Immune-vascular-fibrotic remodeling defines a neuroimmune tissue niche in systemic sclerosis skin and converges with human peripheral nerve injury programs.

Neurological manifestations of systemic sclerosis (SSc), including autonomic dysfunction and peripheral neuropathy, are clinically recognized, but their relationship to SSc tissue injury remains poorly defined. We integrated public SSc blood, PBMC, skin and single-cell transcriptomes with an external human peripheral nerve lesion reference to test whether neuroimmune programs are embedded in immune-vascular-fibrotic remodeling. Across four SSc cohorts, pathway analyses identified recurrent interferon activation and skin-enriched fibrosis/TGF-beta, vascular endothelial, chemokine, complement/phagocytosis, neuroimmune-core and peripheral nerve injury signatures. Rank-AUC, ssGSEA and same-size random gene-set analyses supported these findings, and 22 of 70 curated cohort-signature tests remained significant after global Benjamini-Hochberg correction. A 17-gene exploratory score retained moderate discrimination in independent whole blood (AUC = 0.759), but nested cross-validation and stability analyses supported its use as a molecular summary, not a clinical classifier. In GSE250152, 3972 genes were differentially expressed in human peripheral nerve lesions, and lesion-signature projection showed FDR-significant shifts in SSc skin. Single-cell analysis of 146,426 cells localized vascular, fibrotic, interferon, chemokine and selected neuroimmune signals mainly to fibroblast, endothelial, pericyte, T-cell and myeloid-associated skin compartments. Cell-type-frequency adjustment preserved the direction of all 15 highlighted compartment-signature effects, with seven remaining significant after global correction. Ligand-receptor analyses prioritized IL1B-IL1R1, TNF-TNFRSF1A, VEGFA-KDR and TGFB1-TGFBR1 as speculative expression-potential routes rather than demonstrated communication events. These data support a bounded model linking SSc-related neural vulnerability to an immune-vascular-fibrotic neuroimmune niche. Prospective neurologically phenotyped cohorts are required for clinical validation.