Antiphospholipid Antibodyinduced Pregnancy Loss

The anti-phospholipid syndrome (APS) is characterized by recurrent fetal loss, vascular thrombosis and thrombocytopenia occurring in the presence of anti-phospholipid (aPL) antibodies. Pregnancy loss is a defining criterion for APS and occurs with particularly high frequency in systemic lupus erythematosus (SLE) patients bearing this antibody.

Over the last two decades, APS has emerged as a leading cause of pregnancy loss and pregnancy-related morbidity. It is now recognized that recurrent miscarriage occurs in 1% of couples (39-39), that up to 20% of women with recurrent miscarriage have aPL antibodies, and that in approximately 15% of otherwise apparently normal women aPL is the sole explanation for recurrent fetal loss (31, 40). The primary treatment for these patients, anticoagulation throughout pregnancy, is inconvenient, sometimes painful, expensive, and fraught with potential complications, including hemorrhage and osteoporosis. Moreover, it is often ineffective. Thus, the identification of a novel mechanism for pregnancy loss in women with aPL antibodies holds the promise of new, safer and better treatments.

The pathogenesis of fetal loss and tissue injury in APS is incompletely understood, but is thought to involve platelet and endothelial cell activation as well as the pro-coagulant effects of aPL antibodies acting directly on clotting pathway components. Recent experiments done in our laboratory are based on the hypothesis that aPL antibodies activate complement in the placenta, generating split products that mediate placental injury and lead to fetal loss and growth restriction. To test this hypothesis we used a murine model of APS in which pregnant mice were injected with human IgG containing aPL antibodies. Mice injected with aPL antibodies showed increased fetal resorption frequency. We found that inhibition of the complement cascade in vivo, using a soluble C3 convertase inhibitor, Crry-Ig, blocks fetal loss and growth restriction (7) (Figure 2).

Furthermore, mice deficient in complement C3 were resistant to fetal injury (pregnancy loss and fetal growth restriction) induced by aPL antibodies. To determine whether excessive complement activation occurs within the placenta in aPL-treated mice, we conducted immunohistological analyses of decidua on day 8 of pregnancy, after treatment with aPL-Ig or control IgG. In the aPL-treated mice, the decidua was abnormal morphologically, showing focal necrosis, apoptosis and PMN infiltrates. Extensive C3 deposition was noted. Treatment with Crry-Ig at the time of aPL-IgG administration completely prevented inflammation and C3 deposition. Thus, using three distinct approaches, specific complement inhibitor (Crry-Ig), genetically deficient mice (C3-/-), and immunohistochemical evidence that absence of C3 deposition in Crry-Ig treated mice correlates with improved outcomes, we demonstrated that complement activation is required for fetal loss and growth restriction in a murine model of APS.

Figure 2. Effects of Crry-Ig on aPL-induced fetal resorption Representative uteri from BALB/c mice sacrificed at day 15 of pregnancy are shown. The upper panel, from a mouse treated with aPL-containing IgG, shows 1 amnion sac and 5 resorptions (arrows). The lower panel, from a mouse treated with aPL and Crry-Ig, contains 4 amnion sacs and no resorptions.

Figure 2. Effects of Crry-Ig on aPL-induced fetal resorption Representative uteri from BALB/c mice sacrificed at day 15 of pregnancy are shown. The upper panel, from a mouse treated with aPL-containing IgG, shows 1 amnion sac and 5 resorptions (arrows). The lower panel, from a mouse treated with aPL and Crry-Ig, contains 4 amnion sacs and no resorptions.

We recently demonstrated that complement C5 activation is a central mechanism of pregnancy loss in APS. We identified complement component C5, and particularly its cleavage product, C5a, as well as neutrophils as key mediators of fetal loss. We also show that treatment with antibodies or peptides that block C5a-C5a receptor interactions prevented pregnancy complications. Mice deficient in C5aR were protected from aPL-induced pregnancy complications (41).

Although the cause of tissue injury in APS is likely to prove multifactoral, our studies show that activation of complement is a critical proximal effector in aPL-induced fetal injury and that this pathway acts upstream of other important effector mechanisms.

How To Win Your War Against Allergies

How To Win Your War Against Allergies

Not Able To Lead A Happy Life Because Of Excessive Allergies? Want To Badly Get Rid Of Your Allergy Problems, But Are Super Confused And Not Sure Where To Even Start? Don't Worry, Help Is Just Around The Corner Revealed The All-In-One Power Packed Manual Containing Ample Strategies And Little-Known Tips To Get Rid Of Any Allergy Problems That Are Ruining Your Life Learn How You Can Eliminate Allergies Completely Reclaim Your Life Once Again

Get My Free Ebook


Post a comment