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Trypanosomiasis-induced B cell apoptosis results in loss of protective anti-parasite antibody responses and abolishment of vaccine-induced memory responses.

Radwanska M, Guirnalda P, De Trez C, Ryffel B, Black S, Magez S - PLoS Pathog. (2008)

Bottom Line: Elevated caspase-3 mRNA levels coincided with decreased mRNA levels of the anti-apoptotic Bcl-2 protein and BAFF receptor (BAFF-R), indicating the onset of apoptosis.In vivo, infection-induced loss of IgM(+) B cells coincided with the disappearance of protective variant-specific T-independent IgM responses, rendering the host rapidly susceptible to re-challenge with previously encountered parasites.In particular, these last results call for detailed studies of the effect of HAT on memory recall responses in humans, prior to the planning of any mass vaccination campaign in HAT endemic areas.

View Article: PubMed Central - PubMed

Affiliation: Laboratoire de Parasitologie, Université Libre de Bruxelles, ULB, Brussels, Belgium.

ABSTRACT
African trypanosomes of the Trypanosoma brucei species are extra-cellular parasites that cause human African trypanosomiasis (HAT) as well as infections in game animals and livestock. Trypanosomes are known to evade the immune response of their mammalian host by continuous antigenic variation of their surface coat. Here, we aim to demonstrate that in addition, trypanosomes (i) cause the loss of various B cell populations, (ii) disable the hosts' capacity to raise a long-lasting specific protective anti-parasite antibody response, and (iii) abrogate vaccine-induced protective response to a non-related human pathogen such as Bordetella pertussis. Using a mouse model for T. brucei, various B cell populations were analyzed by FACS at different time points of infection. The results show that during early onset of a T. brucei infection, spleen remodeling results in the rapid loss of the IgM(+) marginal zone (IgM(+)MZ) B cell population characterized as B220(+)IgM(High)IgD(Int) CD21(High)CD23(Low)CD1d(+)CD138(-). These cells, when isolated during the first peak of infection, stained positive for Annexin V and had increased caspase-3 enzyme activity. Elevated caspase-3 mRNA levels coincided with decreased mRNA levels of the anti-apoptotic Bcl-2 protein and BAFF receptor (BAFF-R), indicating the onset of apoptosis. Moreover, affected B cells became unresponsive to stimulation by BCR cross-linking with anti-IgM Fab fragments. In vivo, infection-induced loss of IgM(+) B cells coincided with the disappearance of protective variant-specific T-independent IgM responses, rendering the host rapidly susceptible to re-challenge with previously encountered parasites. Finally, using the well-established human diphtheria, tetanus, and B. pertussis (DTPa) vaccination model in mice, we show that T. brucei infections abrogate vaccine-induced protective responses to a non-related pathogen such as B. pertussis. Infections with T. brucei parasites result in the rapid loss of T-cell independent IgM(+)MZ B cells that are normally functioning as the primary immune barrier against blood-borne pathogens. In addition, ongoing trypanosome infections results in the rapid loss of B cell responsiveness and prevent the induction of protective memory responses. Finally, trypanosome infections disable the host's capacity to recall vaccine-induced memory responses against non-related pathogens. In particular, these last results call for detailed studies of the effect of HAT on memory recall responses in humans, prior to the planning of any mass vaccination campaign in HAT endemic areas.

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T. brucei induced abrogation of B cell proliferation.CD19+ MACS sorted cells derived form control mice or T.brucei AnTat 1.1E infected mice (day 10 post infection) were incubated for 24 h in the presence of different doses of anti-IgM Fab (A,B), or different doses of LPS (C,D). Proliferation was measure by thymidine incorporation. Results were obtained using spleen cell preparations of four individual mice, and represent the mean % of CPM increase ±SD, with the 100% showing the mean CPM level of non-stimulated cells.
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ppat-1000078-g005: T. brucei induced abrogation of B cell proliferation.CD19+ MACS sorted cells derived form control mice or T.brucei AnTat 1.1E infected mice (day 10 post infection) were incubated for 24 h in the presence of different doses of anti-IgM Fab (A,B), or different doses of LPS (C,D). Proliferation was measure by thymidine incorporation. Results were obtained using spleen cell preparations of four individual mice, and represent the mean % of CPM increase ±SD, with the 100% showing the mean CPM level of non-stimulated cells.

Mentions: The RT-PCR data presented above indicates that T. brucei infections induce apoptosis in populations of IgM+ spleen MZ B cells and MACS sorted CD19+ cells, hence, the later population was used to assess the effect of the infection on the IgM+B cell proliferative response. The sorted cells were incubated for 24 hours with different concentrations of anti-IgM Fab or LPS. Figure 5A indicates that naïve splenic B cells contain a cell fraction that is highly responsive to IgM Fab activation and proliferation. This fraction is absent in spleens of T. brucei infected C57Bl/6 mice 10 days after infection (Fig. 5B). Also when cells were stimulated in a non-specific manner with LPS, naïve CD19+ B cells showed a dose dependent proliferative response (Fig. 5C), while infection derived affected B cells showed a complete inhibition of LPS-mediated proliferation (Fig. 5D).


