Figure 1.

  Models of sustained humoral immunity. Several memory B‐cell (MBC)‐dependent and ‐independent models have been developed to explain how long‐term antibody responses are maintained. In this figure, we illustrate how antigen‐specific antibody responses might be maintained under the different proposed models. Chronic infection or cross‐reactivity to either self or environmental antigens is expected to stimulate memory B cells to proliferate and differentiate into antibody‐secreting daughter cells and result in increasing antibody responses over time due to continuous stimulation and accumulation of memory B cells and plasma cells. Repeated infection or booster vaccination will likely lead to periodic increases in antigen‐specific memory B‐cell activation and subsequent increases in antibody responses that would decline during the intervening periods between outbreaks or vaccinations. Persisting antigen in the form of antibody:antigen immune complexes on the surface of follicular dendritic cells (FDCs) will stimulate memory B cells in an antigen‐specific manner, resulting in antibody responses that will decline at the rate of antigen decay or consumption by the memory B‐cell pool. Non‐antigen‐specific polyclonal memory B‐cell stimulation by Toll‐like receptor (TLR) engagement or bystander T‐cell activation will trigger antibody responses to spike during heterologous infections or vaccinations and increase antibody responses to all pre‐existing antibody specificities. Alternatively, long‐term antibody responses may be maintained by long‐lived plasma cells (PCs), and two models are proposed. One model is based on plasma cell competition for space in the bone marrow in which pre‐existing plasma cells are dislodged by incoming plasmablasts, and antibody responses decline as a function of plasma cell displacement. Since there is finite space in the bone marrow, this model would suggest that antibody responses will decline more rapidly during advanced age as a function of increased competition in the bone marrow compartment. Another model of long‐lived plasma cells is based on the theory that plasma cells are imprinted with a specified lifespan, which is determined during the induction phase of the antigen‐specific antibody response.