Date Published: December , 2011
Publisher: Blackwell Publishing Ltd
Author(s): Alexander Ademokun, Yu-Chang Wu, Victoria Martin, Rajive Mitra, Ulrich Sack, Helen Baxendale, David Kipling, Deborah K Dunn-Walters.
It is well known that older people are more susceptible to morbidity and mortality from infectious diseases, particularly from pulmonary diseases such as pneumococcal pneumonia where vaccines do not provide efficient protection as in younger populations. We have previously shown that the B-cell repertoire in the old is reduced and hypothesise that this may contribute to the impaired humoral responses of the elderly. Here, we investigated the repertoire and antibody responses to winter vaccination in two age groups, aged 18–49 and 65–89. We found that the serum IgM and IgA pneumococcal responses were significantly impaired in the older group, with no difference in IgG levels. IGHM spectratype analysis seems to be the most promising in terms of its predictive ability for vaccine responses. Spectratypes showed a clear change in the repertoire at day 7 after vaccination, with a return to the baseline levels at day 28. The changes at day 7 reflected expansion of IGH sequences that have smaller, more hydrophilic, CDR3 regions, and these changes were attenuated in the older group. The older group was more likely to have spectratypes indicative of a reduced diversity at day 0 and day 28. On average, the baseline repertoire in the older group was comprised of larger CDR3 regions than in the younger group. In conclusion, IgA and IgM responses are significantly impaired in the elderly pneumococcal response and are likely key mediators of protection. Hydrophilicity and/or small size of the IGH CDR3 appear to be important in these responses.
Streptococcus pneumoniae causes significant morbidity and mortality in young children and in older adults, and it is the most significant secondary infection associated with influenza. Many deaths attributed to influenza may actually be caused by secondary pneumococcal infection (van der Sluijs et al., 2004). Vaccination against pneumonia has proven difficult in these high-risk groups, where the standard 23-valent pneumococcal polysaccharide (PPS) vaccine has not been as effective as in healthy young adults (Moberley et al., 2008). Conjugate protein–PPS vaccines have had more success in the very young but do not seem to improve vaccination responses in the old (Baxendale et al., 2010). The overall picture of antibody responses in old age seems to be one of changes in specificity and quality rather than a decrease in quantity (Howard et al., 2006). While the efficacy of vaccination against both influenza and pneumonia decreases significantly with age, the levels of poly-specific and autoreactive antibodies increase with age. It has been reported that vaccine challenge in the older population can actually increase levels of anti-DNA autoantibodies, implying an age-related loss of focus in the immune response (Huang et al., 1992). A lack of focus in affinity maturation of antibodies has been implied by the fact that the B cells in germinal centre responses in Peyer’s patches of older people appear to be under less selection pressure than in younger samples, although this may be a tissue-specific phenomenon (Banerjee et al., 2002).
We observed that even in the absence of challenge, there are differences in the B-cell spectratypes between individuals (Fig. 1). These can represent changes in B-cell repertoire because of prior antigen exposure or changes in the naïve repertoire. With regard to the latter, the IGHM spectratypes are particularly interesting, because the assumption is that they largely represent naïve B cells. This would imply that there is an element of interindividual variation in factors affecting repertoire generation in central B-cell development. These could be factors related to gene rearrangement, such as preferential use of different IGH genes or terminal deoxynucleotidyl activity. Alternatively, they could be factors associated with tolerance selection of the repertoire such as occurs in the bone marrow and in the transitional B-cell stages (Wardemann et al., 2003). These factors may also be responsible for the age-related differences in IGHM CDR3 size that we see before vaccine challenge.