Trypanosomiasis-induced B cell apoptosis results in loss of protective anti-parasite antibody responses and abolishment of vaccine-induced memory responses.

Radwanska M, Guirnalda P, De Trez C, Ryffel B, Black S, Magez S - PLoS Pathog. (2008)

T. brucei induced abrogation of B cell proliferation.CD19+ MACS sorted cells derived form control mice or T.brucei AnTat 1.1E infected mice (day 10 post infection) were incubated for 24 h in the presence of different doses of anti-IgM Fab (A,B), or different doses of LPS (C,D). Proliferation was measure by thymidine incorporation. Results were obtained using spleen cell preparations of four individual mice, and represent the mean % of CPM increase ±SD, with the 100% showing the mean CPM level of non-stimulated cells.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2386555&req=5

ppat-1000078-g005: T. brucei induced abrogation of B cell proliferation.CD19+ MACS sorted cells derived form control mice or T.brucei AnTat 1.1E infected mice (day 10 post infection) were incubated for 24 h in the presence of different doses of anti-IgM Fab (A,B), or different doses of LPS (C,D). Proliferation was measure by thymidine incorporation. Results were obtained using spleen cell preparations of four individual mice, and represent the mean % of CPM increase ±SD, with the 100% showing the mean CPM level of non-stimulated cells.
Mentions: The RT-PCR data presented above indicates that T. brucei infections induce apoptosis in populations of IgM+ spleen MZ B cells and MACS sorted CD19+ cells, hence, the later population was used to assess the effect of the infection on the IgM+B cell proliferative response. The sorted cells were incubated for 24 hours with different concentrations of anti-IgM Fab or LPS. Figure 5A indicates that naïve splenic B cells contain a cell fraction that is highly responsive to IgM Fab activation and proliferation. This fraction is absent in spleens of T. brucei infected C57Bl/6 mice 10 days after infection (Fig. 5B). Also when cells were stimulated in a non-specific manner with LPS, naïve CD19+ B cells showed a dose dependent proliferative response (Fig. 5C), while infection derived affected B cells showed a complete inhibition of LPS-mediated proliferation (Fig. 5D).

Bottom Line: Elevated caspase-3 mRNA levels coincided with decreased mRNA levels of the anti-apoptotic Bcl-2 protein and BAFF receptor (BAFF-R), indicating the onset of apoptosis.In vivo, infection-induced loss of IgM(+) B cells coincided with the disappearance of protective variant-specific T-independent IgM responses, rendering the host rapidly susceptible to re-challenge with previously encountered parasites.In particular, these last results call for detailed studies of the effect of HAT on memory recall responses in humans, prior to the planning of any mass vaccination campaign in HAT endemic areas.

View Article: PubMed Central - PubMed

Affiliation: Laboratoire de Parasitologie, Université Libre de Bruxelles, ULB, Brussels, Belgium.

ABSTRACT
African trypanosomes of the Trypanosoma brucei species are extra-cellular parasites that cause human African trypanosomiasis (HAT) as well as infections in game animals and livestock. Trypanosomes are known to evade the immune response of their mammalian host by continuous antigenic variation of their surface coat. Here, we aim to demonstrate that in addition, trypanosomes (i) cause the loss of various B cell populations, (ii) disable the hosts' capacity to raise a long-lasting specific protective anti-parasite antibody response, and (iii) abrogate vaccine-induced protective response to a non-related human pathogen such as Bordetella pertussis. Using a mouse model for T. brucei, various B cell populations were analyzed by FACS at different time points of infection. The results show that during early onset of a T. brucei infection, spleen remodeling results in the rapid loss of the IgM(+) marginal zone (IgM(+)MZ) B cell population characterized as B220(+)IgM(High)IgD(Int) CD21(High)CD23(Low)CD1d(+)CD138(-). These cells, when isolated during the first peak of infection, stained positive for Annexin V and had increased caspase-3 enzyme activity. Elevated caspase-3 mRNA levels coincided with decreased mRNA levels of the anti-apoptotic Bcl-2 protein and BAFF receptor (BAFF-R), indicating the onset of apoptosis. Moreover, affected B cells became unresponsive to stimulation by BCR cross-linking with anti-IgM Fab fragments. In vivo, infection-induced loss of IgM(+) B cells coincided with the disappearance of protective variant-specific T-independent IgM responses, rendering the host rapidly susceptible to re-challenge with previously encountered parasites. Finally, using the well-established human diphtheria, tetanus, and B. pertussis (DTPa) vaccination model in mice, we show that T. brucei infections abrogate vaccine-induced protective responses to a non-related pathogen such as B. pertussis. Infections with T. brucei parasites result in the rapid loss of T-cell independent IgM(+)MZ B cells that are normally functioning as the primary immune barrier against blood-borne pathogens. In addition, ongoing trypanosome infections results in the rapid loss of B cell responsiveness and prevent the induction of protective memory responses. Finally, trypanosome infections disable the host's capacity to recall vaccine-induced memory responses against non-related pathogens. In particular, these last results call for detailed studies of the effect of HAT on memory recall responses in humans, prior to the planning of any mass vaccination campaign in HAT endemic areas.

Show MeSH
Related in: MedlinePlus