Penn Research Offers New Insight Into Why Lupus Disproportionately Affects Women

New research is shedding light on the biological mechanisms that may help explain why systemic lupus erthyematosus (SLE) and other autoimmune diseases are more common in women. Two studies from the University of Pennsylvania found that disruptions in how one X chromosome is normally “silenced” in certain immune cells may help explain why lupus and other autoimmune diseases are more common in females. Typically, individuals with  two X chromosomes (XX) develop as female, and those with one X and one Y (XY) develop as male. Having multiple X chromosomes has been associated with an increased risk of developing lupus. 

Two studies led by Montserrat Anguera, PhD, of Penn’s School of Veterinary Medicine, examined X chromosome inactivation in B cells, a type of white blood cell that plays a key role in the immune response. The first study found that B cells maintain X inactivation through different molecular pathways than other cells in the body, which could help inform future research into gene regulation in B cells and its role in autoimmune disease. The second study found that disrupting the maintenance of  X chromosome inactivation in B cells, may lead to immune-related genes becoming improperly expressed, triggering and worsening lupus-like disease in preclinical models. In people with two X chromosomes, one X chromosome is typically “silenced” early in development, in part because the X chromosome carries many more genes than the Y chromosome.  However, researchers have found that this process may not always be properly maintained in immune cells, particularly during chronic inflammation.  

This research is especially relevant because the X chromosome carries a high number of immune-related genes, including one called TLR7 that, when overexpressed, can contribute to the development of lupus, and has long been associated with female gender bias and the presence of having multiple X chromosomes. 

This study received early funding from the Lupus Foundation of America’s Gina M. Finzi Student Summer Fellowship program in 2022, which funded study author Natalie Toothacre’s research on this topic under the mentorship of lead investigator Dr. Montserrat Anguera. 

While further research is needed, including studies into whether other female-biased autoimmune diseases show similar patterns of impaired –inactivation maintenance, the findings offer a promising step toward better understanding why autoimmune diseases disproportionately impact women and may eventually support more targeted approaches to studying, diagnosing or treating lupus. Learn more about what causes lupus. 

Read the study