Immunoglobulin repertoire defects and pneumococcal infection

Abstract

The central virulence factor of Streptococcus pneumoniae is a polysaccharide capsule. Three (7C5, A7 and 1A2) pneumococcal capsular polysaccharide (PPS) 3-specific MAbs were generated from XenoMouse RTM. These MAbs have similar affinity but different epitope specificities. Challenge experiments in BALB/c mice revealed that for both 7C5 and A7, 10 mug and 1 mug doses were protective, while for 1A2 only a 10 mug dose was protective. 7C5 and A7 were also protective in mice lacking either an intact alternative (FB-/-) or classical (C4-/- ) complement pathway, but 1A2 was not protective in FB-/- mice. 7C5 and A7 have a positive charge at the VH-D junction, whereas 1A2 does not. These observations suggest that PPS-3 consists of epitopes can elicit both highly and less protective antibodies, and the superior efficacy of certain antibodies may be a function of their structure and/or specificity.;Current pneumococcal polysaccharide vaccines have been found to be poorly immunogenic in immunocompromised patients, especially those with HIV. We determined the B cells VH expression in HIV- and HIV+ adults before and after vaccination by PCR-ELISA. The results showed a post-vaccination VH3 increase in HIV- group. We also found reduced pre-vaccination IgG VH3 expression in HIV+ group. These results revealed a vaccine-induced repertoire shift to increased VH3 expression in HIV-, but not HIV+ adults. These findings suggest that aberrant VH3 expression translates into an impaired PPS response in HIV+ individuals.;Children are at high risk for invasive pneumococcal disease (IPD). We analyzed the B cells VH expression in HIV- and HIV+ children with and without a history of invasive pneumococcal disease (HIV+/IPD+ and HIV+/IPD-, respectively). Overall, there were no differences in V H expression in HIV+, compared to HIV- children. However, the HIV+/IPD- children had significantly lower IgG VH3 expression. Rearranged DNA libraries revealed decreased expression of VH3-23, VH3-30 and VH3-33 in HIV+/IPD- children. Correlation analyses revealed an inverse correlation between viral load and IgM V H3 and a direct correlation with IgG VH3 in HIV+/IPD+ children. Our findings reveal quantitative and qualitative differences in VH3 in children that warrant further investigation for their influence on pneumococcal pathogenesis.