Single-cell analysis of skin and blood reveals systemic immune responses to ultraviolet B and their impairment in MS.

Sunlight is a fundamental immune-modulating factor with implications for the pathogenesis of autoimmune diseases such as multiple sclerosis (MS). MS incidence and severity increase with latitude, historically attributed to diminished ultraviolet (UV) exposure and lower serum vitamin D (VitD) levels. While high-level VitD supplementation yields moderate clinical benefit in early MS, the broader immunomodulatory potential of UV radiation remains poorly understood. To further investigate this effect on the immune transcriptome, we conducted a clinical trial (NCT05627609) in which healthy donors (HD) and MS patients were irradiated with narrowband UVB, followed by single-cell transcriptomic analysis of immune cells from the skin, blood, and cerebrospinal fluid (CSF). We revealed profound UV effects not only in the skin but also in peripheral blood and, preliminarily, in CSF. These included immune-modulating and migratory signatures across multiple cell populations, focusing on UVB triggered re-circulating myeloid- and CD8⁺ T cells, revealing a blunted translation from skin to blood in MS. Patients showed an exaggerated cutaneous immune activation with elevated stress-responsive genes (NR4A1, JUN, HSPA1B), while HD showed stronger induction of homeostatic and regulatory genes (EEF1A1, TPT1, TMSB4X) in blood. This uncovers a dysfunctional axis of immunoregulation in MS and reveals the immuno-landscape underlying the latitude-associated MS risk.