Recent advances in somatic mutations and clonal expansion in psoriasis lesional skin

Psoriasis is a chronic immune-mediated inflammatory skin disease primarily driven by T cell-dependent mechanisms, most notably through the IL-23/Th17 signaling axis.Previous work has primarily focused on germline susceptibility, as revealed by genomewide association studies.However, the contribution of somatic mutations and clonal expansion remains relatively underexplored.A landmark study investigating the mutational landscape of psoriasis lesional skin showed highly polyclonal patterns of somatic mutations, resembling those observed in normal aging skin, with recurrent mutations in genes such as NOTCH1, NOTCH2, TP53, FAT1, and PPM1D.A germline gain-of-function mutation in CARD14 has been shown to drive psoriasiform inflammation in transgenic mouse models.A somatic mosaic HRAS mutation has also been reported in a single case of unilateral psoriasis.In other chronic inflammatory diseases, tissue-specific selective pressures shape disease-specific mutational landscapes in distinct cellular compartments.For instance, somatic mutations arise in epithelial cells and are linked to immune pathways in inflammatory bowel disease and to metabolic pathways in chronic liver disease, whereas in rheumatoid arthritis, mutations occur in immune cells such as clonally expanded CD8 + T cells.While immune dysregulation remains central, somatic mutations may play a complementary role in psoriatic pathogenesis, particularly by contributing to treatment recalcitrance or lesion recurrence.Although current findings remain in a preliminary stage, high-resolution genetic and spatial analyses are needed to validate the functional relevance of somatic mutations in psoriasis, which may enable the development of clone-directed therapeutic strategies.