Eosinophilic Fasciitis and Morphea Share Gene Signatures of Inflammatory Cell Death, Self-DNA Recognition, and Enhanced Jak/Signal Transducer and Activator of Transcription Signaling

Abstract

The pathogenesis of eosinophilic fasciitis (EF) and morphea is poorly understood. We analyzed skin biopsies from patients with EF and morphea compared with those from adult healthy skin using gene expression profiling, Ingenuity Pathway Analysis, and immunostaining. EF gene expression showed significant overlap with morphea. Fifty-one of 61 differentially expressed genes, 80 of 99 canonical pathways, and 40 of 51 upstream regulators were shared in EF and morphea. Both conditions exhibited robust T-cell activation and cytotoxic signatures despite their pauci-inflammatory histological appearance, suggesting that small numbers of T cells may drive injury, inflammation, and fibrosis. EF and morphea shared signatures of necroptosis; self-DNA recognition; cyclic GMP-AMP synthase/stimulator of IFN genes activation; induction of types I, II, and III IFN signaling; and fibrosis. Seven Janus kinase (JAK)/signal transducer and activator of transcription (STAT) molecules were significantly upregulated in EF, and 9 were upregulated in morphea. Compared with that in healthy skin, TYK2 was the most significant JAK molecule upregulated in EF (P = .0007) and morphea (P = .0002). Immunostaining demonstrated activated IFN-related molecules JAK1 and STAT 1 in T cells, dendritic cells, and macrophages in both diseases. This study identifies shared molecular mechanisms of EF and morphea and demonstrates strong pathophysiologic similarities between the 2 diseases. Our findings indicate that targeted inhibition of JAK/STAT molecules and mediators of necroptosis may be beneficial in treating these fibrotic diseases.

Keywords: Eosinophilic fasciitis; Fibrosis; JAK/STAT signaling; Morphea; Necroptosis.