Innate Lymphoid Cell Identified As Cause of Multiple Sclerosis Gender Differences

In a recent study published in The Journal of Immunology, researchers from a Northwestern Medicine lab discovered a potential clue about why women are more likely than men to develop autoimmune conditions such as multiple sclerosis (MS).

The researchers used a specific white blood cell, called the innate lymphoid cell, that exhibits different immune mechanisms of action in males versus females.

MS affects the brain and spinal cord and is caused by dysregulated immune response. Using an MS mouse model created for females, this novel research revealed that innate lymphoid cells are triggered and protect male mice from MS, while in female mice the same cells remain inactive.

“Women are three to four times more likely than men to develop MS, and much of the current research focuses on the question, ‘Why do females get worse disease?’” said in a recent news release Melissa Brown, lead author of the study and professor of microbiology-immunology at Northwestern University Feinberg School of Medicine.

“Now, thanks to a serendipitous moment in the laboratory, we are approaching this research from the opposite way, asking, ‘Why are males protected from disease?’” Brown said in the news release. “Understanding the mechanisms that limit disease in men can provide information that could be used in future therapy to block disease progression in women.”

The researchers used female mice models of MS. “When we induce the disease in this strain of female mice, virtually 100 percent of them get very sick,” Brown said in the news release. “Male mice either get no disease or very little, so MS researchers typically use females in their studies.”

A few years ago, results from Brown’s experiments revealed that one group of female mice was normal while the other group of female mice was found to have a genetic mutation in a growth factor receptor (c-kit) that averted the activation of a specific subgroup of cells from the immune system. Consequently, female mice with the genetic mutation became less sick than the normal mice. While looking at the reasons why, the research team found that a graduate student had used male mice for each group instead of female mice.

“It was an honest mistake, but the results were striking; the male mice with the mutation got very, very sick,” Brown said in the news release. “Because this strain of male mice never get very sick, I thought there was some sort of mistake, so I asked the student to repeat the experiment.”

The researchers found that the genetic mutation triggered a different reaction in male and female mice. Specifically, they found in mice that the c-kit mutation lacked type 2 innate lymphoid cells.

According to the researchers these sex differences are thought to be caused by the production of a specific protein that protects males from the condition by interfering with the damaging immune response.

“In the paper we show that when these cells are missing in the males with the mutation, that changes the whole immune response of the male animals and causes this lack of protection,” Russi said in the news release. “We are now looking at what activates these cells preferentially in males and not in females. The next question is can we activate the innate lymphoid cells in females to decrease disease susceptibility?”

In the 90s, researchers found that testosterone had a protective effect in MS women, however, because of the side effects, long-term treatment for MS women with testosterone is not viable.

This study revealed that these particular type 2 innate lymphoid cells, which have been investigated in allergy studies, have sex differences in their mechanism of action and have a protection effect in autoimmune disease.

The researchers hope to have a new understanding of these cells’ activators and if they can be used as a treatment. The results may lead to a new method to develop drugs modulating instead of suppressing MS patients immune system.

“The hope is to target these cells in a sex-specific way and provide a therapy with fewer side effects,” Brown said in the news release. “This early research may have implications for understanding other diseases such as lupus and rheumatoid arthritis, which also show a female bias.”