14 results on '"Cunningham, Adam F"'
Search Results
2. Homeostatic regulation of T cell trafficking by a B cell-derived peptide is impaired in autoimmune and chronic inflammatory disease.
- Author
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Chimen, Myriam, McGettrick, Helen M, Apta, Bonita, Kuravi, Sahithi J, Yates, Clara M, Kennedy, Amy, Odedra, Arjun, Alassiri, Mohammed, Harrison, Matthew, Martin, Ashley, Barone, Francesca, Nayar, Saba, Hitchcock, Jessica R, Cunningham, Adam F, Raza, Karim, Filer, Andrew, Copland, David A, Dick, Andrew D, Robinson, Joseph, and Kalia, Neena
- Subjects
LYMPHOCYTES ,INFLAMMATION ,CHRONIC diseases ,ADIPONECTIN ,B cells - Abstract
During an inflammatory response, lymphocyte recruitment into tissue must be tightly controlled because dysregulated trafficking contributes to the pathogenesis of chronic disease. Here we show that during inflammation and in response to adiponectin, B cells tonically inhibit T cell trafficking by secreting a peptide (PEPITEM) proteolytically derived from 14.3.3 zeta delta (14.3.3.ζδ) protein. PEPITEM binds cadherin-15 on endothelial cells, promoting synthesis and release of sphingosine-1 phosphate, which inhibits trafficking of T cells without affecting recruitment of other leukocytes. Expression of adiponectin receptors on B cells and adiponectin-induced PEPITEM secretion wanes with age, implying immune senescence of the pathway. Additionally, these changes are evident in individuals with type 1 diabetes or rheumatoid arthritis, and circulating PEPITEM in patient serum is reduced compared to that of healthy age-matched donors. In both diseases, tonic inhibition of T cell trafficking across inflamed endothelium is lost. Control of patient T cell trafficking is re-established by treatment with exogenous PEPITEM. Moreover, in animal models of peritonitis, hepatic ischemia-reperfusion injury, Salmonella infection, uveitis and Sjögren's syndrome, PEPITEM reduced T cell recruitment into inflamed tissues. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
3. The RNA-binding protein HuR is essential for the B cell antibody response.
- Author
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Diaz-Muñoz, Manuel D, Bell, Sarah E, Fairfax, Kirsten, Monzon-Casanova, Elisa, Cunningham, Adam F, Gonzalez-Porta, Mar, Andrews, Simon R, Bunik, Victoria I, Zarnack, Kathi, Curk, Tomaž, Heggermont, Ward A, Heymans, Stephane, Gibson, Gary E, Kontoyiannis, Dimitris L, Ule, Jernej, and Turner, Martin
- Subjects
RNA analysis ,CARRIER proteins ,B cells ,IMMUNOGLOBULINS ,MESSENGER RNA ,GENETIC transcription - Abstract
Post-transcriptional regulation of mRNA by the RNA-binding protein HuR (encoded by Elavl1) is required in B cells for the germinal center reaction and for the production of class-switched antibodies in response to thymus-independent antigens. Transcriptome-wide examination of RNA isoforms and their abundance and translation in HuR-deficient B cells, together with direct measurements of HuR-RNA interactions, revealed that HuR-dependent splicing of mRNA affected hundreds of transcripts, including that encoding dihydrolipoamide S-succinyltransferase (Dlst), a subunit of the 2-oxoglutarate dehydrogenase (α-KGDH) complex. In the absence of HuR, defective mitochondrial metabolism resulted in large amounts of reactive oxygen species and B cell death. Our study shows how post-transcriptional processes control the balance of energy metabolism required for the proliferation and differentiation of B cells. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
4. B1b cells recognize protective antigens after natural infection and vaccination.
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Cunningham, Adam F., Flores-Langarica, Adriana, Bobat, Saeeda, Medina, Carmen C. Dominguez, Cook, Charlotte N. L., Ross, Ewan A., Lopez-Macias, Constantino, and Henderson, Ian R.
