Turnier Jessica L, Pachman Lauren M, Lowe Lori, Tsoi Lam C, Elhaj Sultan, Menon Rajasree, Amoruso Maria C, Morgan Gabrielle A, Gudjonsson Johann E, Berthier Celine C, Kahlenberg J Michelle
University of Michigan, Ann Arbor.
Northwestern University Feinberg School of Medicine, Chicago, Illinois.
Arthritis Rheumatol. 2021 Jun;73(6):1062-1072. doi: 10.1002/art.41615. Epub 2021 May 2.
Skin inflammation heralds systemic disease in juvenile myositis, yet we lack an understanding of pathogenic mechanisms driving skin inflammation in this disease. We undertook this study to define cutaneous gene expression signatures in juvenile myositis and identify key genes and pathways that differentiate skin disease in juvenile myositis from childhood-onset systemic lupus erythematosus (SLE).
We used formalin-fixed paraffin-embedded skin biopsy samples from 15 patients with juvenile myositis (9 lesional, 6 nonlesional), 5 patients with childhood-onset SLE, and 8 controls to perform transcriptomic analysis and identify significantly differentially expressed genes (DEGs; q ≤ 5%) between patient groups. We used Ingenuity Pathway Analysis (IPA) to highlight enriched biologic pathways and validated DEGs by immunohistochemistry and quantitative real-time polymerase chain reaction.
Comparison of lesional juvenile myositis to control samples revealed 221 DEGs, with the majority of up-regulated genes representing interferon (IFN)-stimulated genes. CXCL10, CXCL9, and IFI44L represented the top 3 DEGs (fold change 23.2, 13.3, and 13.0, respectively; q < 0.0001). IPA revealed IFN signaling as the top canonical pathway. When compared to childhood-onset SLE, lesional juvenile myositis skin shared a similar gene expression pattern, with only 28 unique DEGs, including FBLN2, CHKA, and SLURP1. Notably, patients with juvenile myositis who were positive for nuclear matrix protein 2 (NXP-2) autoantibodies exhibited the strongest IFN signature and also demonstrated the most extensive Mx-1 immunostaining, both in keratinocytes and perivascular regions.
Lesional juvenile myositis skin demonstrates a striking IFN signature similar to that previously reported in juvenile myositis muscle and peripheral blood. Further investigation into the association of a higher IFN score with NXP-2 autoantibodies may provide insight into disease endotypes and pathogenesis.
皮肤炎症预示着幼年型皮肌炎会发展为全身性疾病，但我们对驱动该疾病皮肤炎症的致病机制尚缺乏了解。我们开展这项研究以确定幼年型皮肌炎的皮肤基因表达特征，并识别出可将幼年型皮肌炎中的皮肤疾病与儿童期起病的系统性红斑狼疮（SLE）相区分的关键基因和信号通路。
我们使用来自15例幼年型皮肌炎患者（9例有皮损，6例无皮损）、5例儿童期起病的SLE患者及8例对照的福尔马林固定石蜡包埋皮肤活检样本进行转录组分析，确定患者组间显著差异表达基因（DEG；q≤5%）。我们使用 Ingenuity 通路分析（IPA）来突出富集的生物学通路，并通过免疫组织化学和定量实时聚合酶链反应对DEG进行验证。
有皮损的幼年型皮肌炎样本与对照样本比较，发现221个DEG，其中大多数上调基因代表干扰素（IFN）刺激基因。CXCL10、CXCL9和IFI44L是排名前3的DEG（倍数变化分别为23.2、13.3和13.0；q<0.0001）。IPA显示IFN信号是排名第一的经典通路。与儿童期起病的SLE相比，有皮损的幼年型皮肌炎皮肤具有相似的基因表达模式，仅有28个独特的DEG，包括FBLN2、CHKA和SLURP1。值得注意的是，核基质蛋白2（NXP - 2）自身抗体呈阳性的幼年型皮肌炎患者表现出最强的IFN特征，并且在角质形成细胞和血管周围区域均显示出最广泛的Mx - 1免疫染色。
有皮损的幼年型皮肌炎皮肤表现出与先前在幼年型皮肌炎肌肉和外周血中报道的相似的显著IFN特征。进一步研究较高的IFN评分与NXP - 2自身抗体之间的关联可能会为疾病亚型和发病机制提供见解。
