| First Author | Moore JR | Year | 2018 |
| Journal | J Neuroimmunol | Volume | 324 |
| Pages | 100-114 | PubMed ID | 30267995 |
| Mgi Jnum | J:290595 | Mgi Id | MGI:6443812 |
| Doi | 10.1016/j.jneuroim.2018.09.008 | Citation | Moore JR, et al. (2018) 1,25-Dihydroxyvitamin D3 increases the methionine cycle, CD4(+) T cell DNA methylation and Helios(+)Foxp3(+) T regulatory cells to reverse autoimmune neurodegenerative disease. J Neuroimmunol 324:100-114 |
| abstractText | 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. |