- Subjects
ANTIGENS ,B cells ,POLYSACCHARIDES ,SALMONELLA typhi ,ANTI-infective agents ,FICOLL - Abstract
There are multiple, distinct B-cell populations in human beings and other animals such as mice. In the latter species, there is a well-characterized subset of B-cells known as B1 cells, which are enriched in peripheral sites such as the peritoneal cavity but are rare in the blood. B1 cells can be further subdivided into B1a and B1b subsets. There may be additional B1 subsets, though it is unclear if these are distinct populations or stages in the developmental process to become mature B1a and B1b cells. A limitation in understanding B1 subsets is the relative paucity of specific surface markers. In contrast to mice, the existence of B1 cells in human beings is controversial and more studies are needed to investigate the nature of these enigmatic cells. Examples of B1b antigens include pneumococcal polysaccharide and the Vi antigen from Salmonella Typhi, both used routinely as vaccines in human beings and experimental antigens such as haptenated-Ficoll. In addition to inducing classical Tdependent responses some proteins are B1b antigens and can induce T-independent (TI) immunity, examples include factor H binding protein from Borrelia hermsii and porins from Salmonella. Therefore, B1b antigens can be proteinaceous or non-proteinaceous, induce TI responses, memory, and immunity, they exist in a diverse range of pathogenic bacteria, and a single species can contain multiple B1b antigens. An unexpected benefit to studying B1b cells is that they appear to have a propensity to recognize protective antigens in bacteria. This suggests that studying B1b cells may be rewarding for vaccine design as immunoprophylactic and immunotherapeutic interventions become more important due to the decreasing efficacy of small molecule antimicrobials. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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- View/download PDF
5. IL-4Rα-Associated Antigen Processing by B Cells Promotes Immunity in Nippostrongylus brasiliensis Infection.
- Author
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Horsnell, William G. C., Darby, Matthew G., Hoving, Jennifer C., Nieuwenhuizen, Natalie, McSorley, Henry J., Ndlovu, Hlumani, Bobat, Saeeda, Kimberg, Matti, Kirstein, Frank, Cutler, Anthony J., DeWals, Benjamin, Cunningham, Adam F., and Brombacher, Frank
- Subjects
INTERLEUKIN-4 ,ANTIGEN processing ,B cells ,IMMUNITY ,NIPPOSTRONGYLUS brasiliensis ,INTERLEUKIN-13 ,ANTIBODY formation ,CD86 antigen - Abstract
In this study, B cell function in protective T
H 2 immunity against N. brasiliensis infection was investigated. Protection against secondary infection depended on IL-4Rα and IL-13; but not IL-4. Protection did not associate with parasite specific antibody responses. Re-infection of B cell-specific IL-4Rα−/− mice resulted in increased worm burdens compared to control mice, despite their equivalent capacity to control primary infection. Impaired protection correlated with reduced lymphocyte IL-13 production and B cell MHC class II and CD86 surface expression. Adoptive transfer of in vivo N. brasiliensis primed IL-4Rα expressing B cells into naïve BALB/c mice, but not IL-4Rα or IL-13 deficient B cells, conferred protection against primary N. brasiliensis infection. This protection required MHC class II compatibility on B cells suggesting cognate interactions by B cells with CD4+ T cells were important to co-ordinate immunity. Furthermore, the rapid nature of these protective effects by B cells suggested non-BCR mediated mechanisms, such as via Toll Like Receptors, was involved, and this was supported by transfer experiments using antigen pulsed Myd88−/− B cells. These data suggest TLR dependent antigen processing by IL-4Rα-responsive B cells producing IL-13 contribute significantly to CD4+ T cell-mediated protective immunity against N. brasiliensis infection. [ABSTRACT FROM AUTHOR]- Published
- 2013
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- View/download PDF
6. CD8 T cells induce T-bet-dependent migration toward CXCR3 ligands by differentiated B cells produced during responses to alum-protein vaccines.
