Consistent with the results of previous studies (32
), we found higher opsonic capacities in young adults than in old adults for serotypes 14 and 23F, with no significant difference in IgG levels between the two groups. However, anti-PPS IgA and IgM antibody levels, in contrast to IgG, are lower in older adults than in young adults. Furthermore, the opsonic capacity differences between the two groups disappeared after the removal of IgM (but not IgA) antibodies from immune sera for all three serotypes. The anti-PPS IgA antibody levels of the immune sera studied here are likely too low to influence the opsonic activity of IgG antibodies (16
). In contrast, low levels of anti-PPS IgM antibodies can account for the functional difference observed between young and old adults immunized with PPV23, since IgM is more efficient at fixing complement than IgG. Indeed, studies with human monoclonal antibodies have shown that IgM antibodies can be 10- to 100-fold more effective than IgG antibodies at opsonizing bacteria or protecting animals from infections (30
Some IgM antibodies that are protective against bacterial infections bind many unrelated antigens, such as single-stranded DNA, thyroglobulin, and β-galactosidase (27
). Such IgM antibodies, which are called polyreactive or natural antibodies, are found in preimmune sera (3
) and have been isolated as hybridomas producing anti-PPS antibody (6
). Also, the level of natural antibodies has been shown to decrease with age (10
). Nevertheless, the absorption of several postimmune sera that are rich in IgM antibody with a mixture of single-stranded DNA, thyroglobulin, and β-galactosidase did not reduce the opsonic activities of the sera (unpublished observation). Thus, the highly opsonic anti-PPS IgM antibody present in our postimmune sera is not likely to be polyreactive but specific for PPS produced in response to vaccination.
A previous study reported that following immunization with PPV23, less anti-PPS IgM antibody appeared in old adults than in young adults (38
). Another study reported that naturally acquired (in nonvaccinated persons) anti-PPS IgM antibody levels decreased with aging (40
) for five out of six different capsule types. However, these studies used a nonspecific ELISA and did not investigate the functional significance of the reduced anti-PPS IgM antibodies. Consequently, to our knowledge, our report may be the first linking anti-PPS IgM antibodies with the observed functional difference between sera from young and old adults immunized with PPV23. Nevertheless, one must be aware that there could be additional explanations, since our studies are limited to several pneumococcal capsule types, and immune responses to some pneumococcal PSs may differ.
The relative deficiency of anti-PPS IgM antibodies observed among older adults may be a result of their deficient IgM memory B cells. Shi et al. reported a significant reduction in the number of IgM+
B cells with aging (38
). Even though Moens et al. reported that IgM+
B lymphocytes are also involved in IgG antibody production in response to PPV23, IgM+
B lymphocytes are generally accepted to be IgM memory B cells and to produce anti-PPS IgM antibody in response to TI-2 antigens, including PPS (25
). Also, common variable immunodeficiency (CVID) patients with an IgM+
B cell deficiency are poorly responsive to pneumococcal vaccines and thus suffer from frequent pneumococcal infections (21
). Therefore, future work should further investigate the impact of aging on IgM+
B cell populations and their role in pneumococcal vaccine responses.
The deficiency in anti-PPS IgM antibody responses may explain the reduced effectiveness of pneumococcal vaccines in populations other than old adults. For instance, HIV+
persons and splenectomized patients have deficient IgM memory B cells (13
). Interestingly, HIV+
persons are known to have normal levels of IgG antibodies against pneumococcal capsular PS but to have reduced OPA titers (23
). Similar observations have been made for patients with certain forms of CVID (21
). Thus, the immunogenicity of pneumococcal vaccines for these populations should be reassessed by investigating the impact of anti-PPS IgM antibodies. Also, it is possible that a new pneumococcal vaccine may elicit anti-PPS IgM antibodies better than current vaccines.
Despite our observation, the deficiency of anti-PPS IgM antibodies is not likely to be the only aging- or HIV-related immune change. Patients with HIV infections have fewer B cells expressing the VH3 subtype (7
). Studies of old adults have suggested an aging-associated reduction in isotype switching and somatic hypermutation and a loss of antibody oligoclonality (20
). Some studies with human antibodies suggested age-related changes in the V regions of pneumococcal antibodies (20
), but another study failed to find such changes (19
). In our study, an OPA showed no evidence that anti-PPS IgG antibodies from older adults are less effective than those from young adults. This finding may suggest that the V regions of anti-PPS IgG antibodies may be similar in young and old adults. However, our studies were not designed to investigate V regions and thus should not be interpreted to mean that there are no aging-associated V region differences.
In conclusion, we show that anti-PPS IgM antibodies can provide significant immune protection despite their low levels of expression. In addition to differences in fixing complement, IgM and IgG antibody responses have different time courses; consequently, their relative levels may differ during the course of a vaccinee's response to a vaccination. For instance, IgM levels were several times higher than IgG levels and correlated with opsonic capacity better than IgG levels among toddlers who received only one dose of a 9-valent pneumococcal conjugate vaccine (B. Simell, B. A. Nurkka, K. Jousimies, S. Gronholm, N. Givon-Lavi, H. Kayhty, and R. Dagan, presented at ISPPD-7, Tel Aviv, Israel, 2010). We propose that both anti-PPS IgM and IgG levels should be used in the future to monitor responses to pneumococcal vaccines as well as to vaccines that are similar to pneumococcal vaccines (e.g., meningococcus vaccines).