Copenhagen Research Center of Autoimmune Connective Tissue Diseases (COPEACT), Copenhagen University Hospital, Rigshospitalet, Denmark.
Copenhagen Research Center of Autoimmune Connective Tissue Diseases (COPEACT), Copenhagen University Hospital, Rigshospitalet, Denmark.
J Autoimmun. 2022 Oct;132:102869. doi: 10.1016/j.jaut.2022.102869. Epub 2022 Aug 4.
Upregulation of interferon-regulated genes (IRGs), denoted IFN signature, in peripheral blood has been used as an indirect measure of IFN pathway activation in patients with systemic lupus erythematosus (SLE). However, it has not been determined, which IFN signatures that optimally reflect clinical disease activity. In this study, we determined an IFN signature based on the expression of 128 IRGs in whole blood from 34 SLE patients in a cross-sectional (CS) study, 11 with active lupus nephritis followed longitudinally (LS) and 15 healthy controls. Blood samples were collected in PAXgene tubes and RNA was extracted and purified using a PAXgene blood RNA kit (Qiagen). Gene expression was measured using the NanoString nCounter Gene Expression platform. The CS SLE patients with higher disease activity displayed thrice as many upregulated IRGs (n = 46) as the rest. These IRGs clustered in three groups, consisting of IRGs known to be predominantly stimulated by type I (gene cluster K1) and type II (gene clusters K2 and 3) IFNs. SLEDAI-2K scores associated with the K2 and K3 gene scores (β = 0.372 and β = 0.419, both p < 0.015) but not with K1. In the longitudinal study, the mean SLEDAI-2K score decreased after an average follow-up of 360 days (β = -2.08, P = 5.09 × 10). The mean K1, K2 and K3 gene scores did not change over time, however longitudinal changes in SLEDAI-2K and K3 scores were associated (β = 0.814, p = 0.007). This study validates the presence of type I IRG subsets that do not associate with disease activity in SLE patients. The novel finding in this study is the association between a type II IRG subset and disease activity. Both findings may have significant implications for choosing IRGs defining clinically relevant IFN signatures.
干扰素调节基因（IRGs）的上调，称为 IFN 特征，已被用作系统性红斑狼疮（SLE）患者 IFN 途径激活的间接衡量标准。然而，尚未确定哪种 IFN 特征能最佳地反映临床疾病活动。在这项研究中，我们基于 34 例 SLE 患者横断面（CS）研究中全血 128 个 IRG 的表达，确定了一个 IFN 特征，其中 11 例有活动性狼疮肾炎，并进行了纵向（LS）随访，15 例为健康对照。血液样本用 PAXgene 管收集，用 PAXgene 血液 RNA 试剂盒（Qiagen）提取和纯化 RNA。使用 NanoString nCounter 基因表达平台测量基因表达。CS 中疾病活动度较高的 SLE 患者有多达三倍的上调 IRGs（n=46），与其余患者相比。这些 IRG 聚类为三组，包括主要由 I 型（基因簇 K1）和 II 型（基因簇 K2 和 3）IFN 刺激的 IRG。SLEDAI-2K 评分与 K2 和 K3 基因评分相关（β=0.372 和 β=0.419，均 p<0.015），但与 K1 不相关。在纵向研究中，平均随访 360 天后，SLEDAI-2K 平均评分下降（β=-2.08，P=5.09×10）。K1、K2 和 K3 基因评分随时间没有变化，但 SLEDAI-2K 和 K3 评分的纵向变化相关（β=0.814，p=0.007）。这项研究验证了在 SLE 患者中存在与疾病活动无关的 I 型 IRG 亚群。本研究的新发现是 II 型 IRG 亚群与疾病活动之间的关联。这两个发现都可能对选择定义临床相关 IFN 特征的 IRG 具有重要意义。
