OBJECTIVE Type I interferon (IFN) responses are broadly associated with autoimmune diseases, including systemic lupus erythematosus (SLE). Given the cardinal role of autoantibodies in SLE, this study was undertaken to investigate whether the findings of a B cell-specific IFN assay correlate with SLE activity. METHODS B cells and peripheral blood mononuclear cells (PBMCs) were stimulated with type I IFN and type II IFN. Gene expression was analyzed, and the expression of pathway-related membrane proteins was determined. A flow cytometry assay for tetherin (CD317), an IFN-induced protein ubiquitously expressed on leukocytes, was validated in vitro and then clinically against SLE diagnosis, plasmablast expansion, and the British Isles Lupus Assessment Group (BILAG) 2004 score in a discovery cohort (n = 156 SLE patients, 30 rheumatoid arthritis [RA] patients, and 25 healthy controls). A second, longitudinal validation cohort of 80 SLE patients was also evaluated for flare prediction. RESULTS In vitro, a close cell-specific and dose-response relationship between type I IFN-responsive genes and cell surface tetherin was observed in all immune cell subsets. Tetherin expression on multiple cell subsets was selectively responsive to stimulation with type I IFN compared to types II and III IFNs. In patient samples from the discovery cohort, memory B cell tetherin showed the strongest associations with diagnosis (SLE:healthy control effect size 0.11 [P = 0.003]; SLE:RA effect size 0.17 [P < 0.001]), plasmablast numbers in rituximab-treated patients (R = 0.38, P = 0.047), and BILAG 2004. These associations were equivalent to or stronger than those for IFN score or monocyte tetherin. Memory B cell tetherin was found to be predictive of future clinical flares in the validation cohort (hazard ratio 2.29 [95% confidence interval 1.01-4.64]; P = 0.022). CONCLUSION Our findings indicate that memory B cell surface tetherin, a B cell-specific IFN assay, is associated with SLE diagnosis and disease activity, and predicts flares better than tetherin on other cell subsets or whole blood assays, as determined in an independent validation cohort.

中文翻译：

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B 细胞系链蛋白：对 I 型干扰素反应的流式细胞仪细胞特异性测定可预测系统性红斑狼疮的临床特征和发作。

目标 I 型干扰素 (IFN) 反应与自身免疫性疾病广泛相关，包括系统性红斑狼疮 (SLE)。鉴于自身抗体在 SLE 中的主要作用，本研究旨在调查 B 细胞特异性 IFN 测定的结果是否与 SLE 活性相关。方法 B 细胞和外周血单个核细胞 (PBMCs) 用 I 型干扰素和 II 型干扰素刺激。分析基因表达，确定通路相关膜蛋白的表达。tetherin (CD317) 的流式细胞术测定法是一种在白细胞上普遍表达的 IFN 诱导蛋白，它在体外得到验证，然后在临床上针对 SLE 诊断、浆母细胞扩增和不列颠群岛狼疮评估组 (BILAG) 2004 年评分在一个发现队列中进行了验证（n = 156 名 SLE 患者，30 名类风湿性关节炎 [RA] 患者和 25 名健康对照者）。还评估了 80 名 SLE 患者的第二个纵向验证队列的发作预测。结果 在体外，在所有免疫细胞亚群中观察到 I 型 IFN 反应基因和细胞表面 tetherin 之间密切的细胞特异性和剂量反应关系。与 II 型和 III 型 IFN 相比，多个细胞亚群上的 Tetherin 表达选择性地响应 I 型 IFN 的刺激。在来自发现队列的患者样本中，记忆 B 细胞系链蛋白显示出与诊断最强的关联（SLE：健康对照效应大小 0.11 [P = 0.003]；SLE：RA 效应大小 0.17 [P < 0.001]），利妥昔单抗中的浆母细胞数量-接受治疗的患者（R = 0.38，P = 0.047）和 BILAG 2004。这些相关性与 IFN 评分或单核细胞系链蛋白的相关性相当或更强。在验证队列中发现记忆 B 细胞系链蛋白可预测未来的临床发作（风险比 2.29 [95% 置信区间 1.01-4.64]；P = 0.022）。结.