359 Pansclerotic morphea is characterized by type II IFN responses priming T cell – cDC2b – fibroblast crosstalk to promote fibrosis

Pansclerotic morphea(PSM) is an extremely rare, devastating disease characterized by extensive soft tissue fibrosis, secondary contractions, and eventual death. The pathogenesis of PSM unknown, aggressive immunosuppressive treatments rarely slow progression. Here, we sought to comprehensively characterize the cellular molecular events underlying identify novel therapeutic targets. We performed single-cell spatial RNA sequencing lesional non-lesional skin 2 patients normal from 6 healthy controls(HCs) validated findings IHC in vitro experiments. most prominent inflammatory signal was a Type II IFN(IFNg) response, with T cells being main source infiltrating immune cell type skin. Myeloid B were also robustly present. Fibrosis hallmark feature amongst fibroblasts (FB) subsets skin, CXCL9+ FBs highly enriched compared HC Upstream regulator analysis identified IFNG as key upstream FBs, which had increased expression genes involved antigen presentation leukocyte chemokines CXCL9, CXCL10, CCL2, CCL5, CCL19. FB TGFB/IFNg costimulation vitroshowed synergistic CXCL9 IFNGR1, perpetuating IFNg response. Further, cell-cell interaction analyses revealed cDC2B communication hub between separate myofibroblast subpopulation, likely promoting collagen ECM production via TGFB, PDGF, VEGF pathways. Overall, these data define inflammatory-driven process dominant IFN responses. These responses drive activation cell—cDC2B—myofibroblast crosstalk, myofibroblasts. This work outlines pathogenic circuits suggests that JAK1/2 inhibition may be potential option for PSM.