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While significant progress has been made in elucidating the pathophysiology of autoimmune diseases, the immunological mechanisms underlying anti\u2010NMDARE remain elusive. This study aimed to characterize immune cell interactions\u00a0and dysregulation in anti\u2010NMDARE by leveraging single\u2010cell multi\u2010omics sequencing technologies.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Peripheral blood mononuclear cells (PBMCs) from patients in the acute phase of anti\u2010NMDARE and healthy controls were sequenced using single\u2010cell joint profiling of transcriptome and chromatin accessibility. Differential gene expression analysis, transcription factor activity profiling, and cell\u2010cell communication modeling were performed to elucidate the immune mechanisms underlying the disease. In parallel, single\u2010cell B cell receptor sequencing (scBCR\u2010seq) and repertoire analysis were conducted to assess antigen\u2010driven clonal expansion within the B cell population.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The study revealed a significant clonal expansion of B cells, particularly plasma cells, in anti\u2010NMDARE patients. The novel finding of type I interferon (IFN\u2010I) pathway activation suggests a regulatory mechanism that may drive this expansion and enhance antibody secretion. Additionally, activation of Toll\u2010like receptor 2 (TLR2) in myeloid cells was noted, which may connect to tumor necrosis factor\u2010alpha (TNF\u2010\u03b1) secretion. This cytokine may contribute to the activation of B and T cells, thereby perpetuating immune dysregulation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This study presents a comprehensive single\u2010cell multi\u2010omics characterization of immune dysregulation in anti\u2010NMDARE, highlighting the expansion of B cell and the activation of the IFN\u2010I and TLR2 pathways. These findings provide deeper insights into the molecular mechanism driving the pathogenesis of anti\u2010NMDARE and offer promising targets for future therapeutic intervention.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Significant B cell clonal expansion, particularly in plasma cells, driven by antigen recognition.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>IFN\u2010I pathway activation in plasma cells boosts their antibody production and potentially exacerbates immune dysregulation.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>TLR2 pathway activation in myeloid cells contributes to TNF\u2010\u03b1 secretion and could influence adaptive immune 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