干扰素调节基因在幼年皮肌炎与孟德尔自身炎症性干扰素病中的表达。
Expression of interferon-regulated genes in juvenile dermatomyositis versus Mendelian autoinflammatory interferonopathies.
机构信息
Pediatric Translational Research Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, MD, USA.
Environmental Autoimmunity Group, Clinical Research Branch, National Institute of Environmental Health Sciences, NIH, Bethesda, MD, USA.
出版信息
Arthritis Res Ther. 2020 Apr 6;22(1):69. doi: 10.1186/s13075-020-02160-9.
BACKGROUND
Juvenile dermatomyositis (JDM) is a systemic autoimmune disease with a prominent interferon (IFN) signature, but the pathogenesis of JDM and the etiology of its IFN signature remain unknown. The Mendelian autoinflammatory interferonopathies, Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated temperature (CANDLE) and STING-Associated Vasculopathy with onset in Infancy (SAVI), are caused by genetic mutations and have extremely elevated IFN signatures thought to drive pathology. The phenotypic overlap of some clinical features of CANDLE and SAVI with JDM led to the comparison of a standardized interferon-regulated gene score (IRG-S) in JDM and myositis-specific autoantibody (MSA) JDM subgroups, with CANDLE and SAVI.
METHODS
A peripheral 28-component IRG-S assessed by NanoString™ in 57 JDM patients subtyped by MSA was compared with IRG-S in healthy controls (HC) and CANDLE/SAVI patients. Principal component analysis (PCA) was performed, and individual genes were evaluated for their contribution to the score. IRG-S were correlated with disease assessments and patient characteristics.
RESULTS
IRG-S in JDM patients were significantly higher than in HC but lower than in CANDLE or SAVI. JDM IRG-S overlapped more with SAVI than CANDLE by PCA. Among MSA groups, anti-MDA5 autoantibody-positive patients' IRG-S overlapped most with SAVI. The IFI27 proportion was significantly higher in SAVI and CANDLE than JDM, but IFIT1 contributed more to IRG-S in JDM. Overall, the contribution of individual interferon-regulated genes (IRG) in JDM was more similar to SAVI. IRG-S correlated moderately with JDM disease activity measures (r = 0.33-0.47) and more strongly with skin activity (r = 0.58-0.79) in anti-TIF1 autoantibody-positive patients. Weakness and joint disease activity (multinomial OR 0.91 and 3.3) were the best predictors of high IRG-S.
CONCLUSIONS
Our findings demonstrate peripheral IRG expression in JDM overlaps with monogenic interferonopathies, particularly SAVI, and correlates with disease activity. Anti-MDA5 autoantibody-positive JDM IRG-S were notably more similar to SAVI. This may reflect both a shared IFN signature, which is driven by IFN-β and STING pathways in SAVI, as well as the shared phenotype of vasculopathy in SAVI and JDM, particularly in anti-MDA5 autoantibody-positive JDM, and indicate potential therapeutic targets for JDM.
背景
幼年型皮肌炎（JDM）是一种具有明显干扰素（IFN）特征的系统性自身免疫性疾病，但 JDM 的发病机制和 IFN 特征的病因仍不清楚。孟德尔自身炎症性干扰素病，包括慢性非典型中性粒细胞性皮病伴脂肪营养不良和发热（CANDLE）和 STING 相关血管病伴婴儿期发病（SAVI），是由基因突变引起的，具有极高的 IFN 特征，被认为是导致疾病的原因。CANDLE 和 SAVI 的一些临床特征与 JDM 的表型重叠，导致在 JDM 和肌炎特异性自身抗体（MSA）JDM 亚组中比较标准化干扰素调节基因评分（IRG-S），并与 CANDLE 和 SAVI 进行比较。
方法
通过 NanoString™评估的 57 例 JDM 患者的外周 28 个成分 IRG-S 进行了亚分型，这些患者根据 MSA 进行了亚分型，并与健康对照组（HC）和 CANDLE/SAVI 患者的 IRG-S 进行了比较。进行了主成分分析（PCA），并评估了单个基因对评分的贡献。IRG-S 与疾病评估和患者特征相关。
结果
JDM 患者的 IRG-S 明显高于 HC，但低于 CANDLE 或 SAVI。通过 PCA，JDM 的 IRG-S 与 SAVI 的重叠程度高于 CANDLE。在 MSA 组中，抗 MDA5 自身抗体阳性患者的 IRG-S 与 SAVI 的重叠程度最高。SAVI 和 CANDLE 中的 IFI27 比例明显高于 JDM，但 IFIT1 对 JDM 的 IRG-S 贡献更大。总的来说，JDM 中单个干扰素调节基因（IRG）的贡献更类似于 SAVI。IRG-S 与 JDM 疾病活动测量（r=0.33-0.47）中度相关，与抗 TIF1 自身抗体阳性患者的皮肤活动（r=0.58-0.79）更强烈相关。肌无力和关节疾病活动（多项分类 OR 0.91 和 3.3）是高 IRG-S 的最佳预测因素。
结论
我们的发现表明，JDM 外周 IRG 表达与单基因干扰素病重叠，特别是 SAVI，并且与疾病活动相关。抗 MDA5 自身抗体阳性 JDM 的 IRG-S 与 SAVI 明显更相似。这可能反映了 IFN-β 和 SAVI 中的 STING 途径驱动的共享 IFN 特征，以及 SAVI 和 JDM 中共享的血管病变表型，特别是在抗 MDA5 自身抗体阳性 JDM 中，这表明 JDM 可能存在潜在的治疗靶点。
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