Age-Associated B Cells: Origins, Regulation, and Tissue-Specific Pathogenic Contributions in Autoimmune, Metabolic,...

Age-associated B cells (ABCs) are a distinct B cell population characterized by coexpression of T-bet and CD11c. First described in aged female mice and autoimmune-prone strains, ABCs are now recognized to be associated with multiple human autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis, where their frequency correlates with disease activity. Their differentiation requires toll-like receptor (TLR) signaling, IFN-γ, IL-21, BCR engagement, with ZEB2 emerging as the nonredundant transcriptional master regulator of ABC identity. Here we review requirements for ABC differentiation, their defining phenotypic and functional features, and their tissue-specific distribution and pathogenic contributions in diverse inflammatory settings. A central theme is that ABCs are tissue-homing cells whose contribution extends beyond blood and lymphoid organs. In kidney, inflamed synovium, salivary glands, and adipose tissue, ABCs drive pathology through locally differentiated autoantibody-secreting cells, stromal activation, antigen presentation, and cytokine production. We further discuss roles for ABCs in neurological diseases, including their enrichment in the cerebrospinal fluid in multiple sclerosis (MS) and their contribution to neuroinflammation in Alzheimer's disease, and highlight the EBV-ABC axis as a mechanism linking viral infection to autoimmunity. In summary, ABCs are multi-functional, tissue-adaptable pathogenic effectors whose contributions to human disease extend beyond classical autoimmunity into metabolic dysfunction and neurodegeneration.