Background/Purpose: Type I interferon (IFN-1) signature is a hallmark of patients with systemic sclerosis (SSc). However, its significance in clinical stratification and contribution to deterioration still need to be better understood.

Methods: For hypothesis generation, we performed single-cell RNA sequencing (scRNAseq) on skin biopsies (SSc=4, control =2) using the BD Rhapsody platform. Two publicly available datasets of skin scRNAseq were used for validation (GSE138669: dcSSc=12, control=10; GSE195452: dcSSc=52, lcSSc=41, control =54). IFN-1 signature was mapped, functionally investigated in a bleomycin plus IFNα2-adeno-associated virus (IFNA2-AAV) induced model, and verified in an SSc cohort (n=61).

Results: The discovery and validation datasets shared findings. The endothelial cells (EC) had the most prominent IFN-1 response among dermal non-immune cells. EC IFN-1 signature was increased both in SSc vs. control and in dcSSc vs. lcSSc. Among EC subclusters, the elevation of IFN-1 signature in dcSSc patients compared to control was still true in capillary, post-capillary venule, and venule ECs in all datasets. Endothelial-to-mesenchymal transition (EndoMT) scores increased in parallel. IFNA2-AAV deteriorated bleomycin-induced dermal fibrosis, EndoMT, and perivascular fibrosis and caused blood vessel loss with EC apoptosis. Vascular MX1, an IFN-1 response protein, was significantly increased both in total SSc skin and in dcSSc vs. lcSSc. To predict disease progression in 6-34 months, the baseline vascular MX1 performed similarly to skin score in total SSc and was superior in the dcSSc subpopulation.

Conclusion: The EC IFN-1 signature distinguished SSc skin subtypes and disease progression and may contribute to vasculopathy and fibrosis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/endothelial-response-to-type-i-interferon-contributes-to-vasculopathy-and-fibrosis-and-predicts-disease-progression-of-systemic-sclerosis/