Division of Rheumatology and Immunology, Medical University of South Carolina, Charleston, South Carolina, USA.
Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China.
Ann Rheum Dis. 2022 Feb;81(2):255-267. doi: 10.1136/annrheumdis-2021-220793. Epub 2021 Sep 23.
We previously identified a hypomorphic variant, p.Arg90His (p.R90H) of neutrophil cytosolic factor 1 ( a regulatory subunit of phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 complex), as an putative causal variant for systemic lupus erythematosus (SLE), and established a knock-in (KI) H90 variant in the C57BL/6 background to study how this variant promotes lupus development.
Wild type (WT) and KI littermates were assessed for immune profiles and lupus-like features. Disease activity and renal damage of patients with SLE were assessed by systemic lupus erythematosus disease activity index (SLEDAI) and renal items of systemic lupus international collaborating clinics (SLICC), respectively.
Compared with WT littermates, 5-week-old homozygous KI mice had reduced oxidative burst, splenomegaly, elevated type I interferon (IFN-I) scores, increased ratios of splenic follicular T helper 2 (Tfh2) to either T follicular regulatory (Tfr) or Tfh1 cells, increased ANA follicular, germinal centre and plasma cells without spontaneous kidney disease up to 1 year of age. Pristane treatment exacerbated the immune dysregulation and induced IFN-I-dependent kidney disease in 36-week-old H90 KI female mice. Decreased efferocytosis of macrophages derived from KI mice and patients with homozygous H90 SLE promoted elevated ratios of Tfh2/Tfr and Tfh2/Tfh1 as well as dysregulated humoral responses due to reduced voltage-gated proton channel 1 (Hv1)-dependent acidification of phagosome pH to neutralise the decreased electrogenic effect of the H90 variant, resulting in impaired maturation and phagosome proteolysis, and increased autoantibody production and kidney damage in mice and patients with SLE of multiple ancestries.
A lupus causal variant, NCF1-H90, reduces macrophage efferocytosis, enhances Tfh2 responses and promotes autoantibody production and kidney damage in both mice and patients with SLE.
我们之前鉴定出中性粒细胞胞浆因子 1（吞噬细胞烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶 2 复合物的调节亚基）的一个低功能变体，p.Arg90His（p.R90H），是系统性红斑狼疮（SLE）的一个潜在致病变体，并在 C57BL/6 背景下建立了一个 knock-in（KI）H90 变体，以研究该变体如何促进狼疮的发展。
评估野生型（WT）和 KI 同窝仔鼠的免疫特征和狼疮样特征。通过系统性红斑狼疮疾病活动指数（SLEDAI）和系统性红斑狼疮国际合作诊所（SLICC）的肾脏项目分别评估 SLE 患者的疾病活动度和肾脏损害。
与 WT 同窝仔鼠相比，5 周龄纯合子 KI 小鼠的氧化爆发减少，脾肿大，I 型干扰素（IFN-I）评分升高，脾滤泡辅助性 T 细胞 2（Tfh2）与滤泡调节性 T（Tfr）或 Tfh1 细胞的比值增加，ANA 滤泡、生发中心和浆细胞增加，在 1 岁之前没有自发的肾脏疾病。36 周龄 H90KI 雌性小鼠用 pristane 处理后，免疫失调加剧，并诱导 IFN-I 依赖性肾脏疾病。来自 KI 小鼠和具有纯合 H90SLE 的患者的巨噬细胞的吞噬作用减少，由于 H90 变体的电压门控质子通道 1（Hv1）依赖性吞噬体 pH 酸化减少，电生成效应降低，导致吞噬体 pH 中性化，促进了 Tfh2/Tfr 和 Tfh2/Tfh1 的比值升高以及体液反应失调，从而导致成熟和吞噬体蛋白水解受损，以及自身抗体产生增加和多种祖源的 SLE 患者的肾脏损害。
一个狼疮致病变体，NCF1-H90，降低了巨噬细胞的吞噬作用，增强了 Tfh2 反应，并促进了小鼠和 SLE 患者的自身抗体产生和肾脏损害。