- Author
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Serre, Karine, Cunningham, Adam F., Coughlan, Ruth E., Lino, Andreia C., Rot, Antal, Hub, Elin, Moser, Katrin, Manz, Rudolf, Ferraro, Alastair, Bird, Roger, Toellner, Kai-Michael, Demengeot, Jocelyne, MacLennan, Ian C. M., and Mohr, Elodie
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T cells , *B cells , *LIGANDS (Biochemistry) , *CHEMOKINES , *INFLAMMATION - Abstract
Antibody-forming cells (AFCs) expressing the chemokine receptor CXCR3 are recruited to sites of inflammation where they help clear pathogens but may participate in autoimmune diseases. Here we identify a mechanism that induces CXCR3 expression by AFC and germinal center (GC) B cells. This happens when CD8 T cells are recruited into CD4 T cell-dependent B-cell responses. Ovalbumin-specific CD4 T cells (OTII) were trans ferred alone or with ovalbumin-specific CD6 T cells (OTI) and the response to subcutaneous alum-precipitated ovalbumin was followed in the draining lymph nodes. OTII cells alone Induce T helper 2-assoclated class switching to lgG1, but few AFC or GC B cells express CXCR3. By contrast, OTI-derived IFN-γ induces most responding GC B cells and AFCs to express high levels of CXCR3, and diverse switching to lgG2a, lgG2b, with some lgG1. Up-regulation of CXCR3 by GC B cells and AFCs and their migration toward Its ligand CXCL10 are shown to depend on B cells' intrinsic T-bet. a transcription factor downstream of the IFN-γR signaling. This model clarifies how precursors of long-lived AFCs and memory B cells acquire CXCR3 that causes their migration to inflammatory foci. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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- View/download PDF
7. Trypanosoma cruzi infection induces a massive extrafollicular and follicular splenic B-cell response which is a high source of non-parasite-specific antibodies.
- Author
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Bermejo, Daniela A., Amezcua Vesely, María C., Khan, Mahmood, Acosta Rodríguez, Eva V., Montes, Carolina L., Merino, Maria C., Toellner, Kai Michael, Mohr, Elodie, Taylor, Dale, Cunningham, Adam F., and Gruppi, Adriana
- Subjects
TRYPANOSOMA cruzi ,PROTOZOAN diseases ,CHAGAS' disease ,PARASITE antigens ,B cells ,LYMPHOCYTE transformation ,LABORATORY mice - Abstract
Acute infection with Trypanosoma cruzi, the aetiological agent of Chagas' disease, results in parasitaemia and polyclonal lymphocyte activation. It has been reported that polyclonal B-cell activation is associated with hypergammaglobulinaemia and delayed parasite-specific antibody response. In the present study we analysed the development of a B-cell response within the different microenvironments of the spleen during acute T. cruzi infection. We observed massive germinal centre (GC) and extrafollicular (EF) responses at the peak of infection. However, the EF foci were evident since day 3 post-infection (p.i.), and, early in the infection, they mainly provided IgM. The EF foci response reached its peak at 11 days p.i. and extended from the red pulp into the periarteriolar lymphatic sheath. The GCs were detected from day 8 p.i. At the peak of parasitaemia, CD138 B220 plasma cells in EF foci, red pulp and T-cell zone expressed IgM and all the IgG isotypes. Instead of the substantial B-cell response, most of the antibodies produced by splenic cells did not target the parasite, and parasite-specific IgG isotypes could be detected in sera only after 18 days p.i. We also observed that the bone marrow of infected mice presented a strong reduction in CD138 B220 cells compared with that of normal mice. Hence, in acute infection with T. cruzi, the spleen appears to be the most important lymphoid organ that lodges plasma cells and the main producer of antibodies. The development of a B-cell response during T. cruzi infection shows features that are particular to T. cruzi and other protozoan infection but different to other infections or immunization with model antigens. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
- View/download PDF
8. Ligation of CD11c during vaccination promotes germinal centre induction and robust humoral responses without adjuvant.
- Author
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White, Ann L., Tutt, Alison L., James, Sonya, Wilkinson, Kevin A., Castro, Fernanda V. V., Dixon, Sandra V., Hitchcock, Jessica, Khan, Mahmood, Al-Shamkhani, Aymen, Cunningham, Adam F., and Glennie, Martin J.
