Bulk and single-cell transcriptome analysis reveal shared key genes and patterns of immune dysregulation in systemic lupus erythematosus and sepsis

Systemic lupus erythematosus (SLE) patients often experience sepsis, a significant clinical challenge that frequently requires intensive care and contributes significantly to morbidity and mortality. However, the molecular mechanisms underlying this comorbidity remain poorly understood. This study investigated the molecular intersection of SLE and sepsis using publicly available gene expression datasets. We identified 93 differentially expressed genes (DEGs) (49 upregulated and 44 downregulated) shared by both conditions, primarily impacting bacterial defense and immune response pathways. Integrated differential expression and weighted gene co-expression network analyses (WGCNA) revealed 11 hub genes, with TNFAIP6 and PLSCR1 showing significant diagnostic potential. Single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) revealed a significant expansion of CD14+ monocytes in both conditions, exhibiting elevated expression of the identified hub genes and similar transcriptional profiles. Upregulation of TNFAIP6 and PLSCR1 was validated using public monocyte datasets and real-time PCR of mouse PBMCs, with PLSCR1 showing markedly increased expression in SLE cases complicated by sepsis. Our findings demonstrate that CD14+ monocytes emerge as a common site of immune dysregulation in these comorbid conditions, with overlapping gene expression and pathway alterations suggesting shared molecular mechanisms that could inform targeted therapeutic strategies.