Molecular pattern recognition in peripheral B cell tolerance: lessons from age-associated B cells

Although central tolerance mechanisms purge self-reactive B cells during development based on BCR signal strength, mechanisms that block the differentiation of autoreactive effector and memory B cells from mature pools remain poorly understood. Prior observations implicate nucleic acid sensing TLRs in autoimmunity, and more recent findings show that TLR9 is also involved in maintaining peripheral tolerance. Studies of the immunological changes that occur during aging revealed a subset of B cells denoted Age-associated B cells which expands in settings of aging and in autoimmunity. Further studies demonstrated that TLR9 signals poise activated B cells to adopt an Age-associated B cell phenotype, but BCR-delivered TLR9 signals cause programmed cell death that, if circumvented by costimulation, allows continued differentiation to the ABC fate. Together, these observations suggest molecular pattern recognition, rather than BCR epitope specificity per se, is a fundamental mediator of tolerogenic outcomes in the peripheral B cell activation.