- Subjects
DENDRITIC cells ,IMMUNITY ,GERM cells ,CELL receptors ,MONOCLONAL antibodies - Abstract
In this study, we investigated the mouse dendritic cell (DC) receptor, complement receptor 4 (CR4; CD11c/CD18), as an immunotarget for triggering humoral immunity. Comparison of antibody titres generated against a panel of 13 anti-antigen-presenting cell receptor monoclonal antibodies, with or without conjugated ovalbumin (OVA), revealed uniquely rapid and robust responses following CR4 targeting, with antibody titres approaching 1 : 100 000 7 days after a single dose of antigen. Furthermore, using just 100 ng OVA conjugated to anti-CD11c Fab′, we generated anti-OVA titres greater than those produced by a 100-fold higher dose of OVA in complete Freund’s adjuvant at day 28. These anti-OVA antibody titres were sustained and could be boosted further with targeted OVA on day 21. Investigations to explain this vaccine potency showed that, in addition to targeting splenic DC, anti-CDl1c antibodies delivered a powerful adjuvant effect and could boost humoral immunity against OVA even when the OVA was targeted to other molecules on DC, such as major histocompatibility complex class II, CD11a and CD11b. However, interestingly, this adjuvant effect was lost if OVA was targeted to other cells such as B cells via CD21 or CD19. The adjuvant effect was mediated through a marked enhancement of both germinal centre and extrafollicular plasma cell formation in responding spleens. These results demonstrate that anti-CD11c monoclonal antibody can both target antigen and act as a powerful adjuvant for rapid and sustained antibody responses. They also point to an interesting role for CR4 on DC in triggering B cells during humoral immunity. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
- View/download PDF
9. The porin OmpD from nontyphoidal Salmonella is a key target for a protective B1b cell antibody response.
- Author
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GiI-Cruz, Cristina, Bobat, Saeeda, MarshaII, Jennifer L., Kingsley, Robert A., Ross, Ewan A., Henderson, Ian R., Leyton, Denisse L., CoughIan, Ruth E., Khan, Mahmood, Jensen, Karma T., BuckIey, Christopher D., Dougan, Gordon, MacLennan, Ian C. M., López-Macías, Constantino, and Cunningham, Adam F.
- Subjects
SALMONELLA ,IMMUNOGLOBULINS ,INFANT death ,GASTROINTESTINAL agents ,ANTIGENS - Abstract
Invasive nontyphoidal Salmonella (NTS), including Salmonella typhimurium (STm), are major yet poorly-recognized killers of infants in sub-Saharan Africa. Death in these children is usually associated with bacteremia, commonly in the absence of gastrointestinal symptoms. Evidence from humans and animal studies suggest that severe infection and bacteremia occur when specific Ab is lacking. Understanding how Ab responses to Salmonella are regulated will help develop vaccines against these devastating infections. STm induces atypical Ab responses characterized by prominent, accelerated, extrafollicular T-independent (TI) Ab against a range of surface antigens. These responses develop without concomitant germinal centers, which only appear as infection resolves. Here, we show STm rapidly induces a population of TI B220
+ CD5- B1b cells during infection and TI Ab from B1b cells targets the outer membrane protein (Omp) porins OmpC, OmpD and OmpF but not flagellin. When porins are used as immunogens they can ablate bacteremia and provide equivalent protection against STm as killed bacterial vaccine and this is wholly B cell-dependent. Furthermore Ab from porin-immunized chimeras, that have Bib cells, is sufficient to impair infection. Infecting with porin-deficient bacteria identifies OmpD, a protein absent from Salmonella Typhi, as a key target of Ab in these infections. This work broadens the recognized repertoire of TI protein antigens and highlights the importance of Ab from different B cell subsets in controlling STm infection. OmpD is a strong candidate vaccine target and may, in part, explain the lack of cross-protection between Salmonella Typhi and STm infections. [ABSTRACT FROM AUTHOR]- Published
- 2009
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- View/download PDF
10. Homeostatic cell-cycle control by BLyS: induction of cell-cycle entry but not G1/S transition in opposition to p18INK4C and p27Kip1.
