Female mice with a Xist deletion in B cells can develop lupus-associated phenotypes
Year: 2026
Type: article
Abstract: 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.
Source: Cell Reports
Institution: University of Pennsylvania
Language: English
Subfield: Rheumatology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,620
Funders: Scleroderma Research Foundation, Lupus Foundation of America, Rheumatology Research Foundation, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Lupus Research Alliance, National Institutes of Health, Penn Skin Biology and Diseases Resource-based Center, University of Pennsylvania, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases
Awards: G1378691022, G4337076128, Medical Scientist Training Program, G5668476823, Elucidating the Role of Dynamic X-Chromosome Inactivation Maintenance in the Pathogenesis of Systemic Sclerosis, G7875879575, Role for nuclear matrix proteins and DNA methylation for XCI maintenance in female lymphocytes, Gene regulation mechanisms involving the inactive X in B cells during lupus disease, Defining the Role of Dynamic X Chromosome Inactivation in Age-Associated B Cells for Female-Biased Systemic Lupus Erythematosus
OpenAlex ID: W7164398534