Extrafollicular and Other Non‐Germinal Center B Cell Responses: An Evolutionary Perspective

Classic models of humoral immunity focus on the role of germinal centers (GCs) in producing high affinity, class switched protective antibodies. However, antibodies can also be produced through a diverse range of GC-independent pathways. Such pathways are often labeled "extrafollicular", even when the localization of individual responses remains unknown, but in this review, we group them together under the broad umbrella of "nonGC responses". Experiments in mammals show that nonGC responses provide important humoral protection against infections and complement the eventual GC-derived antibody response. In this review, we explore the immunological foundations of nonGC and GC responses through an evolutionary lens and investigate the mechanisms of humoral immunity throughout vertebrate evolution. In animals that predate the evolution of GCs as they appear in mammals, B cell responses still occur at organized sites and with features also seen in mammals, including adjacent T cell and B cell regions, sites for antigen deposit, and B cell proliferation and mutation. Here we review the commonalities in nonGC responses across multiple genera, before and after the emergence of GCs. This comparison helps frame current efforts to mechanistically understand pathways for nonGC responses and the relative roles of GC- and nonGC-derived antibodies in humoral immunity.