The pathogenic role of double-negative B cells in autoimmune diseases.

Double-negative (DN) B cells have emerged as pivotal players in autoimmune diseases, transitioning from an overlooked exhausted subpopulation to a lineage with potent pathogenic potential. Based on surface marker expression, DN B cells are subdivided into four distinct subsets: DN1, DN2, DN3, and DN4. This review provides a comprehensive overview of these subsets, focusing on their origins, phenotypes, and developmental trajectories. In disorders such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), primary Sjögren's syndrome (pSS), and multiple sclerosis (MS), expanded DN B cells infiltrate target organs via chemokine receptor-mediated pathways and interact with T cells to drive the pathological remodeling of the local immune microenvironment. Elucidating the regulatory mechanisms of DN B cell differentiation and their functional heterogeneity across disease contexts will provide a critical foundation for the development of targeted precision immunotherapies.