2021 Gina M. Finzi Memorial Student Fellow
School of Medicine at the University of Pennsylvania
Project Title: Defining X Chromosome Inactivation Maintenance and Escape in Age-Associated B Cells
Mentor: Montserrat Anguera, Ph.D. Associate Professor, Department of Biomedical Sciences, University of Pennsylvania School of Veterinary Medicine
Project Summary: Lupus is a devastating disease caused by overactivity of the immune system, and 90% of patients are women. Understanding the cause of this disproportionate sex bias is critical for advancing our understanding of lupus and improving care for patients. Clinical evidence has shown that an important risk factor for developing lupus is having more than one X chromosome, and women have two X chromosomes (XX), while men only have one (XY). The X chromosome contains several genes that encode important instructions for the immune system, and if women have a double “dosage” of immune genes expressed from two X chromosomes, this may contribute to their higher rates of developing lupus. However, women have a mechanism to prevent expression of genes from both of their X chromosomes. This process is called “X chromosome inactivation (XCI)”.
In each cell in a woman’s body, one of their X chromosomes is physically coated in materials that “silence” that X chromosome by preventing gene expression. This silenced X chromosome is called the “inactive” X chromosome (Xi). Our lab has found that some immune system cells from lupus patients have an Xi that is incompletely coated with silencing materials, and these cells have higher expression of immune system genes from the X chromosome compared to healthy cells. These findings suggest that increased expression of immune genes from the Xi due to faulty silencing may cause immune cells to become over-activated in women with lupus and contribute to disease development or severity.
My project will investigate an important type of immune cell for lupus called an “age-associated B cell” (ABCs). I plan to study whether the Xi is fully silenced in ABCs, and determine if immune genes from the X chromosome are highly expressed in these cells. My work will improve our understanding of how ABCs play a role in the female-biased development of lupus.