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 (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.

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Sunlight exposure exerts immunomodulatory effects to reduce multiple sclerosis severity

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2018457118 ◽

2020 ◽

Vol 118 (1) ◽

pp. e2018457118

Author(s):

Patrick Ostkamp ◽

Anke Salmen ◽

Béatrice Pignolet ◽

Dennis Görlich ◽

Till F. M. Andlauer ◽

...

Keyword(s):

Multiple Sclerosis ◽

Immune Modulation ◽

Disease Risk ◽

Sun Exposure ◽

High Serum ◽

Lower Latitude ◽

Type I ◽

Beneficial Effects ◽

Type I Ifns ◽

Increased Sensitivity

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 severity in the setting of two multicenter cohort studies (nNationMS = 946, nBIONAT = 990). Additionally, effect-modification by medication and photosensitivity-associated MC1R variants was assessed. High serum vitD was associated with a reduced MS severity score (MSSS), reduced risk for relapses, and lower disability accumulation over time. Low latitude was associated with higher vitD, lower MSSS, fewer gadolinium-enhancing lesions, and lower disability accumulation. The association of latitude with disability was lacking in IFN-β–treated patients. In carriers of MC1R:rs1805008(T), who reported increased sensitivity toward sunlight, lower latitude was associated with higher MRI activity, whereas for noncarriers there was less MRI activity at lower latitudes. In a further exploratory approach, the effect of ultraviolet (UV)-phototherapy on the transcriptome of immune cells of MS patients was assessed using samples from an earlier study. Phototherapy induced a vitD and type I IFN signature that was most apparent in monocytes but that could also be detected in B and T cells. In summary, our study suggests beneficial effects of sun exposure on established MS, as demonstrated by a correlative network between the three factors: Latitude, vitD, and disease severity. However, sun exposure might be detrimental for photosensitive patients. Furthermore, a direct induction of type I IFNs through sun exposure could be another mechanism of UV-mediated immune-modulation in MS.

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A type I interferon signature in monocytes is associated with poor response to interferon-β in multiple sclerosis

Brain ◽

10.1093/brain/awp228 ◽

2009 ◽

Vol 132 (12) ◽

pp. 3353-3365 ◽

Cited By ~ 145

Author(s):

M. Comabella ◽

J. D. Lünemann ◽

J. Río ◽

A. Sánchez ◽

C. López ◽

...

Keyword(s):

Multiple Sclerosis ◽

Type I Interferon ◽

Poor Response ◽

Type I ◽

Interferon Β ◽

Interferon Signature

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Regulation of the type I interferon genes and interferon-inducible genes. The relationship with the viral reproduction under HIV-infection

Biopolymers and Cell ◽

10.7124/bc.0005c4 ◽

2001 ◽

Vol 17 (5) ◽

pp. 347-355

Author(s):

A. V. Karpov

Keyword(s):

Hiv Infection ◽

Type I Interferon ◽

Type I ◽

Inducible Genes ◽

The Relationship ◽

Viral Reproduction

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Multiple sclerosis: interferon-beta induces CD123+BDCA2− dendritic cells that produce IL-6 and IL-10 and have no enhanced type I interferon production

Journal of Neuroimmunology ◽

10.1016/j.jneuroim.2004.08.014 ◽

2005 ◽

Vol 158 (1-2) ◽

pp. 204-212 ◽

Cited By ~ 16

Author(s):

Y.M. Huang ◽

S. Adikari ◽

U. Båve ◽

A. Sanna ◽

G. Alm

Keyword(s):

Multiple Sclerosis ◽

Dendritic Cells ◽

Interferon Beta ◽

Type I Interferon ◽

Type I ◽

Interferon Production

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On the Nature of Evidence and ‘Proving’ Causality: Smoking and Lung Cancer vs. Sun Exposure, Vitamin D and Multiple Sclerosis

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph15081726 ◽

2018 ◽

Vol 15 (8) ◽

pp. 1726 ◽

Cited By ~ 5

Author(s):

Robyn Lucas ◽

Rachael Rodney Harris

Keyword(s):

Risk Factors ◽

Multiple Sclerosis ◽

Lung Cancer ◽

Vitamin D ◽

Observational Studies ◽

Animal Studies ◽

Disease Risk ◽

Sun Exposure ◽

Sufficient Evidence

If environmental exposures are shown to cause an adverse health outcome, reducing exposure should reduce the disease risk. Links between exposures and outcomes are typically based on ‘associations’ derived from observational studies, and causality may not be clear. Randomized controlled trials to ‘prove’ causality are often not feasible or ethical. Here the history of evidence that tobacco smoking causes lung cancer—from observational studies—is compared to that of low sun exposure and/or low vitamin D status as causal risk factors for the autoimmune disease, multiple sclerosis (MS). Evidence derives from in vitro and animal studies, as well as ecological, case-control and cohort studies, in order of increasing strength. For smoking and lung cancer, the associations are strong, consistent, and biologically plausible—the evidence is coherent or ‘in harmony’. For low sun exposure/vitamin D as risk factors for MS, the evidence is weaker, with smaller effect sizes, but coherent across a range of sources of evidence, and biologically plausible. The association is less direct—smoking is directly toxic and carcinogenic to the lung, but sun exposure/vitamin D modulate the immune system, which in turn may reduce the risk of immune attack on self-proteins in the central nervous system. Opinion about whether there is sufficient evidence to conclude that low sun exposure/vitamin D increase the risk of multiple sclerosis, is divided. General public health advice to receive sufficient sun exposure to avoid vitamin D deficiency (<50 nmol/L) should also ensure any benefits for multiple sclerosis, but must be tempered against the risk of skin cancers.

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