Yuan Xinran, Qin Xiaodong, Takemoto Kenji, Zhao Jian, Sanderson Matthew, Xu Xue, Zhang Yu, Helke Kristi L, Jacobs Wolf Bethany, Guthridge Joel M, James Judith A, Zhou Xiaodong, Assassi Shervin, Feghali-Bostwick Carol, Wang Dandan, Sun Lingyun, Tsao Betty P
Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA; Department of Rheumatology and Immunology, Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital, Nanjing, Jiangsu, China.
Department of Orthopedic Surgery, Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital, Nanjing, China.
Ann Rheum Dis. 2025 Feb;84(2):294-306. doi: 10.1136/ard-2024-226034. Epub 2025 Jan 2.
We assessed the role of a systemic lupus erythematosus causal hypofunctional variant, neutrophil cytosolic factor 1 (NCF1)-p.Arg90His (p.R90H) substitution, in systemic sclerosis (SSc).
Association of NCF1-H90 with SSc was performed in case-control cohorts, bleomycin (BLM)-treated Ncf1-R90 C57BL/6 wildtype and Ncf1-H90 knock-in (KI) littermates. Peripheral blood mononuclear cell (PBMC) subsets were analysed by cytometry by time-of-flight.
The NCF1-H90 allele is associated with risk for diffuse cutaneous SSc (dcSSc) in Chinese and European Americans, and lung fibrosis in Chinese patients with SSc (OR=2.09, p=7.96E-10). Low copy number of NCF1 associated with lung fibrosis in European Americans (OR=4.33, p=2.60E-2). BLM-treated KI mice demonstrated increased pulmonary fibrosis, exhibiting activated type I interferon signature, elevated Spp1, Ccl2, Arg1, Timp1 and Il6 expression, enriched macrophage scores in lung tissues. In a longitudinal observation cohort, homozygous H90 patients with SSc at baseline had increased anti-nuclear antibody titres, anti-topoisomerase antibody seropositivity and anti-centromere antibody seronegativity, increased incidence of lung fibrosis and Gender-Age-lung Physiology index, elevated modified Rodnan Skin Score (mRSS) and elevated plasma osteopontin (OPN, SPP1), CCL2, ARG1, TIMP-1 and IL-6. These H90 patients with SSc sustained elevated mRSS during follow-up years with decreased survival. The 0, 1 and 2 copies of H90 carriage in SSc PBMCs exhibited dose-dependent increases in profibrotic CD14CD68CD11bTim3monocytes. Elevated OPN, CCL2 and ARG1 in CD68CD11bmonocyte-derived macrophages from H90 patients were decreased after co-culturing with anti-CCL2 antibody.
Low NCF1 activity increases the risk for the development of dcSSc and lung fibrosis via expanding profibrotic SPP1MoMs in a CCL2-dependent manner, contributing to the severity of lung fibrosis in both BLM-treated mice and patients with SSc.
我们评估了系统性红斑狼疮致病性功能减退变异体中性粒细胞胞质因子1（NCF1）-p.Arg90His（p.R90H）替代在系统性硬化症（SSc）中的作用。
在病例对照队列、博来霉素（BLM）处理的Ncf1-R90 C57BL/6野生型和Ncf1-H90基因敲入（KI）同窝小鼠中进行NCF1-H90与SSc的关联研究。通过飞行时间流式细胞术分析外周血单个核细胞（PBMC）亚群。
NCF1-H90等位基因与中国人和欧裔美国人的弥漫性皮肤型SSc（dcSSc）风险以及中国SSc患者的肺纤维化相关（OR = 2.09，p = 7.96E - 10）。NCF1低拷贝数与欧裔美国人的肺纤维化相关（OR = 4.33，p = 2.60E - 2）。BLM处理的KI小鼠表现出肺纤维化增加，呈现激活的I型干扰素特征，Spp1、Ccl2、Arg1、Timp1和Il6表达升高，肺组织中巨噬细胞评分增加。在一个纵向观察队列中，基线时携带纯合H90的SSc患者抗核抗体滴度增加、抗拓扑异构酶抗体血清阳性和抗着丝点抗体血清阴性，肺纤维化发生率和性别 - 年龄 - 肺生理指数增加，改良罗丹皮肤评分（mRSS）升高以及血浆骨桥蛋白（OPN，SPP1）、CCL2、ARG1、TIMP - 1和IL - 6升高。这些携带H90的SSc患者在随访期间mRSS持续升高且生存率降低。SSc患者PBMC中H90携带的0、1和2拷贝呈现促纤维化的CD14CD68CD11bTim3单核细胞剂量依赖性增加。与抗CCL2抗体共培养后，H90患者CD68CD11b单核细胞衍生巨噬细胞中升高的OPN、CCL2和ARG1降低。
低NCF1活性通过以CCL2依赖的方式扩增促纤维化SPP1MoM增加dcSSc和肺纤维化的发生风险，导致BLM处理的小鼠和SSc患者肺纤维化的严重程度增加。
