Testosterone. Source of prostates and testes, muscles and machismo, chest hair, and according to some, even math skills. Its levels are only one of the biological differences between males and females, but they may help to explain another: the discrepancies in the incidence of autoimmune diseases.

Women are three to nine times more likely than men to suffer from autoimmune diseases, including multiple sclerosis (MS), Grave’s disease, celiac disease, systemic lupus erythematous, and rheumatoid arthritis. Not only do women get these diseases at higher rates, they usually get them at younger ages.

Men’s higher testosterone levels—about seven to eight times higher than women’s—have been shown to be protective for MS in both mice and men. But it was not clear exactly how this worked. Recent work in a mouse model of MS has filled in the downstream effectors that mediate testosterone’s protective effects. These effectors might be useful as therapeutics, whereas testosterone use really isn’t, especially for women, who are the ones who need it most.

The work focused on a type of immune cell called a mast cell. Mast cells get a bad rap because they release histamine during allergic reactions, but they're generally involved in inflammation. In the mice that recapitulate MS, testosterone influences the behavior of mast cells in the lymph nodes, central nervous system, and lining of the brain. In female mice, which don’t have as much testosterone, mast cells instead produce pro-inflammatory signaling molecules called cytokines.

When mast cells in these areas are exposed to testosterone, however, researchers found that they produce a cytokine with the opposite effect: one that tones down inflammation. In male mice that lack mast cells, MS progresses much like it does in female mice. This suggests that the anti-inflammatory signaling is the key, rather than the promotion of inflammation that happens in females.

Two drugs currently approved for the treatment of MS act by shifting the population of T cells in patients to look more like those seen in male mice, to the kinds of T cells that mitigate inflammation rather than those that promote it. Perhaps the cytokine that testosterone induces mast cells to make, interleukin-33, might one day join them.

PNAS, 2018. DOI: 10.1073.pnas.1710401115 (About DOIs).