Human pregnancy-associated malaria-specific B cells target polymorphic, conformational epitopes in VAR2CSA.

Abstract:

:Pregnancy-associated malaria (PAM) is caused by Plasmodium falciparum-infected erythrocytes (IEs) that bind to chondroitin sulphate A (CSA) in the placenta by PAM-associated clonally variant surface antigens (VSA). Pregnancy-specific VSA (VSA(PAM)), which include the PfEMP1 variant VAR2CSA, are targets of IgG-mediated protective immunity to PAM. Here, we report an investigation of the specificity of naturally acquired immunity to PAM, using eight human monoclonal IgG1 antibodies that react exclusively with intact CSA-adhering IEs expressing VSA(PAM). Four reacted in Western blotting with high-molecular-weight (> 200 kDa) proteins, while seven reacted with either the DBL3-X or the DBL5-epsilon domains of VAR2CSA expressed either as Baculovirus constructs or on the surface of transfected Jurkat cells. We used a panel of recombinant antigens representing DBL3-X domains from P. falciparum field isolates to evaluate B-cell epitope diversity among parasite isolates, and identified the binding site of one monoclonal antibody using a chimeric DBL3-X construct. Our findings show that there is a high-frequency memory response to VSA(PAM), indicating that VAR2CSA is a primary target of naturally acquired PAM-specific protective immunity, and demonstrate the value of human monoclonal antibodies and conformationally intact recombinant antigens in VSA characterization.

journal_name

Mol Microbiol

journal_title

Molecular microbiology

authors

Barfod L,Bernasconi NL,Dahlbäck M,Jarrossay D,Andersen PH,Salanti A,Ofori MF,Turner L,Resende M,Nielsen MA,Theander TG,Sallusto F,Lanzavecchia A,Hviid L

doi

10.1111/j.1365-2958.2006.05503.x

subject

Has Abstract

pub_date

2007-01-01 00:00:00

pages

335-47

issue

2

eissn

0950-382X

issn

1365-2958

pii

MMI5503

journal_volume

63

pub_type

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