1170 Investigating the molecular mechanisms of solar urticaria

Solar Urticaria (SU) is a rapid onset, chronic inducible urticaria characterized by an itching or burning erythemal flare with or without whealing, that is triggered by ultraviolet radiation (UVR) and/or visible light. While SU is hypothesized to be caused by IgE-mediated mast cell degranulation, the evolution of the response and mechanisms involved are not well understood. We examined the early events in SU pathophysiology through a UVR provocation study with transcriptome and immunofluorescence (IF) analysis. Patients with diagnosed SU (n=4) were provoked on photoprotected upper buttock skin with 10J/cm2solar simulated UVR, with collection of skin biopsies at 30min, 3h and 24h post UVR exposure and from adjacent unexposed skin. A comparator group of healthy volunteers (n=4) underwent the same protocol. Transcriptomic analysis demonstrated numerous differentially regulated genes in SU compared to healthy controls (HC), including upstream regulators involved in chemotactic, pro-inflammatory, vasoactive and Toll-like receptor signaling pathways. Characterization of cell type proportions via CIBERSORT analysis as well as IF validation (n=6) revealed increased numbers of neutrophils and eosinophils across all timepoints post UVR in SU, but not HC. Strikingly, transcriptomic analysis of unexposed skin predicted down-regulation of the transcription factor DLX3 in SU patients compared to HC, with IF validation revealing this down-regulation to be in the epidermis. Furthermore, IF displayed an increased number of mast cells co-localized with pSTAT3 in SU, but not in HC at 30min (p=0.01) and 3h (p=0.05) compared to baseline, suggesting that phosphorylation of STAT3 may be involved in mast cell activation in SU. Our data show SU to involve early activation inflammatory pathways and STAT3 activation following UVR exposure, as well as possible disruption of skin homeostasis. Exploration into the early mechanisms underlying SU has potential to identify new therapeutic targets.