Female mice with a Xist deletion in B cells can develop lupus-associated phenotypes.

Systemic lupus erythematosus (SLE) is an autoimmune disease preferentially observed in women. X-linked gene expression in XX females is equalized with that in XY males by X chromosome inactivation (XCI). However, B cells from female patients with SLE and mouse models of SLE exhibit aberrant X-linked gene expression and mislocalization of Xist RNA, a critical regulator of XCI, suggesting that impaired XCI may contribute to the disease. Here, some female mice harboring a B cell-specific Xist deletion ("Xist cKO") spontaneously developed SLE phenotypes, including expanded activated B cell subsets, disease-specific autoantibodies, and glomerulonephritis. Pristane treatment of Xist cKO mice led to an increased expansion of activated B cell subsets, resulting in higher anti-dsDNA autoantibody production. Activated B cells from Xist cKO mice with SLE phenotypes had an increased expression of X-linked and autosomal genes, depletion of X-linked H3K27me3, and were more responsive to stimulation. This work suggests that impaired XCI maintenance in B cells directly contributes to SLE-associated phenotypes in a female-biased manner.