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* Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development/National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892 and Detroit, MI 48201;
Center for Molecular Medicine and Genetics, and Departments
Computer Science, Wayne State University, Detroit, MI 48201; and Departments of
Pathology and
¶ Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI 48201
The co-presence of histoincompatible fetal and maternal cells is a characteristic of human placental inflammation. Villitis of unknown etiology (VUE), a destructive inflammatory lesion of villous placenta, is characterized by participation of Hofbauer cells (placental macrophages) and maternal T cells. In contrast to acute chorioamnionitis of infection-related origin, the fundamental immunopathology of VUE is unknown. This study was performed to investigate the placental transcriptome of VUE and to determine whether VUE is associated with systemic maternal and/or fetal inflammatory response(s). Comparison of the transcriptome between term placentas without and with VUE revealed differential expression of 206 genes associated with pathways related to immune response. The mRNA expression of a subset of chemokines and their receptors (CXCL9, CXCL10, CXCL11, CXCL13, CCL4, CCL5, CXCR3, CCR5) was higher in VUE placentas than in normal placentas (p < 0.05). Analysis of blood cell mRNA showed a higher expression of CXCL9 and CXCL13 in the mother, and CXCL11 and CXCL13 in the fetus of VUE cases (p < 0.05). The median concentrations of CXCL9, CXCL10, and CXCL11 in maternal and fetal plasma were higher in VUE (p < 0.05). Comparison of preterm cases without and with acute chorioamnionitis revealed elevated CXCL9, CXCL10, CXCL11, and CXCL13 concentrations in fetal plasma (p < 0.05), but not in maternal plasma with chorioamnionitis. We report for the first time the placental transcriptome of VUE. A systemic derangement of CXC chemokines in maternal and fetal circulation distinguishes VUE from acute chorioamnionitis. We propose that VUE be a unique state combining maternal allograft rejection and maternal antifetal graft-vs-host disease mechanisms.
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 the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services.
2 R.R. and J.-S.K. are senior co-authors.
3 Address correspondence and reprint requests to Dr. Jung-Sun Kim, Perinatology Research Branch, National Institute of Child Health and Human Development/National Institutes of Health, Department of Health and Human Services, Wayne State University/Hutzel Women’s Hospital, 3990 John R, 4th Floor, Detroit, MI 48201. E-mail address: jkim{at}med.wayne.edu
4 Abbreviations used in this paper: VUE, villitis of unknown etiology; GVHD, graft-vs-host disease; FDR, false discovery rate; ISI, inflammation severity index; KEGG, Kyoto Encyclopedia of Genes and Genomes; PTL, preterm labor and delivery without acute chorioamnionitis; PTLI, preterm labor and delivery with acute chorioamnionitis; qRT-PCR, quantitative RT-PCR; SPIA, signaling pathway impact analysis; TIL, term in labor.
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