- Author
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Xiangao Huang, di Liberto, Maurizio, Cunningham, Adam F., Lin Kang, Shuhua Cheng, Scott Ely, Hsiou-Chi Liou, MacLennan, Ian C M., and Chen-Kiang, Selina
- Subjects
CELL cycle ,B cells ,LYMPHOCYTES ,IMMUNOGLOBULINS ,ANTIGENS ,CYTOKINES - Abstract
Cell-cycle entry is critical for homeostatic control in physiologic response of higher organisms but is not well understood. The antibody response begins with induction of naïve mature B cells, which are naturally arrested in G
0 /G1 phase of the cell cycle, to enter the cell cycle in response to antigen and cytokine. BLyS (BAFF), a cytokine essential for mature B cell development and survival, is thought to act mainly by attenuation of apoptosis. Here, we show that BLyS alone induces cell-cycle entry and early G1 cell-cycle progression, but not 5-phase entry, in opposition to the cyclin-dependent kinase inhibitors p18INK4c . Independent of its survival function, BLyS enhances the synthesis of cyclin 02, in part through activation of NF-κB, as well as CDK4 and retinoblastoma protein phosphorylation. By convergent activation of the same cell-cycle regulators in opposition to p18INK4c , B cell receptor signaling induces cell-cycle entry and G, progression in synergy with BLyS, but also DNA replication. The failure of BLyS to induce S-phase cell-cycle entry lies in its inability to increase cyclin E and reduce p27kip1 expression. Antagonistic cell-cycle regulation by BLyS and p18INK4c is functionally linked to apoptotic control and conserved from B cell activation in vitro to antibody response in vivo. further indicating a physiologic role in homeostasis. [ABSTRACT FROM AUTHOR]- Published
- 2004
- Full Text
- View/download PDF
11. Extrafollicular antibody responses.
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MacLennan, Ian C. M., Toellner, Kai-Michael, Cunningham, Adam F., Serre, Karine, Sze, Daniel M.-Y., Zúñiga, Elina, Cook, Matthew C., and Vinuesa, Carola G.
- Subjects
IMMUNOGLOBULINS ,B cells ,LYMPH nodes ,LYMPHOID tissue ,SPLEEN - Abstract
Summary: In adaptive antibody responses, B cells are induced to grow either in follicles where they form germinal centers or in extrafollicular foci as plasmablasts. Extrafollicular growth typically occurs in the medullary cords of lymph nodes and in foci in the red pulp of the spleen. It is not a feature of secondary lymphoid tissue associated with the internal epithelia of the body. All types of naïve and memory B cells can be recruited into extrafollicular responses. These responses are associated with immunoglobulin class switching but, at the most, only low-level hypermutation. [ABSTRACT FROM AUTHOR]
- Published
- 2003
- Full Text
- View/download PDF
12. Rapid Development of Th2 Activity During T Cell Priming.
- Author
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Cunningham, Adam F. and Toellner, Kai-Michael
- Subjects
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B cells , *T cells , *CYTOKINES - Abstract
The paradigm of T helper-1 (Th-1) and Th-2 cells developing from non-committed naïve precursors is firmly established. Th1 cells are characterized by IFNγ production and, in mice, the selective switching to IgG2a. Conversely IL-4 production and selective switching to IgG1 and IgE characterize Th2 cells. Analysis of Th2 induction in vitro indicates that this polarization develops gradually in T cells activated by anti-CD3 in the presence of IL-4; conversely anti-CD3 and IFNγ induce Th1 cells. In this report, we explore evidence that indicates that the T helper cell polarization in vivo cannot solely be explained by the cytokine environment. This is provided by studying the early acquisition of Th1 and Th2 activities during responses to a mixture of Th1 and Th2-inducing antigens. It is shown that these divergent forms of T cell help can rapidly develop in cells within a single lymph node. It is argued that early polarization to show Th-1 or Th-2 behavior can be induced by signals delivered during cognate interaction between virgin T cells and dendritic cells, in the absence of type 1 or type 2 cytokines. This contrasts with the critical role of the cytokines in reinforcing the Th-phenotype and selectively expanding T helper clones. [ABSTRACT FROM AUTHOR]
- Published
- 2003
- Full Text
- View/download PDF
13. Homeostatic cell-cycle control by BLyS: induction of cell-cycle entry but not G1/S transition in opposition to p18INK4C and p27Kip1.
