Anatomy and Neuroscience - Research Publications

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Type: Journal Article × Author: Jokubaitis, Vilija × Author: Field, Judith ×

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    Multiple sclerosis risk variants regulate gene expression in innate and adaptive immune cells
    Gresle, MM ; Jordan, MA ; Stankovich, J ; Spelman, T ; Johnson, LJ ; Laverick, L ; Hamlett, A ; Smith, LD ; Jokubaitis, VG ; Baker, J ; Haartsen, J ; Taylor, B ; Charlesworth, J ; Bahlo, M ; Speed, TP ; Brown, MA ; Field, J ; Baxter, AG ; Butzkueven, H (LIFE SCIENCE ALLIANCE LLC, 2020-07)
    At least 200 single-nucleotide polymorphisms (SNPs) are associated with multiple sclerosis (MS) risk. A key function that could mediate SNP-encoded MS risk is their regulatory effects on gene expression. We performed microarrays using RNA extracted from purified immune cell types from 73 untreated MS cases and 97 healthy controls and then performed Cis expression quantitative trait loci mapping studies using additive linear models. We describe MS risk expression quantitative trait loci associations for 129 distinct genes. By extending these models to include an interaction term between genotype and phenotype, we identify MS risk SNPs with opposing effects on gene expression in cases compared with controls, namely, rs2256814 MYT1 in CD4 cells (q = 0.05) and rs12087340 RF00136 in monocyte cells (q = 0.04). The rs703842 SNP was also associated with a differential effect size on the expression of the METTL21B gene in CD8 cells of MS cases relative to controls (q = 0.03). Our study provides a detailed map of MS risk loci that function by regulating gene expression in cell types relevant to MS.
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    Ceruloplasmin gene-deficient mice with experimental autoimmune encephalomyelitis show attenuated early disease evolution
    Gresle, MM ; Schulz, K ; Jonas, A ; Perreau, VM ; Cipriani, T ; Baxter, AG ; Miranda-Hernandez, S ; Field, J ; Jokubaitis, VG ; Cherny, R ; Volitakis, I ; David, S ; Kilpatrick, TJ ; Butzkueven, H (WILEY, 2014-06)
    We conducted a microarray study to identify genes that are differentially regulated in the spinal cords of mice with the inflammatory disease experimental autoimmune encephalomyelitis (EAE) relative to healthy mice. In total 181 genes with at least a two-fold increase in expression were identified, and most of these genes were associated with immune function. Unexpectedly, ceruloplasmin (Cp), a ferroxidase that converts toxic ferrous iron to its nontoxic ferric form and also promotes the efflux of iron from astrocytes in the CNS, was shown to be highly upregulated (13.2-fold increase) in EAE spinal cord. Expression of Cp protein is known to be increased in several neurological conditions, but the role of Cp regulation in CNS autoimmune disease is not known. To investigate this, we induced EAE in Cp gene knockout, heterozygous, and wild-type mice. Cp knockout mice were found to have slower disease evolution than wild-type mice (EAE days 13-17; P = 0.05). Interestingly, Cp knockout mice also exhibited a significant increase in the number of astrocytes with reactive morphology in early EAE compared with wild-type mice at the same stage of disease. CNS iron levels were not increased with EAE in these mice. Based on these observations, we propose that an increase in Cp expression could contribute to tissue damage in early EAE. In addition, endogenous CP either directly or indirectly inhibits astrocyte reactivity during early disease, which could also worsen early disease evolution.