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T. cruzi parasite-specific humoral immunity versus polyclonal activation

Bryan, Marianne A (2010) T. cruzi parasite-specific humoral immunity versus polyclonal activation. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

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.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Bryan, Marianne Amarianne.bryan@gmail.com
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairNorris, Karen Akan1@pitt.eduKAN1
Committee MemberFlynn, Joannejoanne@pitt.eduJOANNE
Committee MemberStephano Cole, Kellystefcole@cvr.pitt.eduSTEFCOLE
Committee MemberBorghesi, Lisaborghesi@pitt.eduBORGHESI
Committee MemberSalter, Russellrds@pitt.eduRDS
Committee MemberRoss, Tedtmr15@pitt.eduTMR15
Date: 15 April 2010
Date Type: Completion
Defense Date: 16 December 2009
Approval Date: 15 April 2010
Submission Date: 5 April 2010
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Immunology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: antibody; B cell mitogen; infection; polyclonal activation; trypanosoma cruzi
Other ID: http://etd.library.pitt.edu/ETD/available/etd-04052010-195648/, etd-04052010-195648
Date Deposited: 10 Nov 2011 19:34
Last Modified: 15 Nov 2016 13:38
URI: http://d-scholarship.pitt.edu/id/eprint/6782

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