Th2 immunity plays a paradoxical role in pregnancy—essential for fetal tolerance in healthy gestation yet pathogenic in systemic lupus erythematosus (SLE). However, the mechanisms by which aberrant Th2 responses drive adverse pregnancy outcomes (APOs) in SLE remain incompletely understood. This study aimed to elucidate whether exaggerated Th2 signaling contributes to APOs in SLE through the transcription factor Ikaros-mediated B cell pathology, and to characterize the associated immunological and histopathological features.

We integrated clinical profiling, in vitro functional assays, and in vivo histopathological validation. Peripheral blood mononuclear cells from 30 pregnant SLE (pSLE) patients and 30 healthy pregnant controls (pHCs) were analyzed by flow cytometry for B cell subsets and Ikaros expression. Mechanistically, healthy donor B cells were stimulated with IL-4 (50 ng/mL) to model Th2 conditions, followed by assessment of Ikaros expression and B cell differentiation. Ikaros knockdown was performed in a B cell line using lentiviral shRNA to evaluate functional consequences. Placental histopathology was evaluated in MRL/lpr lupus mice during mid-gestation (E14.5–E16.5), with immunohistochemical staining for B cell infiltration and Ikaros expression.

pSLE patients exhibited significantly higher APO rates, including fetal growth restriction and preterm birth. Immune profiling revealed Th2 polarization and B cell compartment remodeling, characterized by naïve B cell reduction and marked expansion of a CD38⁺IgD⁻ B cell subset. This subset expressed elevated Ikaros levels, which correlated positively with Th2 cell frequencies. In vitro, IL-4 directly upregulated Ikaros in B cells and promoted their differentiation into the CD38⁺IgD⁻ phenotype. In MRL/lpr mice, Ikaros-positive CD138⁺ B cells infiltrated resorption sites and were associated with enhanced placental IgG deposition.

We identify a novel IL-4/Ikaros axis that drives pathogenic CD38⁺IgD⁻ B cell expansion, linking Th2 skewing to APOs in SLE. These findings implicate Ikaros and Th2 cells as potential biomarkers for APO risk and suggest that targeting this axis may offer a promising therapeutic strategy to improve pregnancy outcomes in SLE.