Classical complement activation as a footprint for murine and human antiphospholipid antibody‐induced fetal loss

Abstract

Recurrent miscarriage, fetal growth restriction and intrauterine fetal death are frequently occurring complications of pregnancy in patients with systemic lupus erythaematosus (SLE) and antiphospholipid syndrome (APS). Murine models show that complement activation plays a pivotal role in antiphospholipid antibody-mediated pregnancy morbidity, but the exact pathways of complement activation and their potential role in human pregnancy are insufficiently understood. We hypothesized that the classical pathway would play a major role in inducing fetal loss. Pregnant C57BL/6 mice and mice deficient in C1q and factor D were injected with antiphospholipid antibodies or normal human IgG. Mouse placentas were subsequently stained with an anti-C4 antibody and anti-normal human IgG to determine the presence of classical complement activation and IgG binding. Findings in mice were validated in 88 human placentae from 83 women (SLE and APS cases versus controls), which were immunohistochemically stained for C4d, C1q, properdin and MBL. Staining patterns were compared to pregnancy outcome. In murine placentae of mice pretreated with antiphospholipid antibodies, increased C4 deposition was observed, which was associated with adverse fetal outcome but not with IgG binding. In humans, diffuse C4d staining at the feto-maternal interface was present almost exclusively in patients with SLE and/or APS (p < 0.001) and was related to intrauterine fetal death (p = 0.03). Our data show that presence of C4d in murine and human placentae is strongly related to adverse fetal outcome in the setting of SLE and APS. The excessive deposition of C4d supports the concept of severe autoantibody-mediated injury at the fetal-maternal interface. We suggest C4d as a potential biomarker of autoantibody-mediated fetal loss in SLE and APS.

Management of Women with Recurrent Pregnancy Losses and Antiphospholipid Antibody Syndrome

“…43,44 Recently, in a study of women with SLE and APS, it has been reported that classical complement activation plays a major role in aPL-mediated fetal injury and that placental C4d deposition is a reflection of classical complement activation in women with APS. 12 Similar pathological findings have been reported in endometrium of women with aPL. Although aPL have been reported to activate endothelial cells in vivo, and create a prothrombotic state on endothelial cells, 31 thrombotic occlusion or intimal thickening affecting endometrial blood vessels is not often detected by hematoxylin-eosin staining of specimens from women with aPL.…”

“…However, recent findings from APS research using animal models have demonstrated that APSinduced obstetrical complications are initiated by inflammation rather than thrombosis. [10][11][12] These studies suggest that anti-inflammatory treatment should be considered for APS management. This review will discuss the characteristics of aPL expression in women with RPL, the potential mechanisms of tissue injury by aPL, how heparin therapy might inhibit the pathogenic mediators of disease, and the management of obstetrical APS.…”

Genetic regulation of recurrent spontaneous abortion in humans

“…For instance, mouse models have provided a solid base of the importance of complement activation in successful pregnancies (C3 being a pivotal molecule), as well as its regulation by alias CR1L (complement component (3b/4b) receptor 1-like), sometimes in relation with autoimmune diseases. [40,[141][142][143][144][145] Therefore, while the topic of the present review was human disease, it is clear that much can be understood mechanistically using animal models, especially rodents.…”

The Important Roles of C4d in Systemic Lupus Erythematosus

“…There was evidence showing increased C4d deposition in the trophoblast cytoplasma, trophoblastic cell and basement membrane, and extracillous trophoblasts in patients with APAs compared to control patients [36]. Diffuse C4d staining at the feto-maternal interface was present almost exclusively in patients with SLE and/or APS and was related to intrauterine fetal death [37]. Dramatically increased immunohistochemistry staining of C-4d was statistically associated with low-placental weights and low birth weight in SLE patients [38].…”

“…Adverse events during pregnancy [35][36][37] Renal tissue Related to the presence of microthrombosis and histopathological classification of lupus nephritis [38,42] No relationship with disease activity, histological activity and chronicity of lupus nephritis [41,43,44] …”