Single gene discovery reveals key sex difference in immune response

A new study has uncovered a key difference between the immune system of males and females – and it comes down to a single gene.

It is known that biological sex affects the function of the immune system, with women often being more severely affected by autoimmune conditions or allergic diseases.

Scientists from the University of York have now identified the gene Malat1 as a critical player in regulating immune responses in female immune cells, but not in males. 

The team studied T cells, a pillar of our immune system, in the lab and animal models of inflammation. The study focused on a type of immune cells called Th2 cells, which protect the body from parasitic infections, such as schistosomiasis, but also promote severe allergies, such as severe asthma. 

Malat1 appears to be part of the bigger picture of what makes female T cells different. It is a gene that produces an RNA but not a protein. It is fascinating that even though it is present in both female and male T cells, it seems to be working differently in female cells.”

Professor Dimitris Lagos, University of York and Hull York Medical School

Over 240 million people are affected by asthma worldwide, a quarter of whom exhibit severe disease, with over 60% of severe adult patients being female. Similarly, over 200 million people are affected by schistosomiasis, a disease caused by helminth parasites, with over 100 million adolescent girls and 138 million pregnant women living in endemic areas.

The team discovered that, in female mice, Th2 cells did not develop appropriately during lung inflammation when the gene Malat1 was missing. However, this defect was not seen in male mice.

Professor Lagos said: “We see a drop in immune cell function in females when this gene is absent. Its loss disrupts how immune cells develop – particularly their ability to produce important molecules involved in inflammatory responses called cytokines.

“This contributes to a rapidly developing body of knowledge that tries to explain why men and women sometimes respond differently to the same infection, allergen, inflammation trigger, or immune therapy. It demonstrates that a one-size-fits-all treatment approach may not always be effective.”

“Understanding the biology of female immune cells could lead to more effective treatments, tailored to biological sex, for diseases of the immune system, including infections affecting millions of people in some of the poorest communities in the world and common conditions such as severe asthma.”

The next stage of the work is to examine these results in human immune cells and explore how Malat1 works to fine-tune immune responses, leading to development of more effective treatments.

The study is published in The Journal of Immunology.