cell-intrinsic contribution to lupus risk by modulating endosomal TLR signals.The Journal of experimental medicine · 2024Article
- ATG7/GAPLINC/IRF3 axis plays a critical role in regulating pathogenesis of influenza A virus.PLoS pathogens · 2024Article
- The 330 risk loci known for systemic lupus erythematosus (SLE): a review.Frontiers in lupus · 2024Article
- Deciphering the immunological interactions: targeting preeclampsia with Hydroxychloroquine's biological mechanisms.Frontiers in pharmacology · 2024Review
- Phosphopeptides P140 cause oxidative burst responses of pulmonary macrophages in an imiquimod-induced lupus model.Molecular biomedicine · 2023Article
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14 authors at 3 institutions in 2 countries.
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No grant is acknowledged in the PubMed record.
Abstract
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.
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