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J Neuroimmunol. 2018 Nov 15;324:100-114. doi: 10.1016/j.jneuroim.2018.09.008. Epub 2018 Sep 21.

1,25-Dihydroxyvitamin D3 increases the methionine cycle, CD4+ T cell DNA methylation and Helios+Foxp3+ T regulatory cells to reverse autoimmune neurodegenerative disease.

Author information

1
Department of Biochemistry, College of Agricultural and Life Sciences, University of Wisconsin-Madison, 433 Babcock Drive, Madison, WI 53706, United States.
2
Rhapsody Data, LLC, Madison, WI 53705, United States.
3
Department of Animal Sciences, University of Florida, Gainesville, FL 32611, United States.
4
Rheumatic and Autoimmune Diseases, Center for Immunology, Department of Medicine, University of Minnesota, Minneapolis, MN 55455, United States. Electronic address: span0005@umn.edu.
5
Department of Biochemistry, College of Agricultural and Life Sciences, University of Wisconsin-Madison, 433 Babcock Drive, Madison, WI 53706, United States. Electronic address: hayes@biochem.wisc.edu.

Abstract

We investigated how one calcitriol dose plus vitamin D3 reverses experimental autoimmune encephalomyelitis (EAE), a multiple sclerosis model. This protocol rapidly increased CD4+ T cell Ikzf2 transcripts, Helios protein, and CD4+Helios+FoxP3+ T regulatory cells. It also rapidly increased CD4+ T cell Bhmt1 transcripts, betaine:homocysteine methyltransferase-1 (BHMT1) enzyme activity, and global DNA methylation. BHMT1 transmethylates homocysteine to replenish methionine. Targeting the Vdr gene in T cells decreased Ikzf2 and Bhmt1 gene expression, reduced DNA methylation, and elevated systemic homocysteine in mice with EAE. We hypothesize that calcitriol drives a transition from encephalitogenic CD4+ T cell to Treg cell dominance by upregulating Ikzf2 and Bhmt1, recycling homocysteine to methionine, reducing homocysteine toxicity, maintaining DNA methylation, and stabilizing CD4+Helios+FoxP3+Tregulatory cells. Conserved vitamin D-responsive element (VDRE)-type sequences in the Bhmt1 and Ikzf2 promoters, the universal need for methionine in epigenetic regulation, and betaine's protective effects in MTHFR-deficiency suggest similar regulatory mechanisms exist in humans.

PMID:
30267995
DOI:
10.1016/j.jneuroim.2018.09.008
[Indexed for MEDLINE]

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