Showing the importance in medical research of studying sex differences, a team of scientists based at Northwestern University has discovered a molecular mechanism that could help explain why men are less likely than women to suffer autoimmune disease. Men, new research indicates, may enjoy some degree of protection from multiple sclerosis (MS) because they benefit from a testosterone-activated pathway that helps cools the immune response. If this pathway could be activated without testosterone, it could help men and women alike while avoiding the undesirable side effects of long-term testosterone treatment.

The discovery of the pathway stemmed from a lucky mistake. In the laboratory of Melissa Brown, Ph.D., a graduate student selected male mice instead of female mice for a study. Apparently, the graduate student had yet to learn how to identify the nearly imperceptible genitals of male mouse pups.

The male mice were used to evaluate experimental autoimmune encephalomyelitis (EAE), which resembles MS, a condition in which immune cells attack the myelin sheath, a membrane that wraps around the nerve axons within the brain and spinal cord. When the myelin sheath is damaged, normal nerve signal conduction is interrupted, resulting in a variety of symptoms, including sensory disturbances, loss of motor function, and cognitive deficits.

The Northwestern scientists showed that in male mice testosterone caused mast cells, a type of immune cell, to produce a guardian molecule, the cytokine interleukin-33 (IL-33). The guardian molecule triggers a cascade of chemicals that prevents the development of another type of immune cell, so-called Th17 cells, that can directly attack the myelin.

In the EAE model, females develop more of a disease-causing Th17 immune response than males. These Th17 cells, attack and destroy the myelin. But that damaging response was reversed in females by treatment with IL-33.

Detailed results of the study appeared January 29 in the Proceedings of the National Academy of Sciences (PNAS), in an article entitled “Male-Specific IL-33 Expression Regulates Sex-Dimorphic EAE Susceptibility.” This article notes that while most studies of autoimmune disease focus on what causes the damaging inflammation in females, there is also much to be learned by studying the factors that confer protection to males.

“Our studies…reveal that sex-determined differences in Il33 expression by innate immune cells in response to myelin peptide immunization regulate EAE susceptibility,” wrote the article’s authors. “IL-33 is selectively induced in PLP139–151-immunized males and activates type 2 innate lymphoid cells (ILC2s), cells that promote and sustain a nonpathogenic Th2 myelin-specific response. Without this attenuating IL-33 response, females generate an encephalitogenic Th17-dominant response, which can be reversed by IL-33 treatment.”

Women have three-to-four times the incidence of MS compared to men, and the lower incidence in males is related, in part, to higher levels of testosterone. But until now, scientists haven't understood how the hormone provides protection. The new study discovered how testosterone does it, and how females can glean the benefits.

“[Our work] suggests a mechanism for the reduced incidence of multiple sclerosis and other autoimmune diseases in males compared to females,” said Dr. Brown. “These findings could lead to an entirely new kind of therapy for MS, which we greatly need.”

“This is why it's vital to study sex differences in research,” she added.

In addition to a higher incidence of MS in women, there are also sex-determined differences in the average age of onset and subtype of the disease. Women generally develop MS at a younger age and usually have a relapsing–remitting course of disease. Men develop the disease later in life and it usually continues to worsen without periods of improvement. The development of the disease in men also correlates with age-related reduction of testosterone levels.

While there have been some new breakthroughs in developing effective drug therapies for MS patients, most of these work by suppressing the immune system, making patients more susceptible to certain infections and/or causing a general malaise.

Limited clinical trials in male MS patients have shown that testosterone treatment over 12 months can partially reverse evidence of myelin- and nerve-degeneration and alleviate symptoms. However, short-term testosterone administration is not a viable therapy for either men or women because of the multitude of undesirable side effects.

“Our findings have identified new and more specific cellular and molecular targets for immune intervention that we hope will lead to better therapies that leave most of the immune system intact,” asserted Dr. Brown. “This testosterone-driven protective pathway should also be studied in other female-biased autoimmune diseases.”

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