Systemic lupus pregnancies are characterized by an intrinsic pro-inflammatory monocyte transcriptome, driven by an aberrant miRNA signature.

Objective: Pregnancy induces profound immunological adaptations that usually promote tolerance and reduce autoimmune activity. However, women with systemic lupus erythematosus (SLE) remain at increased risk of disease flares and pregnancy complications, whereas rheumatoid arthritis (RA) often improves during gestation. To better understand this divergence, we longitudinally characterized transcriptomic and microRNA (miRNA) changes in circulating monocytes from healthy, RA, and SLE pregnancies. Methods: Pregnant women with SLE (n = 5), RA (n = 4), and healthy controls (n = 5) were followed from preconception to three months postpartum. CD14+ monocytes were isolated at each visit and profiled using RNA sequencing and miRNA sequencing. Differential expression analyses were performed using DESeq2, modelling patient ID as a covariate. Pathway enrichment and upstream regulator analyses were conducted using Ingenuity Pathway Analysis and Reactome. Correlation-based miRNA-mRNA regulatory networks were inferred using miRTarBase-validated interactions. Results: Healthy and RA pregnancies exhibited a shift toward an alternatively activated (anti-inflammatory) monocyte phenotype, characterized by downregulation of TNF, IFN-γ, and IL-1 signalling pathways. In contrast, SLE pregnancies maintained a persistent M1-like (pro-inflammatory) program throughout gestation and postpartum, independent of clinical flare status. miRNA profiling revealed selective downregulation of miR-106a-5p and miR-148b-5p in SLE monocytes, accompanied by enrichment of cytokine-related pathways among their predicted targets. These dysregulated miRNAs were linked to activation of immune pathways including IL-12 signalling, interferon responses, apoptosis, and complement activation. Conclusion: SLE pregnancies are characterized by a failure to achieve monocyte immunotolerance, driven in part by aberrant miRNA regulation. These findings highlight molecular mechanisms underlying persistent inflammation in SLE pregnancy and identify candidate transcriptomic and miRNA biomarkers that may support future risk stratification or therapeutic modulation.