The etiologic agent of Chagas disease is Trypanosoma cruzi. Patent parasitemia leads to parasite spread throughout the host during acute phase disease. Parasitemia concomitant with polyclonal lymphocyte activation has been reported and is thought to contribute to parasite evasion of host immunity and subsequent parasite persistence, which leads to chronic disease. In the present studies, polyclonal B cell activation was evaluated in relatively susceptible Balb/c versus resistant C57Bl/6 mouse models. Hypergammaglobulinemia and B cell activation in susceptible mice was associated with a large number of antibody secreting cells (ASC) without appreciable parasite-specific ASC. In contrast, in resistant mice, B cell activation and expansion was associated with generation of parasite-specific humoral immunity. These data indicate that the outcome of B cell activation during early T. cruzi experimental infection varies according to host susceptibility.
T. cruzi encodes several proteins with mitogenic capacities that are thought to contribute to dysfunctional polyclonal B cell activation in susceptible mice. One recently identified T. cruzi mitogen is a proline racemase (TcPRAC). Characterization of B cell activation by recombinant protein in this study demonstrates that TcPRAC induced polyclonal B cell activation, evident by proliferation, antibody secretion, IL-10 production, and B cell surface phenotype. MZ B cells were more responsive to T-cell independent TcPRAC stimulation than were follicular mature (FM) B cells. These data provide the first comprehensive characterization of B cell activation by TcPRAC.
During experimental T. cruzi infection, TcPRAC-specific IgG remained undetectable. Conversely, intradermal genetic immunization via gene-gun (GG) induced antigen-specific immunogenic responses, generating TcPRAC-specific high-titer IgG, bone marrow plasma cells, and memory B cells. TcPRAC-specific IgG bound mitogenic rTcPRAC, decreasing subsequent B cell activation. GG immunization with TcPRAC DNA was non-mitogenic and did not effect generation of specific IgG to another T. cruzi antigen, complement regulatory protein (CRP). These data demonstrate the utility of genetic immunization for the conversion of a protein mitogen into an effective immunogen. Furthermore, co-immunization of TcPRAC with another T. cruzi antigen indicated the usefulness of this approach for multivalent vaccine development.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-04052010-195648 |
| Date | 15 April 2010 |
| Creators | Bryan, Marianne A |
| Contributors | Karen A Norris, Kelly Stephano Cole, Joanne Flynn, Lisa Borghesi, Ted Ross, Russell Salter |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-04052010-195648/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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