Mechanisms that determine plasma cell lifespan and the duration of humoral immunity

Abstract

Humoral immunity following vaccination or infection is mainly derived from two types of cells: memory B cells and plasma cells. Memory B cells do not actively secrete antibody but instead maintain their immunoglobulin in the membrane-bound form that serves as the antigen-specific B-cell receptor. In contrast, plasma cells are terminally differentiated cells that no longer express surface-bound immunoglobulin but continuously secrete antibody without requiring further antigenic stimulation. Pre-existing serum or mucosal antibody elicited by plasma cells (or other intermediate antibody-secreting cells) represents the first line of defense against reinfection and is critical for protection against many microbial diseases. However, the mechanisms involved with maintaining long-term antibody production are not fully understood. Here, we examine several models of long-term humoral immunity and present a new model, described as the 'Imprinted Lifespan' model of plasma cell longevity. The foundation of this model is that plasma cells are imprinted with a predetermined lifespan based on the magnitude of B-cell signaling that occurs during the induction of an antigen-specific humoral immune response. This represents a testable hypothesis and may explain why some antigen-specific antibody responses fade over time whereas others are maintained essentially for life.

Antibody persistence and T-cell balance: Two key factors confronting HIV vaccine development

“…Although persistence of vaccine-elicited antibody responses has been known for many years (discussed in refs. 55,56), it was investigated, to our knowledge, for the first time using modern immunological methods in two studies of immunity to vaccinia (57,58), where antibody responses were found to persist for decades after immunization. This observation was confirmed and extended in a comprehensive analysis of antibody persistence to common vaccines and infections (55).…”

“…1 (adapted from figure 3 in ref. 56). Three distinct zones of plasma antibody concentration are apparent after vaccination.…”

“…Zone 1 spans the initial peak of antibody formation after vaccination, where the response is thought to be largely due to shortlived plasmablasts in secondary lymphoid tissues with t 1/2 s measured in days (63)(64)(65)(66). This phase lasts from weeks to months after immunization in humans (56) and represents a rapid exponential expansion of antibodysecreting, short-lived plasmablasts, a steady state period, followed by a rapid exponential decline (α-slope) of these cells and concomitant circulating antibody. Zone 2 is characterized by a more relaxed decay (β-slope) of circulating antibody that persists from 1 to 3 y in humans, depending on the immunogen (56).…”

Defective B-cell proliferation and maintenance of long-term memory in patients with chronic granulomatous disease

“…In vivo exposure to cognate antigens (in the form of reinfection or booster vaccination) results in the activation of memory B cells and their subsequent proliferation and differentiation into antibody-secreting daughter cells. 21,22 To assess whether the impaired B-cell proliferation could affect the capacity of memory B cells to differentiate into ASCs, we measured the in vitro differentiation of total PBMCs after stimulation with PWM and CpG alone or in combination (Fig 4, A).…”

Polysaccharide-specific B cell responses to vaccination in humans

“…This theory suggests that PC life span is dependent on the strength of combined B cell signals experienced by the cell during the encounter with antigen. 46 Mechanisms of long-term maintenance of B MEM are also still unclear but most likely rely on antigen-independent processes. 47 While some studies have demonstrated a relationship between B MEM and antibody concentration at various intervals after immunization this has not been consistent for all antigens or between studies.…”