The geography of memory B cell reactivation in vaccine-induced immunity and in autoimmune disease relapses

Memory B cells (Bmem) provide an active second layer of defense against re-infection by pathogens that have bypassed the passive first layer provided by neutralizing antibodies. Here, we review recent progress in our understanding of Bmem heterogeneity in terms of their origin (germinal center-dependent vs center-independent), phenotype (canonical vs atypical vs age-associated B cells), trafficking (recirculating vs tissue-resident), and fate (plasma cell vs germinal center differentiation). The development of transgenic models and intravital imaging technologies has made it possible to track the cellular dynamics of Bmem reactivation by antigen, their interactions with follicular memory T cells, and differentiation into plasma cells in subcapsular proliferative foci in the lymph nodes of immune animals. Such in situ studies have reinforced the importance of geography in shaping the outcome of the secondary antibody response. We also review the evidence for Bmem reactivation and differentiation into short-lived plasma cells in the pathogenesis of disease flares in relapsing-remitting autoimmune diseases. Elucidating the mechanisms that control the Bmem fate decision to differentiate into plasma cells or germinal center B cells will aid future efforts to more precisely engineer fit-for-purpose vaccines as well as to treat antibody-mediated autoimmune diseases.