Although the development of the immune system is identical in men and women, autoimmune diseases such as multiple sclerosis and SLE are far more common in women. In contrast, women have better resistance to both viral and bacterial infections than men. For example, men are three times more likely to require treatment in intensive care following SARS-CoV-2 infection than women. This ‘sex bias’ in COVID-19 severity and mortality has further highlighted the importance of sex as a contributor to disease.
Whereas men have one X chromosome (which they inherit from their mother), women have two X chromosomes, one inherited from their mother and one inherited from their father. To balance the number of copies of X chromosome genes between men and women, each cell in a woman switches off one of its X chromosomes, a phenomenon called ‘X inactivation’. However, the process of X inactivation is not perfect, and some genes on the inactive X chromosome remain switched on. Consequently, female cells have twice as many of these so-called ‘escape’ genes, many of which perform important roles in the immune system. The Nestor group will investigate whether these genes cause the sex bias observed in many immune-related diseases in women.
The project, called XX-Health, will analyse human blood samples in biobanks held at Linköping University Hospital to assess how X-inactivation patterns are associated with immune-related disorders in women. Further, the project will analyse how individual genes on each X chromosome affect the biology of T cells, an important type of immune cell involved in both fighting infection and causing autoimmune disorders.
“I’m thrilled to receive this grant, which is built on the hard work and innovation of all the researchers in my group. The scale of this financing will allow us to tackle this important, yet poorly understood, part of human genetics with state-of-the-art next-generation sequencing and gene-manipulation technologies. Although the project is technically highly challenging, we are confident we will not only make discoveries about the enigmatic process of X inactivation but also understand how this process contributes to human disease,” says Colm Nestor.