title: The C5b-9 membrane attack complex of complement activation localizes to villous trophoblast injury in vivo and modulates human trophoblast function in vitro.
abstract: The complement system plays an important role in normal human pregnancy. Uncontrolled activation of this system has been associated with many disease states. We tested the hypothesis that the C5b-9 membrane attack complex (MAC) localizes to sites of villous injury and modulates trophoblast function. Placental sections from pregnancies with no complications, intrauterine growth restriction, or preeclampsia were immunostained and the surface density for MAC and fibrin was determined by morphometric analysis. Primary cytotrophoblasts from term placentas were cultured in a FiO(2) of <1%, 8% and 20% with 10% human serum containing active MAC or heat-inactivated control serum. Immunofluorescent MAC binding to trophoblast was quantified, and the neoepitopes formed in cytokeratin 18 filaments and poly-ADP-ribose polymerase during apoptosis were used to measure cell death. Trophoblast differentiation was assessed by HCG secretion, formation of syncytia, and expression of syncytin. MAC localized to fibrin deposits in normal placentas, and especially in placentas from IUGR and preeclampsia. MAC binding to cytotrophoblasts was inversely proportional to FiO(2) and enhanced apoptosis. MAC increased markers of differentiation in cultures at 72h (medium HCG, syncytia and syncytin expression). Our findings demonstrate that MAC associates with fibrin deposits at sites of villous injury in vivo. Hypoxia also enhances MAC deposition in cultured trophoblasts and MAC alters trophoblast function in a phenotype specific manner.
authors.affiliation: Department of Obstetrics and Gynecology, Washington University, 4566 Scott Avenue, Saint Louis, MO 63110, USA. rampersadr@wudosis.wustl.edu
authors.forename: R
authors.initials: R
authors.lastname: Rampersad
authors.forename: A
authors.initials: A
authors.lastname: Barton
authors.forename: Y
authors.initials: Y
authors.lastname: Sadovsky
authors.forename: D M
authors.initials: DM
authors.lastname: Nelson
mesh_terms: D017209:Apoptosis / Q000502:physiology; D002824:Chorionic Villi / Q000378:metabolism* / Q000473:pathology; D015938:Complement Membrane Attack Complex / Q000378:metabolism* / Q000502:physiology; D005260:Female; D005317:Fetal Growth Retardation / Q000503:physiopathology; D005337:Fibrin / Q000378:metabolism; D006801:Humans; D010922:Placenta Diseases / Q000378:metabolism* / Q000473:pathology; D011225:Pre-Eclampsia / Q000503:physiopathology; D011247:Pregnancy; D014327:Trophoblasts / Q000378:metabolism*
chemical_list: D015938:Complement Membrane Attack Complex; D005337:Fibrin
references.citation: Placenta. 1996 Sep;17(7):387-91
references.pmid: 8899866
references.citation: Am J Physiol Cell Physiol. 2000 May;278(5):C982-8
references.pmid: 10794672
references.citation: J Perinat Med. 2005;33(4):296-305
references.pmid: 16207114
references.citation: Placenta. 2005 Jul;26(6):439-48
references.pmid: 15950058
references.citation: Obstet Gynecol. 2002 Jan;99(1):159-67
references.pmid: 16175681
references.citation: J Biol Chem. 2002 Nov 1;277(44):41342-51
references.pmid: 12191998
references.citation: Acta Anat (Basel). 1994;150(1):55-68
references.pmid: 7526588
references.citation: Placenta. 2006 Sep-Oct;27(9-10):978-83
references.pmid: 16376985
references.citation: Am J Pathol. 2006 Aug;169(2):400-4
references.pmid: 16877342
references.citation: Autoimmunity. 2006 Aug;39(5):395-402
references.pmid: 16923539
references.citation: Placenta. 2006 Apr;27 Suppl A:S17-25
references.pmid: 16406003
references.citation: Am J Pathol. 1990 Apr;136(4):855-65
references.pmid: 2327472
references.citation: Placenta. 2003 Feb-Mar;24(2-3):219-26
references.pmid: 12566249
references.citation: J Clin Endocrinol Metab. 2005 Jul;90(7):4299-308
references.pmid: 15840747
references.citation: Am J Obstet Gynecol. 2007 Feb;196(2):167.e1-5
references.pmid: 17306667
references.citation: Mol Immunol. 2004 Jul;41(6-7):583-97
references.pmid: 15219997
references.citation: Obstet Gynecol. 1992 Jan;79(1):19-26
references.pmid: 1727579
references.citation: Clin Immunol. 2006 Feb-Mar;118(2-3):127-36
references.pmid: 16338172
references.citation: Hum Reprod. 2007 Feb;22(2):362-71
references.pmid: 17099209
references.citation: J Exp Med. 2002 Jan 21;195(2):211-20
references.pmid: 11805148
references.citation: Placenta. 2001 Aug;22(7):628-38
references.pmid: 11504531
references.citation: Science. 2000 Jan 21;287(5452):498-501
references.pmid: 10642554
references.citation: Clin Exp Immunol. 1990 May;80(2):236-40
references.pmid: 2357851
references.citation: Clin Chem. 2007 Jan;53(1):42-52
references.pmid: 17202497
references.citation: J Clin Invest. 2003 Dec;112(11):1644-54
references.pmid: 14660741
references.citation: Curr Biol. 2000 May 18;10(10):R381-3
references.pmid: 10837212
references.citation: N Engl J Med. 2001 Apr 12;344(15):1140-4
references.pmid: 11297706
references.citation: Clin Exp Immunol. 1984 Apr;56(1):175-84
references.pmid: 6370518
references.citation: Int Rev Immunol. 1993;10(1):51-64
references.pmid: 8340677
references.citation: Am J Kidney Dis. 2001 Jan;37(1):E6
references.pmid: 11136195
references.citation: Am J Pathol. 2002 Aug;161(2):449-57
references.pmid: 12163370
references.citation: Am J Pathol. 2004 Mar;164(3):1049-61
references.pmid: 14982858
references.citation: Am J Obstet Gynecol. 1999 Apr;180(4):896-902
references.pmid: 10203658
references.citation: Am J Obstet Gynecol. 1997 Jul;177(1):57-65
references.pmid: 9240583