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Published on: December 9, 2015
Multiple Sclerosis: Lipids, Lymphocytes, and Vitamin D
Colleen E Hayes1, James M Ntambi1,2
1Department of Biochemistry, College of Agricultural and Life Sciences, University of Wisconsin-Madison, 433 Babcock Drive, Madison, WI 53706, USA.
Abstract:
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. We review the two core MS features, myelin instability, fragmentation, and remyelination failure, and dominance of pathogenic CD4+ Th17 cells over protective CD4+ Treg cells. To better understand myelin pathology, we describe myelin biosynthesis, structure, and function, then highlight stearoyl-CoA desaturase (SCD) in nervonic acid biosynthesis and nervonic acid's contribution to myelin stability. Noting that vitamin D deficiency decreases SCD in the periphery, we propose it also decreases SCD in oligodendrocytes, disrupting the nervonic acid supply and causing myelin instability and fragmentation. To better understand the distorted Th17/Treg cell balance, we summarize Th17 cell contributions to MS pathogenesis, then highlight how 1,25-dihydroxyvitamin D3 signaling from microglia to CD4+ T cells restores Treg cell dominance. This signaling rapidly increases flux through the methionine cycle, removing homocysteine, replenishing S-adenosyl-methionine, and improving epigenetic marking. Noting that DNA hypomethylation and inappropriate DRB1*1501 expression were observed in MS patient CD4+ T cells, we propose that vitamin D deficiency thwarts epigenetic downregulation of DRB1*1501 and Th17 cell signature genes, and upregulation of Treg cell signature genes, causing dysregulation within the CD4+ T cell compartment. We explain how obesity reduces vitamin D status, and how estrogen and vitamin D collaborate to promote Treg cell dominance in females. Finally, we discuss the implications of this new knowledge concerning myelin and the Th17/Treg cell balance, and advocate for efforts to address the global epidemics of obesity and vitamin D deficiency in the expectation of reducing the impact of MS.
Insights
Multiple sclerosis involves myelin damage and immune cell imbalance. Vitamin D deficiency, linked to obesity, may worsen these by affecting myelin stability and T cell regulation, suggesting interventions to combat these deficiencies could help manage MS.
Area of Science:
- Neuroimmunology
- Cellular Biology
- Metabolic Disorders
Background:
- Multiple sclerosis (MS) is characterized by central nervous system inflammation, demyelination, and remyelination failure.
- Pathogenic CD4+ T helper 17 (Th17) cells dominate over protective CD4+ regulatory T (Treg) cells in MS.
- Myelin integrity relies on specific lipids, and oligodendrocyte function is crucial for myelin maintenance.
Purpose of the Study:
- To elucidate the roles of stearoyl-CoA desaturase (SCD) and nervonic acid in myelin stability.
- To explore the impact of vitamin D deficiency on myelin pathology and Th17/Treg cell balance in MS.
- To investigate the interplay between obesity, vitamin D, estrogen, and immune cell regulation in the context of MS.
Main Methods:
- Review of myelin biosynthesis, structure, and function, focusing on SCD and nervonic acid.
- Analysis of vitamin D signaling pathways involving microglia and CD4+ T cells.
- Examination of epigenetic modifications, including DNA methylation and gene expression in T cells.
- Discussion of the influence of obesity and hormonal factors on vitamin D status and immune responses.
Main Results:
- Vitamin D deficiency is proposed to decrease SCD in oligodendrocytes, impairing nervonic acid synthesis and leading to myelin instability.
- 1,25-dihydroxyvitamin D3 signaling restores Treg cell dominance by modulating the methionine cycle and epigenetic marking.
- Vitamin D deficiency may hinder the epigenetic downregulation of specific genes (e.g., DRB1*1501) associated with MS pathogenesis.
- Obesity exacerbates vitamin D deficiency, while estrogen and vitamin D synergize to promote Treg cell dominance in females.
Conclusions:
- Vitamin D deficiency contributes to myelin fragmentation and Th17/Treg cell imbalance in MS through impaired nervonic acid synthesis and epigenetic dysregulation.
- Addressing global epidemics of obesity and vitamin D deficiency may offer a therapeutic strategy to mitigate MS impact.
- Understanding these molecular and metabolic links provides new avenues for MS research and potential interventions.
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