Gallagher, Patricia J.McCain, Travis WilliamTune, Johnathan D.Bright, John J.2015-03-052015-08-022014https://hdl.handle.net/1805/6018http://dx.doi.org/10.7912/C2/2013Indiana University-Purdue University Indianapolis (IUPUI)Multiple sclerosis (MS) is a disabling disease that afflicts an estimated two million people worldwide. The disease is characterized by degradation of the myelin sheath that insulates neurons of the central nervous system manifesting as a heterogeneous collection of symptoms. Two enzymes, protein arginine deaminases type 2 and 4 (PAD2 and PAD4) have been implicated to play an etiologic role in demyelination and neurodegeneration by catalyzing a post-translational modification of arginine peptide residues to citrulline. The pathogenesis of MS is poorly understood, though vitamin D deficiency is a well-associated risk factor for developing the disorder. Using the experimental autoimmune encephalomyelitis (EAE) model of MS we demonstrate vitamin D treatment to attenuate over-expression of PAD 2 and 4 in the brain and spine during EAE. In addition, we identify two molecules produced by peripheral immune cells, IFNɣ and IL-6, as candidate signaling molecules that induce PAD expression in the brain. We demonstrate vitamin D treatment to inhibit IFNɣ mediated up regulation of PAD2 and PAD4 both directly within the brain and by modulating PAD-inducing cytokine production by infiltrating immune cells. These results provide neuroprotective rational for the supplementation of vitamin D in MS patients. More importantly, these results imply an epigenetic link between vitamin D deficiency and the pathogenesis of MS that merits further investigation.en-USAttribution-NoDerivs 3.0 United StatesPAD2, PAD4, protein arginine deiminase, peptidyl arginine deiminase, vitamin D, 1,25(OH)2D3, multiple sclerosis, MS, EAE, experimental autoimmune encephalomyelitis, epigenetics, methylation, citrullination, citrullineMultiple sclerosis -- Research -- PathophysiologyDemyelination -- Research -- PathophysiologyPhosphorylasePeptides -- SynthesisArginine -- ResearchEnzymes -- RegulationNervous system -- Degeneration -- PathophysiologyVitamin D deficiency -- Research -- PathophysiologyEncephalomyelitisAutoimmunity -- Molecular aspectsEpigenetics -- ResearchMethylation -- Physiological effectOrnithine carbamoyltransferaseAdenosine deaminase -- ResearchPurines -- Metabolism -- DisordersImmunological deficiency syndromes -- ResearchMetabolism, Inborn errors of -- ResearchThesis