Dr Gresle will investigate how small genetic variations in the DNA (known as single nucleotide polymorphisms or SNPs), can increase the risk for developing MS. So far, 110 SNPs have been found to occur more commonly in people with MS compared to the general population, but it is not yet clear how these small genetic variations make some individuals more susceptible to MS. A number of these SNPs are involved in the functioning of immune cells. Using a technique called RNA sequencing, Dr Gresle will determine if certain SNPs affect the number or type of immune cells in a person. This project is likely to provide novel insights into the causes of MS, and in particular how genetic variations contribute to this disease.
During the course of her Fellowship, Dr Gresle aims to investigate how the oral therapies for relapsing MS (fingolimod [Gilenya] and dimethyl fumarate [Tecfidera]) work to modify the course of the disease. These drugs are known to reduce relapse rates and delay disability accumulation but the exact mechanisms remain unclear. She is looking at changes that occur in specific types of immune cells, known as monocytes. It is hoped that by improving our understanding of how these drugs work, it will be possible to design more effective and better tolerated treatments for MS.
During this study, Dr Gresle recruited 118 people with and without MS and collected and processed their blood samples. Of the 85 people with MS, 22 people were taking dimethyl fumarate, 31 were taking fingolimod, and 32 people were not taking any medications. 33 people without MS were also included in the study for comparison.
Using a technique called flow cytometry, where individual cells can be “marked” with a florescent signal, Dr Gresle compared the number of specific types of immune cells between the groups. She found no difference in the number of certain immune cells (monocytes, B-cells, T-cell or Natural Killer cells) between the groups of people. This means that taking dimethyl fumarate or fingolimod does not seem to affect the number of immune cells in a person body.
When examining these populations of immune cells a bit more closely, she discovered minor changes in certain types of B and T cells between people with MS that were not taking any medications, compared to people without MS. Dr Gresle found that these differences were not seen in the people with MS on the medications, and they had similar numbers of these B and T cells to people without MS. This suggests that the medications might be working to restore the balance in B and T cell numbers and this might be how they help to prevent the relapses of MS.
Next, Dr Gresle used the RNA sequencing technique to look at the genes that were switched on or off specifically in the monocytes (type of immune cell). She found that 31 genes were active at different levels in people with MS whom were not taking medication, compared to people without MS. Currently, Dr Gresle is performing further analysis to determine what cell functions these genes are involved in.
Dr Gresle also found that the gene activity profile in the monocytes of people taking dimethyl fumarate or fingolimod were different from those with MS whom were not taking any medication. She is now working with an industry partner to investigate the meaning and implications of this in more detail.
During the course of this fellowship Dr Gresle was able to learn a range of new laboratory based techniques to expand her skills and expertise and also presented her work to others in the MS research field. She was also successful in obtaining industry funding to continue her promising investigations into the immunology and genetics of MS.
It is hoped that these studies will provide new insights into how genetic variation contributes to changes in immune cells that are associated with the development of MS. Specifically, in the inflammatory attacks involved in MS.
Updated 6th June 2017
Updated: 05 January, 2015