Effect of Vitamin D on Experimental Autoimmune Neuroinflammation Is Dependent on Haplotypes Comprising Naturally Occurring Allelic Variants of CIITA (Mhc2ta)

Abstract

An increasing body of evidence associates low vitamin D levels with increased risk of multiple sclerosis (MS), suggesting the possibility of a gene-environment interaction for this environmental factor in MS pathogenesis. Moreover, it has been shown that vitamin D downregulates major histocompatibility complex (MHC) class II expression in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. We here report about the impact of a dietary vitamin D supplementation on EAE in the rat strains having functionally relevant allelic variations in the CIITA ( Mhc2ta ) gene, a master regulator of MHC class II expression. Full length myelin oligodendrocyte glycoprotein (MOG)-EAE was induced in DA.PVG av1 - Vra4 congenic rats harboring the Vra4 locus from PVG strain in the EAE- susceptible DA background, and compared to the parental strains. The congenic rats fed with either vitamin D supplemented, deprived or regular diet developed an intermediate clinical EAE phenotype, in contrast to DA and PVG strains. Immunopathological studies revealed vitamin D dose-dependent effect on demyelination and inflammatory infiltration of the central nervous system (CNS), expression of MHC class II and CIITA, as well as downregulation of a range of pro-inflammatory genes. Taken together, our findings demonstrate an impact of vitamin D on the target tissue pathology and peripheral immune response during EAE in DA.PVG av1 - Vra4 congenic strain. Thereby, our data provide evidence of a modulatory effect of vitamin D in context of genetic variances in the Vra4 locus/ Mhc2ta gene in MS-like neuroinflammation, with potential relevance for the human demyelinating disease.

Full spectrum of vitamin D immunomodulation in multiple sclerosis: mechanisms and therapeutic implications

“…In line with this hypothesis, many studies have shown that VitD pre-treatment reduces immune cell infiltration into the CNS during EAE. 26 , 50 , 149 , 160 , 163 , 181 , 182 However, the exact mechanisms by which VitD might modulate the BBB to control immune cell migration into the CNS still have to be elucidated. Furthermore, the effect of VitD on the expression of other important BBB adhesion molecules, which contribute to the recruitment of immune cells into the CNS have not been investigated yet.…”

Vitamin D in Multiple Sclerosis—Lessons From Animal Studies

“…So far, it has been shown that vitD promotes negative feedback regulation of Toll-like receptor (TLR) signaling in macrophages in vitro , which in turn ameliorates inflammation. Naturally occurring allelic differences in the Vra4locus/Mhc2ta could be relevant for the efficacy of vitD in modulation of MS-like neuroinflammation and potentially even in MS, but sufficient information about response to vitD within the Vra4 gene locus is still missing ( 10 ). Data from EAE allow the conclusion that vitD synthesis by activated microglial cells and macrophages in the CNS preserves neurological function by dampening the inflammatory process.…”

“…An inverse vitD dose-dependent effect on demyelination and inflammatory infiltration of the CNS, as well as downregulation of some pro-inflammatory genes, indicated an impact of vitD on pathophysiology and immune response during EAE. A modulatory effect of vitD regarding genetic variances in MS is therefore most likely probably relevant for the human disease as well ( 10 ). Additionally, vitD may reduce the MS risk in part through a mechanism involving myeloid cell vitD production and CTLA-4 upregulation in CNS-infiltrating T-cells.…”

Differential expression of the inflammatory ciita gene may be accompanied by altered bone properties in intact sex steroid-deficient female rats

“…This results in lower Ciita expression in the DA.VRA4 strain (DA has normal-to-high expression). Development of the congenic strain has been described in detail [ 10 , 12 ] and the differential expression characterised in a variety of tissues [ 9 – 11 ].…”

“…To investigate the connection between bone properties and different inflammatory backgrounds associated with differences in expression of the Ciita gene, we performed a preliminary study using a well-characterised rat model consisting of two strains with differing expression levels of Ciita [ 9 – 11 ]. In this exploratory study of female rats using OVX to model estrogen-deficiency, our endpoint was to describe differences in bone structural integrity and strength phenotypes.…”