Male Immune Cells Drive More Severe MS, Study Suggests

Due to differences in sex chromosomes, certain immune cells cause more severe disease in males than females, according to a new study in a mouse model of multiple sclerosis (MS).

The findings could help to explain why biological males with MS tend to have more severe disease.

The study, “Male sex chromosomal complement exacerbates the pathogenicity of Th17 cells in a chronic model of central nervous system autoimmunity,” was published in Cell Reports.

Biological sex has well-established effects on MS: data show that while females are substantially more likely to develop the disorder, males usually have more severe disease. The reason for this difference, however, is not completely understood.

Now, a team led by researchers at Université Laval, in Canada, sought to better understand how biological sex affects the activity of immune cells. The researchers performed a series of experiments in mice with experimental autoimmune encephalitis (EAE) — a mouse disease commonly used to model MS — to examine cells believed to be involved in driving MS. Specifically, the team looked at a type of immune cell called T helper 17 (Th17) cells.

First, immune Th17 cells were taken from either male or female mice, and stimulated so they would be inflammatory. These cells then were put into other mice.

The team found that Th17 cells from male mice induced substantially more severe EAE than did cells from female mice. The results showed that mice given female Th17 cells often lived for at least 70 days, while mice given male Th17 cells rarely lived that long.

“These data gave us our first indication that male Th17 cells have a greater intrinsic pathogenic [disease-causing] capacity,” the researchers wrote.

Notably, this difference was independent of the recipient animal’s sex. In other words, male Th17 immune cells induced more severe disease in both male and female mice.

Further experiments indicated that male Th17 cells produced higher levels of interferon gamma, a signaling molecule that drives disease-causing inflammation in MS. The male cells also had greater plasticity, which is the ability to rapidly change cellular activity.

The researchers then sought to understand what was causing this sex-based difference. Biologically, males have one X chromosome and one Y chromosome, and their bodies have higher levels of “male” hormones, called androgens. By contrast, biological females have two X chromosomes, and higher levels of “female” hormones such as estrogen.

First, the team tested whether the sex-based difference in pathogenicity — or disease-causing capacity — could be a result of hormonal differences. To do this, they repeated similar cell-transferring experiments using Th17 cells from mice that had had their gonads (ovaries or testis) surgically removed so that they would not produce sex hormones.

The results were similar to the original experiments: Th17 cells from male mice were more pathogenic, and those from females were less pathogenic, irrespective of the hormonal differences.

“These data demonstrate that the increased pathogenicity of male Th17 is not explained by either the presence of androgens or the absence of female sex hormones,” the researchers wrote.

In further experiments, the researchers engineered mice that were chromosomally male or female, but produced the opposite set of hormones. Irrespective of the hormones, chromosomally male (XY) Th17 cells were more pathogenic and more plastic than chromosomally female (XX) cells, suggesting that it is the chromosomes themselves responsible for the sex-based difference.

The investigators then found that male Th17 cells have lower expression of an X-linked gene called Jarid1c, which normally regulates inflammatory activity. Increasing Jarid1c expression in male Th17 cells made them less pathogenic, whereas female cells with lessened Jarid1c expression were more pathogenic.

The team also found that Jarid1c levels were abnormally low in T-cells taken from MS patients, particularly from male patients.

“These findings represent an important advance in our understanding of how biological sex acts as a determinant of disease severity in [MS],” the researchers concluded. Additional research is now needed to understand how Jarid1c modulates disease severity and whether it could be used as a potential drug target for MS.