Sex differences in autoimmune disorders: Inspecting the roles of the X chromosome

Autoimmune disorders are complex, heterogeneous conditions that can severely impact an individual’s quality of life. These diseases are associated with a breakdown of central and peripheral processes controlling self-tolerance, causing the presence of circulating autoreactive immune cells that target the body’s own cells and tissues. Some data suggest that autoimmune diseases (ADs) are becoming increasingly prevalent in modern society. Possibly, both genetic and environmental factors contribute to the rise. ADs disproportionally affect females compared to males. Hormonal determinants, particularly sex-steroid hormones, have historically been proposed as key modulators of the differential susceptibility to ADs between the mammalian sexes. Emerging evidence has more recently generated significant focus on the X chromosome as a potential key player in ADs pathogenesis. The X chromosome, one of the largest chromosomes in the mammalian genome, exhibits a different pattern of inheritance between the sexes. In females, one X chromosome is typically silenced in somatic cells to balance the active X dosage between the sexes. The X-inactivation process is not fully efficient as a proportion of X-linked genes is capable to escape silencing and maintaining variable, biallelic expression degree within each cell. Notably, the X chromosome is rich in genes related to immune functions; variations in X chromosome dosage can alter the susceptibility of developing autoimmune traits. Both X-linked genes and X-linked mechanisms have been associated with ADs. In this review, we discuss the X chromosome’s crucial roles in ADs.