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

Area of Science:

• Immunology
• Genetics
• Systemic Lupus Erythematosus (SLE) research

Background:

• Systemic lupus erythematosus (SLE) is an immune-mediated disease with a notable female predominance.
• This sex bias may stem from inadequate dosage compensation of the two X chromosomes via X chromosome inactivation (XCI).
• Altered X-linked gene expression could impact immune function and autoimmunity susceptibility.

Purpose of the Study:

• To investigate the role of X-linked gene expression in SLE pathogenesis.
• To analyze X-linked gene expression patterns across diverse immune cell types in SLE patients.
• To develop models for classifying SLE patients based on X-linked expression.

Main Methods:

• Comprehensive transcriptome analysis of 27 immune cell types from 125 female SLE patients and 66 healthy controls.
• Multivariate analysis to integrate and classify X-linked gene expression across immune cells.
• Exploration of correlations between autosome markers, XIST-interactome, and X-linked expression.

Main Results:

• Significant increases in X-linked gene expression were observed in T cells, B cells, and plasmablasts, contrasting with monocytes and dendritic cells.
• Multivariate models using X-linked expression accurately identified disease markers.
• XIST lncRNA downregulation correlated with increased SLE-associated genes, interferon signaling, and epigenetic regulators, particularly in monocytes and Th1 cells.

Conclusions:

• This study provides a comprehensive analysis of X-linked gene expression in SLE immune cells, revealing distinct patterns in innate and adaptive immunity.
• Findings highlight the complex role of the X-transcriptome in sex-biased autoimmune susceptibility.
• The results offer potential molecular targets for future SLE therapeutic strategies.