Molecular mechanism underlying the impact of vitamin D on disease activity of MS

Kassendra Munger (1) , Karl Köchert (2) , Kelly C Simon (1) , Ludwig Kappos (3) , Chris H Polman (4) , Mark S Freedman (5) , Hans P Hartung (6) , David Miller (7) , Xavier Montalban (8) , Gilles Edan (9, 10) , Frederik Barkhof (4) , Dirk Pleimes (2) , Rupert Sandbrink (2, 6) , Alberto Ascherio (1) , Christoph Pohl (2, 11)

1 HMS - Harvard Medical School [Boston]
2 Bayer HealthCare AG
3 Felix Splatter Hospital [Bâle]
4 VU University Medical Center [Amsterdam]
5 OHRI - Ottawa Hospital Research Institute [Ottawa]
6 Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf]
7 UCL Institute of Neurology
8 Vall d'Hebron University Hospital [Barcelona]
9 VisAGeS - Vision, Action et Gestion d'informations en Santé
10 Centre Hospitalier Universitaire de Rennes [CHU Rennes] = Rennes University Hospital [Ponchaillou]
11 Department of Neurology

Objective: Some previous studies suggest modest to strong effects of 25-hydroxyvitamin D (25(OH)D) on multiple sclerosis (MS) activity. The objective of this study was to explore the mechanistic rationale that may explain poten-tial clinical effects of 25(OH)D. Methods: This study measured serum 25(OH) D levels and global gene expression profiles over a course of up to 2 years in patients starting treatment with interferon beta-1b (IFNB-1b) after a clinically isolated syndrome. MS disease activity was assessed by the number of gadolin-ium-enhancing lesions present on repeated magnetic resonance imaging (MRIs). Results: The number of gadolinium-enhancing lesions was highly sig-nificantly associated with 25(OH)D levels. Conducting various systems-level analyses on the molecular level, multiple lines of evidence indicated that 25 (OH)D regulates expression dynamics of a large gene–gene interaction system which primarily regulates immune modulatory processes modulating MS activ-ity. The vitamin D response element was significantly enriched in this system, indicating a direct regulation of this gene interaction network through the vita-min D receptor. With increasing 25(OH)D levels, resulting regulation of this system was associated with a decrease in MS activity. Within the complex net-work of genes that are regulated by 25(OH)D, well-described targets of IFNB-1b and a regulator of sphingosine-1-phosphate bioavailability were found. The 25(OH)D effects on MS activity were additively enhanced by IFNB-1b. Inter-pretation: Here, we provide mechanistic evidence that an unbalanced 25(OH)D gene expression system may affect MS activity. Our findings support a potential benefit of monitoring and managing vitamin D levels (e.g., through supplemen-tation) in early MS patients treated with IFN-beta-1b.

Domaines: Neurosciences [q-bio.NC]

Kassendra Munger, Karl Köchert, Kelly C Simon, Ludwig Kappos, Chris H Polman, et al.. Molecular mechanism underlying the impact of vitamin D on disease activity of MS. Annals of Clinical and Translational Neurology, 2014, 1 (8), pp.605 - 617. ⟨10.1002/acn3.91⟩. ⟨inserm-01103106⟩