133 Multimodal analyses of vitiligo skin identifies tissue characteristics of stable disease

Abstract

Vitiligo is an autoimmune skin disease that is characterized by the progressive destruction of melanocytes by autoreactive CD8+ T cells. Melanocyte destruction in active vitiligo is mediated by CD8+ T cells but why white patches in stable disease persist is poorly understood. The interaction between immune cells, melanocytes, and keratinocytes in situ in human skin has been difficult to study due to the lack of proper tools. We combine non-invasive multiphoton microscopy (MPM) imaging and single-cell RNA sequencing (scRNA-seq) to identify distinct subpopulations of keratinocytes in lesional skin of stable vitiligo patients. We show that these keratinocytes are enriched in lesional vitiligo skin and differ in metabolism, an observation corroborated by both MPM and scRNA-seq. Systematic investigation of cell-cell communication show that CXCL is the prominent signaling change in this small population of keratinocytes, which secrete CXCL9 and CXCL10 to create local inflammatory cytokine loops with T cells to drive stable vitiligo persistence. Further MPM imaging of patients undergoing punch grafting treatment showed that metabolically altered keratinocytes persist in non-responders but normalize in treatment responders. In summary, we couple advanced imaging with transcriptomics and bioinformatics to discover cell-cell communication networks and keratinocyte cell states that persist in stable disease and potentially prevent repigmentation.