Natural genetic variation profoundly regulates gene expression in immune cells and dictates susceptibility to CNS autoimmunity

Abstract

Regulation of gene expression in immune cells is known to be under genetic control, and likely contributes to susceptibility to autoimmune diseases, such as multiple sclerosis (MS). How this occurs in concert across multiple immune cell types is poorly understood. Using a mouse model that harnesses the genetic diversity of wild-derived mice, more accurately reflecting genetically diverse human populations, we provide an extensive characterization of the genetic regulation of gene expression in five different naïve immune cell types relevant to MS. The immune cell transcriptome is shown to be under profound genetic control, exhibiting diverse patterns: global, cell-specific, and sex-specific. Bioinformatic analysis of the genetically-controlled transcript networks reveals reduced cell type-specificity and inflammatory activity in wild-derived PWD/PhJ mice, compared with the conventional laboratory strain C57BL/6J. Additionally, candidate MS-GWAS genes were significantly enriched among transcripts overrepresented in C57BL/6J cells compared to PWD. These expression level differences correlate with robust differences in susceptibility to experimental autoimmune encephalomyelitis, the principal model of MS, and skewing of the encephalitogenic T cell responses. Taken together, our results provide functional insights into the genetic regulation of the immune transcriptome, and shed light on how this in turn contributes to susceptibility to autoimmune disease.

Sex-Specific Gene-by-Vitamin D Interactions Regulate Susceptibility to Central Nervous System Autoimmunity

“…When gene expression data were analyzed for effect of genotype, sex, and VitD, it was found that genotype accounted for the largest effect size, with modest effects of sex and VitD (Figure 3 A). This is consistent with our published data showing strikingly divergent transcriptomes between B6 and PWD immune cells ( 50 ). Consistent with these observations, when both strains and sexes were pooled and analyzed together for effect of VitD, very few differentially expressed (DE) genes were detected in either cell type (Figures 3 B,C).…”

“…We have previously shown that PWD mice are almost completely resistant to EAE ( 50 ). To test whether this resistance could be affected by VitD status, PWD mice were subjected to the dietary regimen as above, followed by EAE induction.…”

“…CFA was supplemented with 4 mg/ml Mycobacterium tuberculosis H37Ra (Difco, USA). EAE was induced in PWD mice using the following modifications to the protocol above, as previously described ( 50 ). Mice were injected subcutaneously with 0.1 ml of emulsion containing 2.5 mg of MSCH in PBS and 50% CFA on day 0 and day 7.…”

“…We and others have attempted to more closely model human genetic diversity by incorporating into the experimental design wild-derived inbred strains of mice, such as PWD/PhJ (PWD), or chromosome substitution (consomic) strains that carry individual PWD chromosomes on the common B6 background (B6.Chr PWD ) ( 48 , 49 ). We have shown that compared with B6 mice, a classical inbred laboratory strain, wild-derived inbred PWD mice have widely divergent immune cell transcriptomes, which result in differential expression of MS relevant genes and reduced susceptibility to EAE ( 50 ). We have also used the B6.Chr PWD consomic model to identify multiple EAE susceptibility loci, many of which were sex specific ( 51 ).…”

Burkholderia pseudomallei invades the olfactory nerve and bulb after epithelial injury in mice and causes the formation of multinucleated giant glial cells in vitro

“…These findings may also suggest that outbred mice are more resistant to olfactory nerve infection than inbred mice. Outbred mice are well known to exhibit stronger resistance to infections, to be more "immunocompetent" and to better reflect immune responses in humans than inbred mice [57][58][59][60][61][62][63][64][65]. Differences in the response to B. pseudomallei infection has also been demonstrated between different inbred mouse strains.…”