More X’s, more problems: how contributions from the X chromosomes enhance female predisposition for autoimmunity

Many autoimmune diseases exhibit a strong female bias. While sex hormones may influence sex bias in disease, recent studies suggest that the X chromosome itself directly contributes to female-biased susceptibility to autoimmunity. Females with two X chromosomes utilize X Chromosome Inactivation (XCI) to silence gene expression from one X chromosome, equalizing expression between the sexes. The X chromosome is highly enriched with immune-related genes, and recent work indicates that the fidelity of XCI maintenance in lymphocytes from female systemic lupus erythematosus patients is compromised, suggesting that aberrant X-linked gene expression contributes to autoimmune phenotypes. XCI is initiated and maintained by the long noncoding RNA XIST/Xist through its interactions with the inactive X chromosome and numerous interacting proteins, and recent studies also implicate XIST/Xist RNA in driving endosomal Toll-like receptor signaling and XIST/Xist RNA-protein complexes in serving as a source of autoantigens to respectively drive autoimmunity. Here, we will review these three distinct pathways that underscore the significance of X-linked genetics for understanding the origins of the female bias in autoimmune disease.