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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 6

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Neutrophil depletion protects mice from aPL Ab–induced pregnancy complic...
Neutrophil depletion protects mice from aPL Ab–induced pregnancy complications and limits C3 deposition. BALB/c mice received anti-mouse granulocyte RB6-8C5 mAb (anti-Gr) (100 μg, intraperitoneally) or IgG2b isotype control mAb on day 7 of pregnancy. On days 8 and 12, mice were treated with aPL-IgG or NH-IgG (n = 5–11 mice/group). (a and b) Neutrophil depletion protected mice from (a) fetal resorption (*P < 0.01, aPL-IgG plus anti-Gr versus aPL-IgG plus IgG2b) and (b) growth restriction (*P < 0.01, aPL-IgG plus anti-Gr versus aPL-IgG plus IgG2b). (c and d) Histologic sections of deciduas from day 8 of pregnancy were stained with H&E. In deciduas from mice treated with anti-Gr plus aPL-IgG (c) there were intact embryos (E) and no inflammatory infiltrates, while in deciduas from mice treated with aPL-IgG plus IgG2b (d) there was extensive neutrophilic infiltration (stained with anti-Gr shown in e) surrounding embryonic debris (ED). Original magnification was ×400. (e) Immunohistochemistry to detect infiltrating granulocytes in decidua from an aPL-IgG plus IgG2b–treated mouse. Original magnification was ×1,000. (f and g) Immunohistochemistry for C3 deposition in decidual tissue. Staining for C3 (arrows) was less intense and limited to the fetal-maternal interface in deciduas from mice that had received anti-Gr before treatment with aPL-IgG (f), compared with that of mice treated with aPL-IgG plus IgG2b (g). In the presence of infiltrating neutrophils, C3 deposits were present throughout decidual tissue (g), with particularly intense staining at the fetal-maternal interface surrounding the necrotic residual embryonic debris (arrows). Original magnification was 0400.

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

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