Single-cell analysis reveals key differences between early-stage and late-stage systemic sclerosis skin across autoantibody subgroups

Journal article

OBJECTIVES: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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

Authors: Clark, KEN; Xu, S; Attah, M; Ong, VH; Buckley, CD

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Elsevier
• Journal: Annals of the Rheumatic Diseases
• Volume: 82
• Issue: 12
• Pages: 1568-1579
• Publication date: 2023-08-14
• DOI: 10.1136/ard-2023-224184
• EISSN: 1468-2060
• ISSN: 0003-4967
• Language: English
• Keywords: Antibody; Medicine; Pathology; Fibroblast; Cell culture; Autoantibody; Stage (stratigraphy); Immunology; Skin biopsy; Biology; Genetics; Biopsy