No conflicts of interest were declared.
Classical complement activation as a footprint for murine and human antiphospholipid antibody-induced fetal loss†
Article first published online: 20 JUN 2011
Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
The Journal of Pathology
Volume 225, Issue 4, pages 502–511, December 2011
How to Cite
Cohen, D., Buurma, A., Goemaere, N. N., Girardi, G., le Cessie, S., Scherjon, S., Bloemenkamp, K. W., de Heer, E., Bruijn, J. A. and Bajema, I. M. (2011), Classical complement activation as a footprint for murine and human antiphospholipid antibody-induced fetal loss. J. Pathol., 225: 502–511. doi: 10.1002/path.2893
- Issue published online: 24 OCT 2011
- Article first published online: 20 JUN 2011
- Accepted manuscript online: 10 MAR 2011 09:23AM EST
- Manuscript Accepted: 4 MAR 2011
- Manuscript Revised: 22 FEB 2011
- Manuscript Received: 20 DEC 2010
- antiphospholipid syndrome;
- systemic lupus erythaematosus;
- classical complement activation;
- mannose-binding lectin;
- alternative pathway activation;
- antibody-mediated rejection;
- fetal loss;
- recurrent miscarriage
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. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.