Paul J. Utz, MD, PhD
Stanford University School of Medicine
Project Overview
The majority of patients with scleroderma are female, with women having an incidence four times that of men. Scleroderma in men, although rarer, can be a more aggressive form of the disease. Despite compelling epidemiological evidence of sex-related differences in the pathogenesis of the disease, there is very little consensus as to what is happening at the molecular level. We are investigating “X chromosome inactivation,” a female-specific cellular mechanism that silences one of the cell’s two X chromosomes. The body’s inefficient or incomplete silencing of the activity of one X chromosome in female cells (known as X chromosome inactivation escape), has been theorized to be involved in scleroderma and other autoimmune diseases. This project aims to build upon our finding of strong sex-related differences in gene regulation in T cells from scleroderma skin.
Research Update
Using a technique we developed called ATAC-seq, we have demonstrated marked differences in gene regulation in immune cells from males and females. We have discovered that the inactive X chromosome has many proteins associated with it that are autoantigens in systemic autoimmune diseases and we are investigating this connection to scleroderma and other autoimmune disorders. We are testing whether a male animal engineered to have a chromosome resembling the inactive X will experience female-level risk of autoimmunity.
