Classical complement activation as a footprint for murine and human antiphospholipid antibody-induced fetal loss

J Pathol. 2011 Dec;225(4):502-11. doi: 10.1002/path.2893. Epub 2011 Jun 20.


Recurrent miscarriage, fetal growth restriction and intrauterine fetal death are frequently occurring complications of pregnancy in patients with systemic lupus erythaematosus (SLE) and antiphospholipid syndrome (APS). Murine models show that complement activation plays a pivotal role in antiphospholipid antibody-mediated pregnancy morbidity, but the exact pathways of complement activation and their potential role in human pregnancy are insufficiently understood. We hypothesized that the classical pathway would play a major role in inducing fetal loss. Pregnant C57BL/6 mice and mice deficient in C1q and factor D were injected with antiphospholipid antibodies or normal human IgG. Mouse placentas were subsequently stained with an anti-C4 antibody and anti-normal human IgG to determine the presence of classical complement activation and IgG binding. Findings in mice were validated in 88 human placentae from 83 women (SLE and APS cases versus controls), which were immunohistochemically stained for C4d, C1q, properdin and MBL. Staining patterns were compared to pregnancy outcome. In murine placentae of mice pretreated with antiphospholipid antibodies, increased C4 deposition was observed, which was associated with adverse fetal outcome but not with IgG binding. In humans, diffuse C4d staining at the feto-maternal interface was present almost exclusively in patients with SLE and/or APS (p < 0.001) and was related to intrauterine fetal death (p = 0.03). Our data show that presence of C4d in murine and human placentae is strongly related to adverse fetal outcome in the setting of SLE and APS. The excessive deposition of C4d supports the concept of severe autoantibody-mediated injury at the fetal-maternal interface. We suggest C4d as a potential biomarker of autoantibody-mediated fetal loss in SLE and APS.

MeSH terms

  • Adult
  • Animals
  • Antibodies, Antiphospholipid / administration & dosage
  • Antibodies, Antiphospholipid / immunology*
  • Antiphospholipid Syndrome / complications
  • Antiphospholipid Syndrome / immunology*
  • Antiphospholipid Syndrome / pathology
  • Biomarkers
  • Complement Activation / immunology*
  • Complement C1q / deficiency
  • Complement C1q / immunology*
  • Complement C4 / metabolism
  • Disease Models, Animal
  • Female
  • Fetal Death / chemically induced
  • Fetal Death / immunology*
  • Gestational Age
  • Humans
  • Lupus Erythematosus, Systemic / complications
  • Lupus Erythematosus, Systemic / immunology
  • Lupus Erythematosus, Systemic / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Placenta / immunology
  • Placenta / metabolism
  • Placenta / pathology
  • Pregnancy
  • Pregnancy Outcome


  • Antibodies, Antiphospholipid
  • Biomarkers
  • Complement C4
  • Complement C1q