A two-step model of age-associated autoreactivity: B cell-intrinsic aging meets inflammaging.

Aging is associated with declining protective immunity and increased autoreactivity, yet the mechanisms linking these processes remain incompletely understood. B lymphocytes are central to this paradox because they integrate antigen recognition, innate signaling, and differentiation under tightly regulated tolerance checkpoints. This review advances the hypothesis that aging appears to drive a progressive, B cell-intrinsic relaxation of central and peripheral tolerance, leading to the accumulation of autoreactive clones. These defects are reinforced by transcriptional, epigenetic, metabolic, and signaling remodeling that durably reshapes B-cell responsiveness. In parallel, chronic low-grade inflammation (inflammaging) acts as a selective pressure that preferentially expands inflammation-adapted B-cell subsets, including age-associated B cells (ABCs) and related DN2 populations, rather than uniformly activating the B-cell compartment. This synergy promotes extrafollicular differentiation while bypassing key germinal-center tolerance checkpoints, thereby enriching for autoreactive B-cell states. A unifying model is proposed in which intrinsic aging establishes susceptibility, whereas inflammaging amplifies pathogenic B-cell programs, linking immune senescence to autoimmunity and highlighting potential targets for selective therapeutic intervention.