Single-Cell Immune Profiling Reveals Neutrophils Promote Myasthenia Gravis Exacerbation Through BAFF Secretion

Abstract

Neutrophils play a critical role in the pathogenesis of autoimmune diseases, including myasthenia gravis (MG), but their specific function in MG exacerbations remains unclear. This study utilizes single-cell RNA sequencing (scRNA-seq) of bone marrow and peripheral blood from MG patients during acute exacerbations, combined with experimental autoimmune myasthenia gravis (EAMG) mouse models and clinical cohort analyses, to investigate the potential involvement of a neutrophil-B-cell activating factor (BAFF) -plasma cell axis. The results reveal that, during MG acute exacerbation, bone-marrow neutrophils exhibit significantly enhanced maturation. Upon migration to the peripheral blood, these neutrophils secrete increased amounts of BAFF, further promoting pathological B-cell differentiation and plasma cell activation. Moreover, gene knockout models and serum cytokine analyses reveal that the IFN-γ signaling pathway is a key driver of this excessive BAFF secretion, supporting the existence of a neutrophil-BAFF-plasma cell interaction relevant to MG exacerbation. Clinical data analysis shows that MG patients with high baseline neutrophil levels derive greater benefit from treatment with the BAFF/APRIL dual-target inhibitor telitacicept. Collectively, this study reveals the mechanistic link between neutrophil activation and MG exacerbation, providing insights that may inform precision-targeted immunotherapy.

Keywords: B‐cell activating factor; myasthenia gravis; neutrophils; single‐cell RNA sequencing.