Molecular analysis of age-associated B cells (ABCs)

Age-associated B cells (ABCs) are a phenotypically and functionally distinct mature B cell subset that accumulates with age. Unlike follicular (FO) B cells, ABCs do not rely on B lymphocyte stimulator (BLyS) to survive, and are likely derived from mature B cells that exhaustively expand throughout the animal’s lifespan. Because ABCs respond to innate but not adaptive stimuli, produce cytokines, and potentiate Th17 polarization, they may alter the quality of immune responses in aged animals, thereby contributing to age-associated increases in susceptibility to infection and inflammation. In order to further investigate ABC origins, relationships to other B cell subsets, and roles in immunosenescence, we have undertaken detailed gene expression and BCR repertoire analyses. Microarray results show striking differences in gene expression patterns between ABCs and FO B cells from aged and young mice. Heavy-chain gene analysis indicates that ABCs display a diverse VH repertoire, with a mutation frequency ~6-fold higher than that observed among FO B cells, indicating previous activation and concomitant somatic hypermutation. Despite this, the ratio of CDR to FWR mutations indicates a lack of antigen-mediated selection. Taken together, our results suggest that ABCs are derived from a diverse progenitor pool and reflect prior activation; however, expansion of the ABC subset either does not include selection based on CDR specificity, or involves aberrant selection.