Background. A 23-valent unconjugated pneumococcal polysaccharide vaccine (23vP), routinely administered at the age of 65, has limited effectiveness, and revaccination induces attenuated antibody responses. It is not known whether pneumococcal polysaccharide-protein conjugated vaccines (PCV), although highly effective in infants, offer any immunological advantages over 23vP in adults.Methods. We immunized adults with schedules combining both PCV and 23vP and investigated B-cell responses to establish whether PCV7 (a 7-valent PCV) induced T-dependent responses in adults, to assess the role of memory B cells in 23vP-induced antibody hyporesponsiveness, and to identify the B-cell subtypes involved.Results. A single dose of PCV7 induced significant increases in serotype-specific memory B-cell populations in peripheral blood indicating a T-dependent response. Conversely, immunization with 23vP resulted in a decrease in memory B-cell frequency. Furthermore, memory B-cell responses to subsequent immunization with PCV7, when given after 23vP, were attenuated. Notably, B1b cells, a subset important in protecting mice against pneumococci, were also depleted following immunization with 23vP in humans.Conclusions. This study indicates that PCV7 may have an immunological advantage over 23vP in adults and that 23vP-induced depletion of memory and B1b-cell subsets may provide a basis for antibody hyporesponsiveness and the limited effectiveness of 23vP.Clinical Trials Registration. ISRCTN: 78768849.

Objective. The spondyloarthritides share genetic susceptibility, interleukin-23 (IL-23) dependence, and the involvement of microbiota. The aim of the current study was to elucidate how host genetics influence gut microbiota and the relationship between microbiota and organ inflammation in spondyloarthritides.Methods. BALB/c ZAP-70 W163C -mutant (SKG) mice, Toll-like receptor 4 (TLR-4)-deficient SKG mice, and wild-type BALB/c mice were housed under specific pathogen-free conditions. SKG and wild-type BALB/c mice were maintained under germ-free conditions, and some of these mice were recolonized with altered Schaedler flora. All of the mice were injected intraperitoneally with microbial ␤-1,3-glucan (curdlan). Arthritis, spondylitis, and ileitis were assessed histologically. Microbiome composition was analyzed in serial fecal samples obtained from mice that were co-housed beginning at the time of weaning, using 454 pyrosequencing. Infiltrating cells and cytokines in the peritoneal cavity were measured by flow cytometry and enzyme-linked immunosorbent assay. Cytokine, endoplasmic reticulum (ER) stress marker, and tight junction protein transcription was measured by quantitative real-time polymerase chain reaction.Results. Microbiota content and response to curdlan varied according to whether T cell receptor signal strength was normal or was impaired due to the ZAP-70 W163C mutation. Curdlan triggered acute inflammation regardless of the presence of the SKG allele or microbiota. However, no or limited microbiota content attenuated the severity of arthritis. In contrast, ileal IL-23 expression, ER stress, lymph node IL-17A production, goblet cell loss, and ileitis development were microbiotadependent. Ileitis but not arthritis was suppressed by microbiota transfer upon co-housing SKG mice with wild-type BALB/c mice, as well as by TLR-4 deficiency.Conclusion. The interaction between immunogenetic background and host microbiota leads to an IL-23-dependent loss of mucosal function, triggering ileitis in response to curdlan.The human genome has been shaped by interaction with commensal and pathogenic microorganisms. Spondyloarthritides (SpA) are strongly heritable conditions affecting 2% of the population and include ankylosing spondylitis (AS), psoriatic arthritis, reactive arthritis, uveitis, and arthritis associated with inflammatory bowel disease (IBD) (1). The genetic associations of these diseases overlap and identify genes essential for host microbial defense, including class I major histocompatibility complex, antigen processing, T cell signaling, interleukin-23 receptor (IL-23R), caspase recruitment domain 9, and NF-B (2). Although clinical

In adults, vaccination schedules combining PCV7 and 23vP do not provide improved immunogenicity over the use of a single dose of 23vP for most of the serotypes contained in PCV7.

A previous study used a mouse model to demonstrate protection after challenge with Porphyromonas gingivalis ATCC 33277. In the present study, this same model was used to determine the phenotype of cells recruited into the lesions during the course of the protective immune response after immunization with this periodontal pathogen. BALB/c mice were immunized with 100 micrograms of P. gingivalis outer membrane antigens per mouse weekly for 3 weeks followed by challenge with live organisms 3 weeks after the final immunization. Hematoxylin and eosin-stained sections showed inflammatory infiltrates in all lesions from control (immunized with adjuvant only) and immunized mice. The lesions developed central necrotic cores surrounded by neutrophils, phagocytic macrophages and lymphocytes. Neutrophils were the predominant cells in the lesions 1 day after challenge with significantly more in immunized than control mice. Acid phosphatase and nonspecific esterase-positive macrophages were detected at day 4 and became the predominant cells in the healing lesions. CD4- and CD8-positive T-cells were present from day 1, and while numbers increased over time, there were no significant differences in control or immunized mice. When mice were depleted of CD4 or CD8 cells prior to immunization with P. gingivalis, fewer neutrophils were found in the lesions 1 day after challenge compared with undepleted immunized mice. Acid phosphatase and nonspecific esterase-positive macrophages were not affected by T-cell depletion. The results suggest that the P. gingivalis-induced lesion in immunized BALB/c mice is consistent with a strong innate immune response involving the recruitment of neutrophils in the first instance which may be under the control of T cells. This is followed by the infiltration of phagocytic macrophages which are involved in the healing process and do not appear to be regulated by T cells.

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