X-linked transcriptome dysregulation across immune cells in systemic lupus erythematosus.

Background: Systemic lupus erythematosus (SLE) is a complex immune-mediated disease with a strong female predominance. This sex bias may be linked to the presence of two X chromosomes, which are not always adequately dosage compensated by X chromosome inactivation (XCI). Disruption in X-linked transcriptome expression may contribute to altered immune function and increased susceptibility to autoimmunity.

Methods: To investigate the role of X-linked gene expression in SLE, we performed a comprehensive transcriptome analysis of 27 immune cell types from 125 female SLE patients and 66 healthy controls. We further applied a multivariate approach to integrate X-linked gene expression across all immune cell types and classify SLE patients. Additionally, we extended these models to other chromosomes and explored the correlation between autosome disease markers, including members of the XIST-interactome, and X-linked expression.

Results: We observed a significant increase in X-linked gene expression in T cells, B cells and plasmablasts, while monocytes and plasmacytoid dendritic cells exhibited the opposite trend. Multivariate models based solely on X-linked expression were highly accurate and highlighted key disease-associated markers. Interestingly, autosome-based models relied on markers highly correlated with X-linked gene expression and components of the XIST-interactome, which regulates XCI. Notably, we found that XIST lncRNA was consistently downregulated across multiple cell types, particularly in monocytes and Th1 cells. Such downregulation correlated with increased expression of SLE-associated genes, interferon signalling, and epigenetic regulators like KMT2D. Further analysis revealed extensive dysregulation of the XIST-interactome in SLE, predicting X-linked transcriptome alterations in a cell-type-specific manner.

Conclusions: Here, we present a comprehensive analysis of X-linked gene expression across immune cells in SLE. Our study highlights the complexity of X-linked transcriptional changes, with distinct patterns observed across both innate and adaptive immune cell types. These findings offer novel insights into the role of the X-transcriptome in sex-biased autoimmune susceptibility and may support future efforts to identify molecular targets relevant to SLE pathogenesis.