Michel Gilliet

Recent evidence implicates altered RNA editing and dysregulated type I IFN signaling in immune-mediated diseases, including psoriasis, although the underlying genetic mechanisms remain poorly defined. We investigated four unrelated multiplex families with early-onset plaque psoriasis, with or without psoriatic arthritis, segregating as a monogenic trait and characterized by a strong IFN signature in skin and blood. Whole-exome sequencing identified four rare heterozygous loss-of-function mutations in ADAR1 cosegregating with disease and elevated IFN-stimulated gene expression. Six additional rare variants were detected in an independent cohort of 125 psoriasis patients. Single-cell transcriptomics identified keratinocytes and melanocytes as major IFN sources. Functional studies showed that ADAR1 knockdown or expression of ADAR1G1119R and ADAR1P3A alleles pathogenic variants reduced adenosine-to-inosine RNA editing and increased IFN-stimulated genes and inflammatory cytokines, effects reversed by upadacitinib and deucravacitinib. These findings define a novel IFN-dependent psoriasis subtype caused by inborn defects of ADAR1-mediated RNA editing, with direct implications for precision medicine in psoriatic disease.

Recent advances in immunology and transcriptomics have transformed dermatology, redefining inflammatory skin diseases as distinct molecular entities characterized by dominant immune pathways such as Th17, Th2, Th1, type I interferon (IFN) and myeloid modules. We transcriptionally delineated these immune modules, constructed a reference immune cartography to map patient skin biopsies and developed a digital platform that enables clinicians to analyse individual molecular profiles, facilitating precise diagnosis for clinically overlapping or diagnostically ambiguous dermatoses. Beyond diagnostic utility, this platform supports therapeutic decision‐making by aligning each patient's dominant immune module with the most appropriate targeted treatment. Analyses of treatment failures reveal that discordance between therapy and immune module dominance, as well as immune shifts between modules, account for most cases of non‐response. Realigning therapy with the patient's molecular profile restores efficacy and enables rational adaptation or repurposing of existing agents. By integrating molecular diagnostics with immune module‐guided therapy, this approach establishes a precision medicine framework that optimizes outcomes and advances personalized care for patients with inflammatory skin disease.

Supplementary Table S2. Spatial TME1 (STME1) and TME2 (STME2) gene signatures.

Supplementary Table S6. Clinical response annotation of the scRNAseq dataset obtained from BCCs treated with ICI.

Supplementary Figure S3: Immunosuppressive TME2 are enriched in ECM-remodeling CAFs.

Supplementary Table S3. Cluster marker genes of the Fibroblast populations.

Supplementary Figure S8: Activin A exposure in Fibroblasts and Macrophages clusters.