- Author
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Xiangao Huang, di Liberto, Maurizio, Cunningham, Adam F., Lin Kang, Shuhua Cheng, Scott Ely, Hsiou-Chi Liou, MacLennan, Ian C M., and Chen-Kiang, Selina
- Subjects
- *
CELL cycle , *B cells , *LYMPHOCYTES , *IMMUNOGLOBULINS , *ANTIGENS , *CYTOKINES - Abstract
Cell-cycle entry is critical for homeostatic control in physiologic response of higher organisms but is not well understood. The antibody response begins with induction of naïve mature B cells, which are naturally arrested in G0/G1 phase of the cell cycle, to enter the cell cycle in response to antigen and cytokine. BLyS (BAFF), a cytokine essential for mature B cell development and survival, is thought to act mainly by attenuation of apoptosis. Here, we show that BLyS alone induces cell-cycle entry and early G1 cell-cycle progression, but not 5-phase entry, in opposition to the cyclin-dependent kinase inhibitors p18INK4c. Independent of its survival function, BLyS enhances the synthesis of cyclin 02, in part through activation of NF-κB, as well as CDK4 and retinoblastoma protein phosphorylation. By convergent activation of the same cell-cycle regulators in opposition to p18INK4c, B cell receptor signaling induces cell-cycle entry and G, progression in synergy with BLyS, but also DNA replication. The failure of BLyS to induce S-phase cell-cycle entry lies in its inability to increase cyclin E and reduce p27kip1 expression. Antagonistic cell-cycle regulation by BLyS and p18INK4c is functionally linked to apoptotic control and conserved from B cell activation in vitro to antibody response in vivo. further indicating a physiologic role in homeostasis. [ABSTRACT FROM AUTHOR]
- Published
- 2004
- Full Text
- View/download PDF
14. The Capsular Polysaccharide Vi from Salmonella Typhi Is a Bib Antigen.
- Author
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Marshall, Jennifer L., Flores-Langarica, Adriana, Kingsley, Robert A., Hitchcock, Jessica R., Ross, Ewan A., López-Macías, Constantino, Lakey, Jeremy, Martin, Laura B., Toellner, Kai-Michael, MacLennan, Caiman A., MacLennan, Ian C., Henderson, Ian R., Dougan, Gordon, and Cunningham, Adam F.
- Subjects
- *
BACTERIAL capsules , *POLYSACCHARIDES , *SALMONELLA typhi , *BACTERIAL antigens , *TYPHOID fever , *DRUG efficacy , *B cells , *LABORATORY mice , *PREVENTION - Abstract
Vaccination with purified capsular polysaccharide Vi Ag from Salmonella typhi can protect against typhoid fever, although the mechanism for its efficacy is not clearly established. In this study, we have characterized the B cell response to this vaccine in wild-type and T cell-deficient mice. We show that immunization with typhoid vi polysaccharide vaccine rapidly induces proliferation in Bib peritoneal cells, but not in Bla cells or marginal zone B cells. This induction of Bib proliferation is concomitant with the detection of splenic Vi-specific Ab-secreting cells and protective Ab in Rag 1-deficient Bib cell chimeras generated by adoptive transfer-induced specific Ab after Vi immunization. Furthermore, Ab derived from peritoneal B cells is sufficient to confer protection against Salmonella that express Vi Ag. Expression of Vi by Salmonella during infection did not inhibit the development of early Ab responses to non-Vi Ags. Despite this, the protection conferred by immunization of mice with porin proteins from Salmonella, which induce Ab-mediated protection, was reduced postinfection with Vi-expressing Salmonella, although protection was not totally abrogated. This work therefore suggests that, in mice, Bib cells contribute to the protection induced by Vi Ag, and targeting non-Vi Ags as subunit vaccines may offer an attractive strategy to augment current Vi-based vaccine strategies. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
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