How genetic risk factors affect the function of immune cells in MS

Jordon, Margaret cropped.jpg
Investigator

Supervisor

Funding

  • MS Research Australia-NHMRC Betty Cuthbert Fellowship - $304,596 for 2013 - 2016

Summary

After a worldwide effort, a large number of genetic risk factors have been identified for MS. This project will attempt to identify how these genes contribute to the risk of developing disease. This project will examine three candidate genes in greater detail, known as RGS1, HHEX and THEMIS. The first phase will take specific types of immune cell, known as natural killer cells and monocytes, from people with MS and people without disease.

The natural killer cells and monocytes will be grown in the laboratory and used to make comparisons between diseased and healthy cells. Dr Jordan will also compare different versions of each gene and different levels of gene activity in the cells to what determine kind of effect this has on function. The second phase will use animal models with specific versions of each gene to test how this affects susceptibility to MS.

Progress to Date

Three genes forming the focus of this project were initially identified from a sample of 39 healthy controls and 30 untreated patients with relapsing remitting MS. Since this initial analysis, the data sample size has increased to 110 healthy controls and 80 untreated patients, which is approaching the original goal of 100 individuals in each group.

Using a powerful technique called microarray analysis, the primary goal of Dr Jordan’s project is to look for changes in the activity of these three genes in different immune cells extracted from blood samples from the volunteers, comparing affected and unaffected individuals. These analyses have shown that gene activity occurs in some cell subtypes and not others. Dr Jordan has confirmed the importance of two of these genes for affecting the immune system in MS, but the results for the third gene suggest it may not be as important as previously thought. Dr Jordan has now included another gene in her analysis called AHI1.

Further analyses are currently underway to more thoroughly characterise the two key genes of interest, and understand how the expression of these genes may affect the function of different types of cells grown in the laboratory. In addition, mouse models of MS have been created that have also manipulated the expression of these genes, in order to identify how these genes might affect the expression of disease. Early results show that changing the expression of one of the genes appears to be having an effect on a single cell type. While continuing with the experiments to look at the effect of the genes across all cell types, Dr Jordan is now undertaking further experiments to characterise in more detail the effects on the single cell subtype.

This project applies modern genomic techniques to identify how MS genes affect the white blood cells of the immune system so that we can develop better predictive and diagnostic tools that may lead in the future to new therapies for MS.

Publications

  • Jordan MA, Field J, Foo G, Johnson L, Laverick L, Gresle M, Spelman T, Stankovich J, Butzkueven H and Baxter AG. Causes of Multiple Sclerosis: a functional genomics approach. Front. Immunol. (2013) Conference Abstract: 15th International Congress of Immunology (ICI). doi: 10.3389/conf.fimmu.2013.02.00482
  • Jordan MA, Field J, Butzkueven H, Baxter AG. Genetic Predisposition-Humans, in Mackay IR, Rose N (ed), The Autoimmune Diseases, 5th Edition, Elsevier. Boston, (2014) pp 341-364 (Chapter 26) ISBN: 978-0-12-384929-8.

Updated 20/4/2015