Sex Chromosomes Dictate T Cell (Th17) Pathogenicity

Background: A person’s sex is an important, yet complex factor in the development and progression of multiple sclerosis (MS). Current evidence indicates that 75% of people in Canada living with MS are women - women are three times more likely to develop MS than men, while men with MS progress more rapidly. While sex clearly impacts MS incidence and progression, its role in affecting disease outcomes is not well understood.

Overview: This research aims to address why males develop progressive disease more quickly. The researchers developed a system in mice that undergo MS-like disease, including relapses and remissions, and then start to develop progressive-like symptoms, as characterized by the loss of motor function. In severe cases, they cannot move their lower extremities and even have difficulty feeding themselves. Dr. Manu Rangachari and team previously found that male mice develop very severe progressive disease as compared to females, and that their immune cells (T cells, specifically Th17 cells) are responsible for the difference. Using the Four Core genotypes genetic model, they also showed that the hormone, testosterone, is not making the disease worse, rather it may instead be the genes on the X chromosome. This research hypothesizes that there may be protective genes on the X chromosome and will test this idea using a unique mouse model called XY* in which males have either one X chromosome (as per normal, XY), or two X chromosomes (XXY). If the hypothesis is correct, then the XXY mice will get less severe MS-like disease. If protective, the researchers will use genetic techniques to identify the specific X chromosome genes responsible for the effect. Overall, this work will provide insights into the complex mechanisms by which male Th17 induce a more severe MS-like disease and whether the X-chromosome genes function as critical regulators of disease progression.

Impact: Many clinical trials that test new disease modifying treatments have not formally tested whether men and women respond differently to these treatments, and thus we may be missing important sex-specific differences. This mouse model could provide important experimental evidence to support further and more careful analyses of sex and its contribution to MS. Additionally, the X chromosome genes identified through this work could be potential drug targets.

Project Status: Closed.

• April 14, 2021 - Researchers Identify a New Mechanism for Sex Differences in Disease Severity of Multiple Sclerosis