Xist Deletion in B Cells Results in Systemic Lupus Erythematosus Phenotypes.
Claudia D LovellNikhil JiwrajkaHayley K AmermanMichael P CancroMontserrat C AngueraPublished in: bioRxiv : the preprint server for biology (2024)
Systemic lupus erythematosus (SLE) is an autoimmune disease preferentially observed in females. X-linked gene expression in XX females is normalized to that of XY males by X-Chromosome Inactivation (XCI). However, B cells from female SLE patients and mouse models of SLE exhibit mislocalization of Xist RNA, a critical regulator of XCI, and aberrant expression of X-linked genes, suggesting that impairment of XCI may contribute to disease. Here, we find that a subset of female mice harboring a conditional deletion of Xis t in B cells ("Xist cKO") spontaneously develop SLE phenotypes, including expanded activated B cell subsets, disease-specific autoantibodies, and glomerulonephritis. Moreover, pristane-induced SLE-like disease is more severe in Xist cKO mice. Activated B cells from Xist cKO mice with SLE phenotypes have increased expression of proinflammatory X-linked genes implicated in SLE. Together, this work indicates that impaired XCI maintenance in B cells directly contributes to the female-bias of SLE.
Keyphrases
- systemic lupus erythematosus
- disease activity
- gene expression
- poor prognosis
- high fat diet induced
- end stage renal disease
- chronic kidney disease
- dna methylation
- mouse model
- multiple sclerosis
- genome wide
- rheumatoid arthritis
- early onset
- adipose tissue
- metabolic syndrome
- peripheral blood
- skeletal muscle
- high glucose
- endothelial cells
- genome wide identification