Extrafollicular Antibody Responses

Antibody responses are a major form of defense against microbes and require terminal differentiation of B cells into plasma cells. This differentiation can occur within follicles, as B cells differentiate into germinal centers (GCs), or in extrafollicular foci. Stochastic competition and asymmetric cell division have been proposed to explain how B cells follow the follicular or extrafollicular fate. Lineage and location also appear to play a role, with marginal zone B cells and memory B cells readily forming robust extrafollicular plasma cell foci. Localization to follicles or extrafollicular sites is determined by key changes in transcription factors and receptors for chemoattractants. Extrafollicular responses develop faster than GC responses, but also are relatively short lived and of lower affinity, due to limited accumulation of somatic mutations. They provide an important early wave of protection upon infection. In the context of protein antigens, B cell differentiation along both follicular and extrafollicular routes requires priming by follicular helper T cells that produce the key cytokine IL-21. Extrafollicular antibody responses can be an important source of autoantibodies in the context of autoimmunity. Furthermore, inflammatory conditions can increase the life span of extrafollicular plasma cells in secondary lymphoid tissues enhancing their pathogenicity.