ObjectivesReactivation of anergic autoreactive B cells (B_NDcells) is a key aetiological process in systemic lupus erythematosus (SLE), yet the underlying mechanism remains largely elusive. This study aimed to investigate how B_NDcells participate in the pathogenesis of SLE and the underlying mechanism.MethodsA combination of phenotypical, large-scale transcriptome and B cell receptor (BCR) repertoire profiling were employed at molecular and single cell level on samples from healthy donors and patients with SLE. Isolated naïve B cells from human periphery blood were treated with anti-CD79b mAb in vitro to induce anergy. IgM internalisation was tracked by confocal microscopy and was qualified by flow cytometer.ResultsWe characterised the decrease and disruption of B_NDcells in SLE patients and demonstrated IL-4 as an important cytokine to drive such pathological changes. We then elucidated that IL-4 reversed B cell anergy by promoting BCR recycling to the cell surface via STAT6 signalling.ConclusionsWe demonstrated the significance of IL-4 in reversing B cell anergy and established the scientific rationale to treat SLE via blocking IL-4 signalling, also providing diagnostic and prognostic biomarkers to identify patients who are most likely going to benefit from such treatments.