Quantity, not quality, of antibody response decreased in the elderly (original) (raw)
Antibodies play a key role in protecting against infection with the influenza virus, and these are induced upon vaccination with current influenza vaccines, especially in healthy adults (4, 5). Vaccination induces a population of circulating antibody-secreting cells (ASCs; also known as plasmablasts), defined as CD19+CD20lo/–CD3–CD38hiCD27hi cells, which are detected with a peak around seven days after vaccination (6, 7). Plasmablasts are short lived, although some of these cells become long lived if rescued in available niches, such as the bone marrow (8). Generation of T cell responses is also important for eradicating influenza virus infections. In this context, CD4+ helper T cells activate B cells to make antibodies, while CD8+ cytotoxic T cells destroy virus-infected cells. Current influenza vaccines primarily stimulate an antibody response, and this vaccine-induced antibody response allows time for the host T cell response to develop as well as decreases the initial viral load.
There is substantial evidence that the antibody response induced by influenza vaccines decreases with age (9–11). Most of the studies conducted so far have shown that this correlates with the well-characterized age-dependent decrease in T cell functions (12–14). However, immune defects with age do not occur in T cells alone. Recently, age-related autonomous B cell defects have been described (15, 16). These include decreased class switch recombination (CSR), the process by which activated B cells change the isotype of the antibody that they are producing so that antibodies with the same specificity but different effector function can participate in the immune response; decreased expression of components of the molecular pathway controlling CSR, which include the enzyme activation-induced cytidine deaminase and the transcription factor E47; and decreased levels of switch memory B cells (15, 16). These changes completely correlate with the reduced antibody response of elderly individuals to the influenza vaccine (17), and we suggest that they could be used as biomarkers to predict immune/vaccine responsiveness.
Despite agreement that the limited efficacy of vaccination against influenza in the elderly is linked to reduced serum antibody responses, it is not clear whether this is due to decreases in the quantity and/or the quality of the antibodies produced. If it is the quantity, is it due to a decrease in the number of ASCs or in the amount of antibody secreted per cell? The quantity of the serum antibody response is determined by the number of plasmablasts and the amount of antibody secreted by each plasmablast, whereas the quality, or avidity, depends on the affinity of the Igs produced for their cognate antigen. A paper in this issue of the JCI by Sasaki and collaborators addresses these key questions (18). The paper confirms previous studies showing that the serum response, evaluated as fold increase in titer after vaccination, is reduced in elderly individuals and, importantly, extends these findings to show that the number of responding plasmablasts and hence plasmablast-derived polyclonal antibodies (PPAbs) is dramatically reduced in elderly individuals compared with that in young individuals (Figure 1). In addition to answering the questions above, Sasaki et al. have efficiently used a system, previously established by Wilson, Ahmed, and colleagues (6, 7), to assay the quality of antibodies secreted from single cells in elderly individuals compared with that in young individuals.
Mechanistic explanation for the inferior antibody response to influenza vaccination in the elderly. The efficacy of influenza vaccination wanes with age. This is linked to a reduced ability to induce a robust serum antibody response. However, whether it is due to decreases in the quantity and/or the quality of the antibodies produced is not clear. In this issue of the JCI, Sasaki et al. answer this question (18), showing that the reduced serum antibody response generated by the elderly after vaccination with inactivated seasonal influenza vaccine is a result of a decrease in the number of responding plasmablasts and hence a decrease in the concentration of PPAbs, rather than a result of a decrease in the quality of the response. Importantly, the amount of antibody secreted was about the same for individual plasmablasts isolated from (A) young and (B) elderly individuals.