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 1

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Activating FcγRs are not required for aPL Ab–mediated pregnancy loss. Pr...
Activating FcγRs are not required for aPL Ab–mediated pregnancy loss. Pregnant FcRγ+/+ and FcRγ–/– mice were treated with IgG from a healthy non-autoimmune individual (NH-IgG), three different patients with APS (aPL-IgG1, aPL-IgG2, aPL-IgG3), F(ab)′2 fragments from a pool of aPL-IgG from patients 2 and 3 [aPL-F(ab)′2], or human monoclonal aPL Ab (aPL mAb) on days 8 and 12 of pregnancy. Mice were sacrificed on day 15 of pregnancy, fetuses were weighed, and frequency of fetal resorption calculated (n = 4–7 mice/group). (a) Treatment with all intact aPL-IgG preparations and aPL mAb caused an increase in fetal resorptions in FcRγ+/+. *P < 0.05 versus NH-IgG, Student’s t test. Administration of aPL-F(ab)′2 did not affect pregnancy outcome. FcRγ–/– mice were not protected from fetal loss induced by intact aPL-IgG. *P < 0.05 versus NH-IgG, Student’s t test). In surviving fetuses from FcRγ–/– mice there was 36% decrease in weight. (b–e) Immunohistochemical analysis of decidual tissue from day 8 of pregnancy. Sections were stained with goat anti-human IgG, the chromogen was DAB (brown), and the counterstain was hematoxylin. Human IgG was deposited in deciduas from FcRγ+/+ mice within 60 minutes of administration of aPL-IgG (b) or aPL-F(ab)′2 (c), whereas no IgG was detected in deciduas from FcRγ+/+ mice treated with NH-IgG (d). Deposition of human IgG was similar after treatment with aPL-IgG in FcRγ–/– (e) and FcRγ+/+ mice (b). Data are representative of observations from three to six decidua from mice in each experimental group. Original magnification was ×200.