A central role of plasmin in cardiac injury initiated by fetal exposure to maternal anti-Ro autoantibodies

Paraskevi Briassouli, Marc K. Halushka, Joanne H. Reed, Yair Molad, Karen Fox-Talbot, Lucas Buyon, Edwin Guzman, Achiau Ludomirsky, Robert M. Clancy, Jill P. Buyon

Research output: Contribution to journalArticlepeer-review

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. Conclusion. 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.

Original languageEnglish (US)
Article numberket156
Pages (from-to)1448-1453
Number of pages6
JournalRheumatology (United Kingdom)
Volume52
Issue number8
DOIs
StatePublished - Aug 2013

Keywords

  • Apoptosis
  • Fibrosis
  • Inflammation

ASJC Scopus subject areas

  • Rheumatology
  • Pharmacology (medical)

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