Viral subversion of B-cell tolerance: mechanisms linking infection to autoimmunity

Viral infections are increasingly recognized as triggers of autoimmunity, yet the mechanisms linking viral infection to breakdown of B-cell tolerance remain incompletely understood. B-cell tolerance is maintained through sequential central and peripheral checkpoints that normally eliminate or silence self-reactive clones. Viral infections converge on shared mechanisms, including inflammatory cytokines, innate immune activation, molecular mimicry, and persistent antigen exposure, while also promoting polyreactivity, thereby enhancing the survival, activation, and expansion of autoreactive B cells. In this review, we propose that autoimmune outcomes are determined less by viral identity than by the immunological and anatomical context in which tolerance fails. We integrate mechanistic and clinical evidence across systemic, localized, and neurotropic viral infections to present a unifying framework for virus-induced B-cell tolerance breakdown. This framework identifies conserved principles underlying post-viral autoimmunity and provides a foundation for developing therapeutic strategies to preserve B-cell tolerance.