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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 Article has an altmetric score of 9

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

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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 7

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The absence of fB protects mice from aPL Ab–induced fetal loss and exten...
The absence of fB protects mice from aPL Ab–induced fetal loss and extensive C3 deposition within deciduas. fB+/+ and fB–/– mice were treated with aPL-IgG (10 mg, intraperitoneally) or NH-IgG (10 mg, intraperitoneally) on days 8 and 12 of pregnancy. Fetal resorption frequencies and fetal weights were determined on day 15 of pregnancy (n = 4–8 mice/group). (a and b) In contrast to fB+/+ mice, those deficient in fB were protected from fetal resorption (*P < 0.05, fB+/+ aPL-IgG versus NH-IgG) and growth restriction (P < 0.001, fB+/+ aPL-IgG versus NH-IgG). (c–e) Immunohistochemistry for C3 deposition in decidual tissue from day 8 of pregnancy following aPL-IgG administration. In deciduas from fB+/+ mice treated with NH-IgG (c), there was minimal C3 deposition and an intact embryo (E). In fB+/+ mice treated with aPL-IgG (d), C3 deposits were present throughout decidual tissue surrounding the necrotic residual embryonic debris (arrows). In contrast, in fB–/– mice treated with aPL-IgG (e), C3 deposition was limited (arrows) and the embryos remained intact (E). (f) Detection of C3 by Western blotting. Lysates from deciduas of fB+/+ mice and fB–/– mice were resolved by electrophoresis and blotted with anti-murine C3 Ab. C3 deposition was greater in deciduas from aPL-IgG–treated fB+/+ mice than in fB–/– mice, as evidenced by the presence of the cleaved C3-α′ chain.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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