Background/Purpose: Recurrent pregnancy loss (RPL) and unexplained infertility (UIF) are significant reproductive health challenges in patients with systemic lupus erythematosus (SLE). SLE causes systemic inflammation and multi-organ involvement, potentially affecting reproductive outcomes. This study uses transcriptomic data to analyze the pathogenesis of RPL and UIF in patients with SLE.

Methods: Datasets GSE185047, GSE26787, and GSE165004 were downloaded from the Gene Expression Omnibus. Table 1 summarizes dataset characteristics. Dysregulated genes (DEGs) were identified using GEO2R with thresholds: false discovery rate < 0.05, log2 fold change > 1 for upregulated genes, and < -1 for downregulated genes. Enrichment analysis was performed using Metascape to retrieve enriched terms. Shared upregulated DEGs were visualized with a Venn diagram.A gene activation network of overlapping upregulated DEGs was constructed using Cytoscape. The top ten hub genes (HGs) were identified using five algorithms: DMNC, Degree, Eccentricity, Stress, and Radiality. Validation was conducted in GSE165004. Immune profiling analyzed 22 immune cell types using CIBERSORT. A two-way ANOVA with the two-stage step-up method compared immune cell abundances across groups. Spearman correlation tests analyzed relationships between gene expression and immune cell proliferation, using mean fluorescence intensity values and immune cell percentages as variables.

Results: We identified 74 upregulated and 75 downregulated DEGs. Upregulated DEGs were enriched in pathways related to cytokine production, myeloid differentiation, and immune response signaling (Figure 1A). Downregulated DEGs were enriched in osteoblast differentiation, breast cancer, and cardiac muscle development (Figure 1B). 72 upregulated genes overlapped across datasets, and ten HGs were consistently identified by at least three algorithms: STAT5B, CD38, PRKCB, INPP5D, SPTBN1, SIRPA, IKZF1, HAVCR2, PLEK, and CASP (Figure 1D)Immune profiling revealed decreased CD38 expression in RPL and UIF groups compared to healthy controls (Figure 1E). Correlations were observed between gene expression and immune cell proportions: PRKCB with eosinophils, macrophages M0, and T cells gamma delta; INPP5D with naïve B cells, plasma cells, follicular helper T cells, and neutrophils; SPTBN1 with activated mast cells; SIRPA with eosinophils; IKZF1 with memory B cells; HAVCR2 with naïve B cells, macrophages M0, resting mast cells, and neutrophils; and PLEK with CD4+ memory T cells, follicular helper T cells, T cells gamma delta, resting NK cells, and macrophages M2 (Figure 1F).

Conclusion: This study analyzed the pathogenesis of RPL and UIF in SLE patients using transcriptomic data. Ten candidate hub genes were identified that may predict reproductive risks in SLE patients. Decreased CD38 expression was observed in RPL and UIF groups. Correlations between hub genes and infiltrated immune cell proportions highlight their role in disease mechanisms. These findings provide a molecular framework for understanding pregnancy loss and infertility in SLE, warranting validation in longitudinal cohort studies.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/transcriptomic-and-immune-landscape-of-recurrent-pregnancy-loss-and-unexplained-infertility-in-systemic-lupus-erythematosus/