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Consortium Finds Immune Related MicroRNA Changes in Multiple Sclerosis

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – A pair of microRNAs thought to regulate immune genes are found at lower levels in the blood of those with multiple sclerosis than in unaffected individuals, according to a study appearing online yesterday in PLoS ONE.

Members of the Australia and New Zealand Multiple Sclerosis Genetics Consortium, known as ANZgene, used miRNA microarray profiling to compare miRNA patterns in blood samples from 59 individuals with MS and 37 unaffected controls. The researchers found lower expression of two miRNAs — miR-17 and miR-20a — in individuals with all three forms of MS tested in the study.

Meanwhile, the team's follow-up experiments indicated that these miRNAs curb the expression of genes involved in activating T cells in the immune system — genes that also tend to be more highly expressed in MS blood samples. As such, they argued, the newly identified miRNAs may prove useful for those looking to come up with new MS treatments.

"In all MS sub-types miR-17 and miR-20a were significantly under-expressed in MS," corresponding author Rodney Scott, a medical genetics researcher at the University of Newcastle in Australia, and his colleagues wrote. "The same T cell activation genes are also up-regulated in MS whole blood [messenger RNA], suggesting these miRNAs or their analogues may provide useful targets for new therapeutic approaches."

MS is a neurodegenerative disease typically diagnosed in adults younger than 35 years old. Symptoms of the autoimmune condition may flare up intermittently and then subside in those who have a form of the disease known as relapsing remitting MS. In other cases, termed progressive MS, the condition advances slowly but continuously without this reprieve.

Genetic studies have uncovered changes to both human leukocyte antigen (HLA) loci and non-HLA loci associated with MS risk. And a study of methylation patterns in MS discordant identical twins published this spring suggests epigenetics also have a role in disease risk.

In an effort to find miRNAs involved in MS, ANZgene researchers used the Illumina Sentrix array matrix to assess 733 miRNA transcripts in 59 Caucasian individuals with MS who had not received T cell targeting treatment for the condition for three months or more. Among them: two-dozen individuals with relapsing remitting MS, 18 individuals with the primary progressive form of the disease, and 17 individuals with secondary progressive MS.

They compared these miRNA profiles with those in 37 healthy, age-matched control individuals, identifying 26 miRNAs that are expressed at lower levels in blood samples from individuals with MS and a single miRNA expressed at higher levels in the patients.
From the 26 up-regulated miRNAs in MS, the researchers narrowed in on two miRNAs with the most pronounced differences between cases and controls: miR-17 and miR-20a, miRNAs implicated in immune function.

After verifying the differential expression of these miRNAs using real-time PCR, the team did a series of experiments in a Jurkat cell line generated from to a T cell lymphoma sample, looking at how knocking down or adding in the miRNAs affects gene expression.

Their results suggest that miR-17 and miR-20a down-regulation is linked to enhanced messenger RNA levels for some of the same T cell related genes that get over-expressed in MS patient blood samples.

Based on these findings, the researchers believe miR-17 and miR-20a might contribute to MS development. And regardless of whether the miRNAs directly contribute to the disease, they added, it may be possible to tweak immune related gene levels in MS by targeting these sorts of regulatory miRNAs.

"Even if the miRNAs under-expressed in MS were not directly contributing to the immune cell signature observed in MS whole blood, the excessive T cell activation signature seen in MS and other autoimmune diseases suggest agents which can reduce this activity may be therapeutically beneficial," the team concluded.

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