Department of Rheumatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Rheumatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
Arthritis Rheumatol. 2024 Jan;76(1):78-91. doi: 10.1002/art.42662.
Interferon (IFN)-1 signatures are a hallmark of patients with systemic sclerosis (SSc). However, its significance in clinical stratification and contribution to deterioration still need to be better understood.
For hypothesis generation, we performed single-cell RNA sequencing (scRNA-seq) on skin biopsies (four patients with SSc and two controls) using the BD Rhapsody platform. Two publicly available data sets of skin scRNA-seq were used for validation (GSE138669: 12 patients with diffuse cutaneous SSc [dcSSc] and 10 controls; GSE195452: 52 patients with dcSSc and 41 patients with limited cutaneous SSc [lcSSc] and 54 controls). The IFN-1 signature was mapped, functionally investigated in a bleomycin plus IFNα-2 adenovirus-associated virus (AAV)-induced model and verified in an SSc cohort (n = 61).
The discovery and validation data sets showed similar findings. Endothelial cells (ECs) had the most prominent IFN-1 signature among dermal nonimmune cells. The EC IFN-1 signature was increased both in patients with SSc versus controls and in patients with dcSSc versus those with lcSSc. Among EC subclusters, the IFN-1 signature was statistically higher in the capillary ECs of patients with dcSSc, which was higher than those in patients with lcSSc, which in turn was higher than those in healthy controls (HCs). Endothelial-to-mesenchymal transition (EndoMT) scores increased in parallel. Deteriorated bleomycin-induced dermal fibrosis, EndoMT, and perivascular fibrosis and caused blood vessel loss with EC apoptosis. Vascular myxovirus resistance (MX) 1, an IFN-1 response protein, was significantly increased both in total SSc versus HC skin and in dcSSc versus lcSSc skin. Baseline vascular MX1 performed similarly to skin score in predicting disease progression over 6 to 34 months in total SSc and was superior in the dcSSc subpopulation.
The EC IFN-1 signature distinguished SSc skin subtypes and disease progression and may contribute to vasculopathy and fibrosis.
干扰素（IFN）-1 特征是全身性硬皮病（SSc）患者的一个标志。然而，其在临床分层中的意义及其对病情恶化的影响仍需要进一步了解。
为了提出假设，我们使用 BD Rhapsody 平台对皮肤活检（四名 SSc 患者和两名对照者）进行单细胞 RNA 测序（scRNA-seq）。使用两个公开的皮肤 scRNA-seq 数据集进行验证（GSE138669：12 名弥漫性皮肤 SSc [dcSSc] 患者和 10 名对照者；GSE195452：52 名 dcSSc 患者和 41 名局限性皮肤 SSc [lcSSc] 患者和 54 名对照者）。映射 IFN-1 特征，在博来霉素加 IFNα-2 腺相关病毒（AAV）诱导的模型中进行功能研究，并在 SSc 队列（n=61）中进行验证。
发现和验证数据集显示出相似的结果。真皮非免疫细胞中内皮细胞（ECs）具有最显著的 IFN-1 特征。与对照组相比，SSc 患者和与 lcSSc 患者相比，dcSSc 患者的 EC IFN-1 特征均增加。在 EC 亚群中，dcSSc 患者的毛细血管 ECs 的 IFN-1 特征统计学上更高，高于 lcSSc 患者，而 lcSSc 患者又高于健康对照者（HCs）。内皮-间充质转化（EndoMT）评分也随之增加。恶化的博来霉素诱导的皮肤纤维化、EndoMT 和血管周围纤维化导致血管损失和 EC 凋亡。血管粘液病毒抗性（MX）1，一种 IFN-1 反应蛋白，在总 SSc 与 HC 皮肤相比和在 dcSSc 与 lcSSc 皮肤相比均显著增加。在总 SSc 中，基线血管 MX1 在预测 6 至 34 个月的疾病进展方面与皮肤评分相似，在 dcSSc 亚群中更具优势。
EC IFN-1 特征区分了 SSc 皮肤亚型和疾病进展，可能与血管病变和纤维化有关。
