Female Mice with an Xist Deletion in B Cells Can Develop Lupus-Associated Phenotypes

Systemic lupus erythematosus (SLE) is a female-biased autoimmune disease. X-Chromosome Inactivation (XCI) dosage compensates X-linked genes in females. Disrupted localization of Xist, a critical regulator of XCI, and aberrant expression of X-linked genes in female SLE patients and SLE mouse models suggest that XCI impairment contributes to disease. To test this, we conditionally deleted Xist in B cells (Xist cKO mice). Remarkably, some female Xist cKO mice spontaneously develop SLE phenotypes, including expansion of activated B cell subsets, development of disease-associated autoantibodies, and glomerulonephritis. Moreover, female Xist cKO mice with chemically induced SLE developed more activated B cells and dsDNA autoantibodies compared to treated wildtype female mice. Activated B cells from Xist cKO mice with SLE phenotypes have increased expression of X-linked immunity genes implicated in female-biased SLE. Our findings demonstrate that perturbations in B cell XCI maintenance directly contribute to female-biased SLE via upregulation of X-linked immunity-related genes.