Sunlight exposure exerts immunomodulatory effects to reduce multiple sclerosis severity

Background Multiple sclerosis (MS) disease risk is associated with reduced sun exposure. This study assessed the relationship between measures of sun-exposure (vitamin D (vitD), latitude) and MS disease severity, the mechanisms of action, and effect-modification by medication and sun-sensitivity associated MC1R variants. Methods Two multi-center cohort studies (n NationMS =946, n BIONAT =991). Outcomes were the multiple sclerosis severity score (MSSS) and the number of Gd-enhancing lesion (GELs). RNAseq of four immune cell populations before and after UV-phototherapy of five MS patients. Results High serum vitD was associated with reduced MSSS ( P NationMS =0.021; P BIONAT =0.007) and reduced risk for disease aggravation ( P NationMS =0.032). Low latitude was associated with higher vitD, lower MSSS ( P NationMS =0.018), fewer GELs ( P NationMS =0.030) and reduced risk for aggravation ( P NationMS =0.044). The influence of latitude on disability seemed to be lacking in the subgroup of interferon-β treated patients (interaction- P BIONAT =0.042, interaction- P NationMS =0.053). In genetic analyses, for carriers of MC1R :rs1805008(T), who reported increased sensitivity towards sunlight ( P NationMS =0.038), the relationship between latitude und the number of GELs was inversed ( P NationMS =0.001). Phototherapy induced a vitD and type I interferon signature that was most apparent in the transcriptome of monocytes ( P =1×10 −6 ). Conclusion VitD is associated with reduced MS severity and disease aggravation. This is likely driven by sun-exposure, as latitude also correlated with disability and serum vitD. However, sun-exposure might be detrimental for sun-sensitive patients. A direct induction of type I interferons through sun-exposure could explain a reduced effect of latitude in interferon-β treated patients. This could also explain opposite effects of sun-exposure in MS and the type I interferon and sun-sensitivity-associated disease Lupus.