Using immune gene networks to understand risk in MS

Professor Alan Baxter

James Cook University, QLD

| Better treatments | Genetics | Project | 2016 | Investigator Led Research |
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Summary

MS can result from the interaction of genetic and environmental risk factors. Studies have shown that many genes contribute to a person’s susceptibility of developing MS, and many of these genes are related to the immune system. Analysis of genetic ‘networks’ have shown that many of the genes work together in the same pathways, and that modulating pathways as a whole may provide protection from risk.

In previous research, Professor Baxter compared the activity levels of genes in a number of different types of immune cells in people with MS. He found that the gene activity in part of a network in monocytes (a type of immune cell) was different in people with MS than those without MS. The first part of this research project will validate these differences using other scientific methods to ensure that this finding was accurate. Professor Baxter will then modulate these pathways by controlling the activity of certain genes, to determine interactions within the gene network.

This network approach will provide more information about MS risk factors than the analysis of individual risk factors separately and may provide a multi-faceted target for treatment.

Progress to Date

Professor Baxter has collected and analysed immune cells of the blood in 50 people, these including cells called monocytes, B cells, NK cells, CD4 T cells and CD8 T cells. He has measured the activity (the expression) of thousands of genes at once, to create a global picture of how these cells were functioning.

In preliminary findings, Professor Baxter has found a group of genes that are behaving differently in people with relapsing remitting MS compared to those without MS. From this group, he has come up with a list of candidate genes to test in a model of MS. Professor Baxter removed two of these genes (Tbx21 and Eomes) in some of the immune cells and examined the effects this has on the severity of the disease. He found that deletion of Tbx21 or Eomes in monocytes reduced the severity of the disease however, deletion of either of these genes in NK cells increased the severity. He found that there was no effect on the severity of the disease when either of these genes were deleted in T cells, although he is in the process of confirming this finding.

These findings suggest these different cell types play a different role in the development of MS, and these genes can have both a positive and negative effect on the development of MS. Further understanding of this group of genes will provide more information about MS risk factors and help people determine how they can reduce their risk of developing MS.

Professor Baxter is in the process of preparing a patent based on findings identified from this work. He has presented his research findings at several national and international conferences and has also published a number of scientific manuscripts, with a book chapter currently in preparation.

 

Publications

  • Interleukin-2 receptor-α proximal promoter hypomethylation is associated with multiple sclerosis. Field J, Fox A, Jordan MA, Baxter AG, Spelman T, Gresle M, Butzkueven H, Kilpatrick TJ, Rubio JP. Genes Immun. 2017 Mar;18(2):59-66.
  • Common and Low Frequency Variants in MERTK Are Independently Associated with Multiple Sclerosis Susceptibility with Discordant Association Dependent upon HLA-DRB1*15:01 Status. Binder MD, Fox AD, Merlo D, Johnson LJ, Giuffrida L, Calvert SE, Akkermann R, Ma GZ; ANZgene., Perera AA, Gresle MM, Laverick L, Foo G, Fabis-Pedrini MJ, Spelman T, Jordan MA, Baxter AG, Foote S, Butzkueven H, Kilpatrick TJ, Field J. PLoS Genet. 2016 Mar 18;12(3):e1005853.
  • Altered behaviour and cognitive function following combined deletion of Toll-like receptors 2 and 4 in mice. Too LK, McGregor IS, Baxter AG, Hunt NH. Behav Brain Res. 2016 Apr 15;303:1-8.

Updated: 11 June 2020

Updated: 28 January, 2016

Investigator

Co-investigator

Grant Awarded

  • Project Grant

Total Funding

  • $240,000

Duration

  • 5 years over 2016 - 2020

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