Unlocking the Female Bias in Lupus

The autoimmune disease lupus strikes females far more often than males. According to a new study by Penn researchers, females with lupus don’t fully “silence” their second X chromosome in the immune system’s T cells, leading to abnormal expression of genes linked to that chromosome.

The work, led by Montserrat Anguera, an assistant professor in the department of biomedical sciences at Penn Vet and published in the journal JCI Insight, is the first to connect disruptions in maintaining X chromosome inactivation in T cells to lupus. It also suggests that changes to the nuclear structure in the inactive X chromosome of T cells may play a part in the genetic missteps that can arise in lupus.

In earlier studies, Dr. Anguera’s lab found that in females both T cells and B cells have incomplete inactivation of the second X chromosome due to changes in the patterns of Xist, an RNA molecule that is necessary for X inactivation. In the new work, they wanted to more closely examine this process in T cells in the context of an autoimmune disease.

Tracking the process of X inactivation in T cells from healthy mice, they found as T cells develop, Xist temporarily diffuses away from the inactive X chromosome. When a T cell is activated, Xist RNA returns to this chromosome. They then used a mouse model that spontaneously developed lupus in a female-biased manner. All female mice of this strain developed the disease; only 40% of males did. Those at early stages of disease resembled healthy controls in their patterns of Xist localization. Those in the later stages had a very different pattern.

“Abnormal X inactivation is a consequence of the disease; it’s not predisposing the animal to develop the disease,” noted Dr. Anguera. When the researchers looked at T cells from pediatric lupus patients, provided by study co-author Edward M. Behrens, Joseph Hollander Associate Professor in Pediatric Rheumatology at PSOM, they found the same mislocalization of Xist, even though the children were in remission. Comparing additional data from female and male lupus patients with either severe or mild disease, as well as healthy controls, they found a subset of genes altered only in the females with lupus. The research team also found that a subset of the altered genes in the lupus patients belonged to regions of the X chromosome that didn’t normally escape inactivation. Of this smaller group, some were lower in expression in lupus patients are involved in controlling nuclear organization and structure.