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* Mother-Offspring Malaria Study (MOMS) Project, Seattle Biomedical Research Institute, Seattle, WA 98109;
University of Washington, Seattle, WA 98195;
London School of Hygiene and Tropical Medicine, London, United Kingdom;
National Institute for Medical Research, Dar es Salaam, Tanzania;
¶ Muheza Designated District Hospital, Muheza, Tanzania; and
|| Walter Reed Army Institute of Research, Silver Spring, MD 20910
Chronic inflammation during placental malaria (PM) is most frequent in first time mothers and is associated with poor maternal and fetal outcomes. In the first genome-wide analysis of the local human response to sequestered malaria parasites, we identified genes associated with chronic PM and then localized the corresponding proteins and immune cell subsets in placental cryosections. B cell-related genes were among the most highly up-regulated transcripts in inflamed tissue. The B cell chemoattractant CXCL13 was up-regulated >1,000-fold, and B cell-activating factor was also detected. Both proteins were expressed by intervillous macrophages. Ig L and H chain transcription increased significantly, and heavy depositions of IgG3 and IgM were observed in intervillous spaces. The B cell phenotype was heterogenous, including naive (CD27-negative), mature (CD138-positive), and cycling (Ki-67-positive) cells. B cells expressed T-bet but not Bcl-6, suggesting T cell-independent activation without germinal center formation. Genes for the Fc binding proteins Fc
RIa, FcRIIIa, and C1q were highly up-regulated, and the proteins localized to intervillous macrophages. Birth weight was inversely correlated with transcript levels of CXCL13, IgG H chain, and IgM H chain. The iron regulatory peptide hepcidin was also expressed but was not associated with maternal anemia. The results suggest that B cells and macrophages contribute to chronic PM in a process resembling lymphoid neogenesis. We propose a model where the production of Ig during chronic malaria may enhance inflammation by attracting and activating macrophages that, in turn, recruit B cells to further produce Ig in the intervillous spaces.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by a grant from the Bill and Melinda Gates Foundation (to P.E.D.), National Institutes of Health Grant R01AI52059 (to P.E.D.), and funds from the American Medical Association Foundation and the Washington State Obstetrical Association (to A.M.). The gene expression arrays were funded by National Institutes of Health Grant HL072370. A.M. was supported by National Institutes of Health Training Grant T32 HL07312.
2 Address correspondence and reprint requests to Dr. Patrick Duffy, Seattle Biomedical Research Institute, 307 Westlake Avenue North Suite 500, Seattle WA 98109. E-mail address: pduffy{at}sbri.org
3 Abbreviations used in this paper: PM, placental malaria; BAFF, B cell-activating factor; CT, threshold cycle; IE, infected erythrocyte.
4 The online version of this article contains supplemental material.
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