title: A central role of plasmin in cardiac injury initiated by fetal exposure to maternal anti-Ro autoantibodies.
abstract: OBJECTIVE
  Cardiac neonatal lupus (cardiac-NL), initiated by surface binding of anti-Ro60 autoantibodies to apoptotic cardiocytes during development, activates the urokinase plasminogen activator/urokinase plasminogen activator receptor (uPA/uPAR) system. Subsequent accumulation of apoptotic cells and plasmin generation facilitates increased binding of anti-Ro60 by disrupting and cleaving circulating β2-glycoprotein I (β2GPI) thereby eliminating its protective effect. The association of soluble levels of components of the uPA/uPAR system with cardiac-NL was examined.
  
  
  METHODS
  Levels of the uPA/uPAR system were assessed by ELISA in cord blood and immunohistological evaluation of autopsies.
  
  
  RESULTS
  uPA, uPAR and plasminogen levels were each significantly higher in cord blood from cardiac-NL (n = 35) compared with non-cardiac-NL (n = 26) anti-Ro-exposed neonates: 3.3 ± 0.1 vs 1.9 ± 0.05 ng/ml (P < 0.0001), 6.6 ± 0.3 vs 2.1 ± 0.2 ng/ml (P < 0.0001) and 435 ± 34 vs 220 ± 19 ng/ml (P < 0.0001), respectively. In three twin pairs discordant for cardiac-NL, the twin with cardiac-NL had higher levels of uPA, uPAR and plasminogen than the unaffected twin (3.1 ± 0.1 vs 1.9 ± 0.05 ng/ml; P = 0.0086, 6.2 ± 1.4 vs 2.2 ± 0.7 ng/ml; P = 0.147 and 412 ± 61 vs 260 ± 27 ng/ml; P = 0.152, respectively). Immunohistological evaluation of three hearts from fetuses dying with cardiac-NL revealed macrophages and giant cells expressing uPA and plasminogen in the septal region.
  
  
  CONCLUSIONS
  Increased soluble uPA, uPAR and plasminogen in cord blood and expression in affected tissue of fetuses with cardiac-NL supports the hypothesis that fetal cardiac injury is in part mediated by plasmin generation initiated by anti-Ro binding to the apoptotic cardiocyte.
authors.affiliation: Department of Rheumatology, New York University School of Medicine, 550 1st Avenue, New York, NY 10016, USA. pbriassou@mac.com
authors.forename: Paraskevi
authors.initials: P
authors.lastname: Briassouli
authors.forename: Marc K
authors.initials: MK
authors.lastname: Halushka
authors.forename: Joanne H
authors.initials: JH
authors.lastname: Reed
authors.forename: Yair
authors.initials: Y
authors.lastname: Molad
authors.forename: Karen
authors.initials: K
authors.lastname: Fox-Talbot
authors.forename: Lucas
authors.initials: L
authors.lastname: Buyon
authors.forename: Edwin
authors.initials: E
authors.lastname: Guzman
authors.forename: Achiau
authors.initials: A
authors.lastname: Ludomirsky
authors.forename: Robert M
authors.initials: RM
authors.lastname: Clancy
authors.forename: Jill P
authors.initials: JP
authors.lastname: Buyon
mesh_terms: D000974:Antibodies, Antinuclear / Q000276:immunology / Q000378:metabolism; D015415:Biomarkers; D016022:Case-Control Studies; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005312:Fetal Blood / Q000276:immunology*; D005341:Fibrinolysin / Q000276:immunology* / Q000378:metabolism; D006331:Heart Diseases / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D007231:Infant, Newborn; D008180:Lupus Erythematosus, Systemic / Q000151:congenital* / Q000276:immunology / Q000401:mortality / Q000473:pathology; D008264:Macrophages / Q000276:immunology; D032383:Myocytes, Cardiac / Q000276:immunology / Q000378:metabolism; D011247:Pregnancy; D055293:Receptors, Urokinase Plasminogen Activator / Q000097:blood / Q000276:immunology*; D012016:Reference Values; D012261:Ribonucleoproteins / Q000276:immunology* / Q000378:metabolism; D015996:Survival Rate; D014568:Urokinase-Type Plasminogen Activator / Q000097:blood / Q000276:immunology; D000099207:SS-A Antigen
chemical_list: D000974:Antibodies, Antinuclear; D015415:Biomarkers; D005341:Fibrinolysin; D055293:Receptors, Urokinase Plasminogen Activator; D012261:Ribonucleoproteins; D014568:Urokinase-Type Plasminogen Activator; D000099207:SS-A Antigen; C035356:SS-A antibodies
keywords: apoptosis; fibrosis; inflammation