Centre for Rheumatology, Royal Free Campus, University College London, London, UK.
Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.
Ann Rheum Dis. 2023 Dec;82(12):1568-1579. doi: 10.1136/ard-2023-224184. Epub 2023 Aug 14.
The severity of skin involvement in diffuse cutaneous systemic sclerosis (dcSSc) depends on stage of disease and differs between anti-RNA-polymerase III (ARA) and anti-topoisomerase antibody (ATA) subsets. We have investigated cellular differences in well-characterised dcSSc patients compared with healthy controls (HCs).
We performed single-cell RNA sequencing on 4 mm skin biopsy samples from 12 patients with dcSSc and HCs (n=3) using droplet-based sequencing (10× genomics). Patients were well characterised by stage (>5 or <5 years disease duration) and autoantibody (ATA+ or ARA+). Analysis of whole skin cell subsets and fibroblast subpopulations across stage and ANA subgroup were used to interpret potential cellular differences anchored by these subgroups.
Fifteen forearm skin biopsies were analysed. There was a clear separation of SSc samples, by disease, stage and antibody, for all cells and fibroblast subclusters. Further analysis revealed differing cell cluster gene expression profiles between ATA+ and ARA+ patients. Cell-to-cell interaction suggest differing interactions between early and late stages of disease and autoantibody. TGFβ response was mainly seen in fibroblasts and smooth muscle cells in early ATA+dcSSc skin samples, whereas in early ARA+dcSSc patient skin samples, the responding cells were endothelial, reflect broader differences between clinical phenotypes and distinct skin score trajectories across autoantibody subgroups of dcSSc.
We have identified cellular differences between the two main autoantibody subsets in dcSSc (ARA+ and ATA+). These differences reinforce the importance of considering autoantibody and stage of disease in management and trial design in SSc.
弥漫性皮肤系统性硬化症（dcSSc）皮肤受累的严重程度取决于疾病分期，且在抗 RNA 聚合酶 III（ARA）和抗拓扑异构酶抗体（ATA）亚群之间存在差异。我们比较了特征明确的 dcSSc 患者与健康对照（HC）之间的细胞差异。
我们对 12 例 dcSSc 患者（n=3）和 HC 的 4 mm 皮肤活检样本进行了基于液滴的单细胞 RNA 测序（10×基因组学）。患者根据疾病阶段（>5 年或<5 年病程）和自身抗体（ATA+或 ARA+）进行了很好的特征描述。通过分析整个皮肤细胞亚群和成纤维细胞亚群，以及根据这些亚群解释潜在的细胞差异。
分析了 15 例前臂皮肤活检样本。所有细胞和成纤维细胞亚群均根据疾病、阶段和抗体清楚地区分了 SSc 样本。进一步分析显示，ATA+和 ARA+患者之间存在不同的细胞簇基因表达谱。细胞间相互作用表明，疾病早期和晚期以及自身抗体之间存在不同的相互作用。在早期 ATA+dcSSc 皮肤样本中，TGFβ 反应主要见于成纤维细胞和平滑肌细胞，而在早期 ARA+dcSSc 患者皮肤样本中，反应细胞为内皮细胞，这反映了临床表型之间的显著差异以及 dcSSc 自身抗体亚群之间不同的皮肤评分轨迹。
我们已经确定了 dcSSc 中两种主要自身抗体亚群（ARA+和 ATA+）之间的细胞差异。这些差异强调了在 SSc 的管理和试验设计中考虑自身抗体和疾病阶段的重要性。
