Complement C5a receptors and neutrophils mediate fetal injury in the antiphospholipid syndrome
Guillermina Girardi, … , V. Michael Holers, Jane E. Salmon
Guillermina Girardi, … , V. Michael Holers, Jane E. Salmon
Published December 1, 2003
Citation Information: J Clin Invest. 2003;112(11):1644-1654. https://doi.org/10.1172/JCI18817.
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Article Immunology

Complement C5a receptors and neutrophils mediate fetal injury in the antiphospholipid syndrome

Abstract

Antiphospholipid syndrome (APS) is defined by recurrent pregnancy loss and thrombosis in the presence of antiphospholipid (aPL) Ab’s. Currently, therapy for pregnant women with APS is focused on preventing thrombosis, but anticoagulation is only partially successful in averting miscarriage. We hypothesized that complement activation is a central mechanism of pregnancy loss in APS and tested this in a model in which pregnant mice receive human IgG containing aPL Ab’s. Here we identify complement component C5 (and particularly its cleavage product C5a) and neutrophils as key mediators of fetal injury, and we show that Ab’s or peptides that block C5a–C5a receptor interactions prevent pregnancy complications. The fact that F(ab)′2 fragments of aPL Ab’s do not mediate fetal injury and that C4-deficient mice are protected from fetal injury suggests that activation of the complement cascade is initiated via the classical pathway. Studies in factor B–deficient mice, however, indicate that alternative pathway activation is required and amplifies complement activation. In contrast, activating FcγRs do not play an important role in mediating aPL Ab–induced fetal injury. Our findings identify the key innate immune effectors engaged by pathogenic autoantibodies that mediate poor pregnancy outcomes in APS and provide novel and important targets for prevention of pregnancy loss in APS.

Authors

Guillermina Girardi, Jessica Berman, Patricia Redecha, Lynn Spruce, Joshua M. Thurman, Damian Kraus, Travis J. Hollmann, Paolo Casali, Michael C. Caroll, Rick A. Wetsel, John D. Lambris, V. Michael Holers, Jane E. Salmon

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Figure 3

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C5 deficiency limits inflammation, necrosis, and activation of C3 by aPL...
C5 deficiency limits inflammation, necrosis, and activation of C3 by aPL Ab’s. Pregnant C5+/+ and C5–/– mice were treated with aPL-IgG (a, b, d, and e) or NH-IgG (c and f) as described in the legend to Figure 2, and immunohistochemical analysis was performed on decidual tissue from day 8 of pregnancy. (a–c) Detection of C3 in day-8 deciduas from aPL-IgG– and NH-IgG–treated mice. The deciduas were stained with anti-mouse C3, the chromogen was DAB (brown), and the counterstain was hematoxylin. Decidua from C5+/+ mice (a) had extensive C3 deposition (arrows), inflammatory cell infiltrates, and necrotic fetal debris, whereas embryos from C5–/– mice (b) treated with aPL-IgG appeared normal, and there was limited C3 deposition in deciduas at the maternal-fetal interface compared with that of C5+/+ treated with NH-IgG (c). Original magnification was ×50. (d–f) Detection of human IgG in deciduas. Sections were stained with goat anti-human IgG, the chromogen was DAB (brown), and the counterstain was hematoxylin. Within 60 minutes of administering aPL-IgG, human IgG was detectable in deciduas from C5+/+ mice (d) and C5–/– mice (e), whereas no IgG was detected in deciduas from C5+/+ mice treated with NH-IgG (f). Data are representative of observations from three to six mice in each experimental group. Original magnification was ×200.