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

Sonja Hochmeister,Shahin Aeinehband,Tomas Olsson,Rasmus Berglund,Sven A Gustafsson,Fredrik Piehl,Charles Dorris,Maja Jagodic,Michaela T Haindl,Milena Z Adzemovic,Vid Velikic,Manuel Zeitelhofer

doi:10.3389/fneur.2020.600401

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.PVGav1-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.PVGav1-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.

Highlights

Numerous studies implicate gene-environment interactions in the complex pathogenesis of multiple sclerosis (MS) [1]
In order to investigate the impact of vitamin D on MS-like neuroinflammation in the context of Vra4 haplotype/Mhc2ta variants, DA.PVGav1-Vra4 congenic rats were subjected to previously established diet regimen based on either: (i) regular, (ii) vitamin D supplemented, or (iii) vitamin D deprived rodent chow [23] (Figure 1A)
Concomitantly immunized age-matched DA rats subjected to the regular diet developed expectedly severe disease course (Figure 2A), while PVG strain remained unsusceptible to EAE regardless of the vitamin D concentration in the chow

Summary

Introduction

Numerous studies implicate gene-environment interactions in the complex pathogenesis of multiple sclerosis (MS) [1]. Allelic variations in the human leucocyte antigen (HLA) system, a group of genes on chromosome 6p21 that serves as the major histocompatibility complex (MHC), have been shown to enhance the probability for developing MS [2, 3]. Polymorphisms in this locus have been implicated in development of other autoimmune diseases such as Type I diabetes [4, 5], systemic lupus erythematosus [6], rheumatoid arthritis (RA) [7, 8] and narcolepsy [9]. Further study from our lab demonstrated less severe EAE in the congenic DA.PVGav1-Vra rats compared to the susceptible DA strain, which was primarily attributed to the Vra allele-dependent quantitative differences in MHC class II expression [15]

Methods

Results

Conclusion