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. 2002 Nov;61(Suppl 2):ii46–ii50. doi: 10.1136/ard.61.suppl_2.ii46

Complement activation as a mediator of antiphospholipid antibody induced pregnancy loss and thrombosis

J Salmon, G Girardi, V Holers
PMCID: PMC1766708  PMID: 12379621

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Figure 1 .

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The complement cascade. *Indicates known biologically active complement fragments with the potential to influence the pathophysiology of disease.

Figure 2 .

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Inhibiton of C3 convertase ameliorates aPL-IgG induced pregnancy complications. Female BALB/c mice were treated ip with IgG (10 mg) from a patient with APS (aPL), normal human IgG (Cntrl IgG) or saline (Vehicle) on days 8 and 12 of pregnancy. Some of the mice received an inhibitor of C3 convertase, Crry-Ig (3 mg ip) every other day from days 8–12. Mice were killed on day 15 of pregnancy, uteri were dissected, fetuses were weighed, and frequency of fetal resorption calculated (number of resorptions/number of fetuses + number of resorptions). There were six mice in each group. (A) Treatment with aPL-IgG caused an increase in fetal resorptions compared with vehicle or control human IgG (*p<0.05), which was prevented by Crry-Ig (*aPL v aPL + Crry-Ig p<0.05). (B) aPL-IgG caused fetal growth retardation (*aPL v Cntrl IgG p<0.01), which was also prevented by Crry-Ig (*aPL v aPL + Crry-Ig p<0.01). Reproduced from the J Exp Med 2001;195:214 by copyright permission of The Rockefeller Press.

Figure 3 .

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C3 deficient mice are protected from aPL antibody induced pregnancy complications. C3+/+ mice (B6/Sv129F1) were treated with aPL-IgG (10 mg ip) (aPL) or normal human IgG (Cntrl IgG) on days 8 and 12 of pregnancy. Half of the mice in each group received Crry-Ig (3 mg ip) every other day from days 8–12 and half received control murine IgG (mIgG). C3-/- mice were treated with either aPL-IgG or normal human IgG. Pregnancy outcomes were assessed as described in the legend for fig 2. There were 10–14 mice in each experimental group. (A) Analysis of the four groups of C3+/+ mice shows that treatment with aPL-IgG caused an increase in frequency of fetal resorptions in this strain (*aPL + mIgG v Cntrl IgG + mIgG p<0.01), while C3-/- were protected from aPL induced pregnancy loss (aPL v Cntrl IgG p=NS). In the C3+/+ mice, Crry-Ig prevented aPL induced fetal resorption (*aPL + mIgG v aPL + Crry-Ig p<0.01). (B) Similarly, aPL treatment caused a decrease in fetal weight in C3+/+ mice (*aPL + mIgG v Cntrl IgG + mIgG p<0.01), which was absent in C3-/- mice, and this was ameliorated by Crry-Ig (*aPL + mIgG v aPL + Crry-Ig p<0.01). Reproduced from the J Exp Med 2001;195:216 by copyright permission of The Rockefeller Press.

Figure 4 .

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C3 activation is required for aPL induced thrombophilia. (A) aPL-IgG induced thrombophilia is inhibited by Crry-Ig. CD-1 mice were injected ip with affinity purified aPL-IgG (aPL) or normal human (Cntrl IgG) at 0 hours and 48 hours. Half the mice in each group received Crry-Ig, and half the mice received control murine IgG (mIgG). At 72 hours after the first injection, surgically induced thrombus formation was measured as described in the text. There were 11–14 mice in each experimental group. Treatment with aPL-IgG caused an increase in thrombus size (*aPL + mIgG v Cntrl IgG + mIgG p<0.05), while Crry-Ig prevented aPL induced enhancement of thrombosis (*aPL + mIgG v aPL + Crry-Ig p<0.05; Cntrl IgG + Crry-Ig v aPL + Crry-Ig, p=NS). In a separate series of experiments, aPL did not significantly increase thrombosis in C3-/- mice (aPL v control IgG 1524 (825) µm v 1083 (443), p=NS). There was no difference in the levels of human aPL activity between C3+/+ mice and C3-/- mice. Reproduced from the J Exp Med 2001;195:217 by copyright permission of The Rockefeller Press.

Figure 5 .

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Proposed mechanism for the pathogenic effects of aPL antibodies on pregnancy outcome. aPL antibodies are preferentially targeted to the placenta where they may promote platelet and endothelial cell activation and directly induce procoagulant activity through interaction with elements of the coagulation pathway. This activity, however, does not seem to be sufficient to cause fetal loss or growth restriction; C3-/- are protected. Activation of the complement pathway by aPL-IgG overwhelms the normally adequate inhibitory mechanisms and amplifies these effects by stimulating the generation of further potent mediators of effector cell activation, including C3a, C5a, and the C5b-9 MAC. The addition of these complement activation products causes thrombosis, tissue hypoxia, and inflammation within the placenta, and ultimately leads to fetal injury.

Selected References

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