Sunlight exposure exerts immunomodulatory effects to reduce multiple sclerosis severity

Abstract

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 (nNationMS=946, nBIONAT=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 (PNationMS=0.021; PBIONAT=0.007) and reduced risk for disease aggravation (PNationMS=0.032). Low latitude was associated with higher vitD, lower MSSS (PNationMS=0.018), fewer GELs (PNationMS=0.030) and reduced risk for aggravation (PNationMS=0.044). The influence of latitude on disability seemed to be lacking in the subgroup of interferon-β treated patients (interaction-PBIONAT=0.042, interaction-PNationMS=0.053). In genetic analyses, carriers of MC1R:rs1805008(T), who reported increased sensitivity towards sunlight (PNationMS=0.038), the relationship between latitude und the number of GELs was inversed (PNationMS=0.001). Phototherapy induced a vitD and type I interferon signature that was most apparent in the transcriptome of monocytes (P=1x10-6). 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.

Effects of Vitamin D and Body Mass Index on Disease Risk and Relapse Hazard in Multiple Sclerosis

“…The proportion of variance explained by the selected SNVs is 2%-5% for 25OHD, with the weakest IV data set 24 corresponding to the largest CIs, and 6% for BMI. Importantly, our MR study agrees with observational studies in pointing to an overall protective effect of higher baseline 25OHD levels on subsequent relapse occurrence in cohorts of pediatric or adult MS cases (between 73 and 1,482 participants per study) 13,15,16,46 or meta-analyses of up to 3,130 patients. 14 On the contrary, randomized controlled trials (RCTs), of which the largest to date include up to 412 individuals, [47][48][49] provide inconclusive evidence regarding the benefits of vitamin D supplement intake after disease onset.…”

“…Relapses are a core feature of relapsing remitting MS and a common primary outcome of clinical trials. Observational studies show that lower 25OHD levels are associated with a higher relapse rate in MS, [13][14][15][16] whereas there are conflicting results for BMI. 17,18 However, observational studies are prone to reverse causation and recall bias and thereby preclude drawing conclusions regarding causality.…”

Low sun exposure acts synergistically with high Epstein−Barr nuclear antigen 1 (EBNA‐1) antibody levels in multiple sclerosis etiology

“…Another mechanism that might contribute to explaining the interaction is upregulation of the type I interferon pathway by vitamin D or sun exposure [35,36] which could influence EBNA-1 antibody levels. Further studies in order to increase the understanding of what aspects of sun exposure are involved in the interaction with EBV in MS development would be valuable and could elucidate MS pathogenesis.…”

Adaptive immunity, chronic inflammation and the clock

“…A more likely and well-supported mediator is vitamin D (which requires UVB radiation for synthesis) [69].…”