Absence of Distinct Immunohistochemical Distribution of Annexin A5, C3b, C4d, and C5b-9 in Placentas From Patients With Antiphospholipid Antibodies, Preeclampsia, and Systemic Lupus Erythematosus

Abstract

Introduction In pregnancy, the presence of preeclampsia (PEC), systemic lupus erythematosus (SLE), and/or antiphospholipid antibody syndrome (APLS) is characterized by poor obstetric outcomes, with potential adverse effects for both mother and fetus. Although the histopathologic changes observed in these entities have been well established, the pathogenic mediators associated with tissue injury are poorly understood. Methods Forty placentas were evaluated, including 10 patients with preeclampsia, 9 with SLE, 11 with APLS, and 10 disease-free controls. Each case was subjected to a panel of immunohistochemical markers including C3b, C4d, Annexin A5, and C5b-9. Staining was graded on intensity and distribution. Results C4d staining was distinctly different among disease groups and controls. Moreover, 6/10 PEC cases, 3/9 SLE cases, and 4/11 APLS cases showed at least focal staining for C4d. All controls were negative. Annexin A5 (AnxA5) staining showed intrinsic variability in all disease groups, while 10/10 controls showed diffuse, strong staining (2+ or 3+). C3b staining was heterogeneous among groups. Discussion Previously, antiphospholipid antibody (aPLA)-associated pregnancy complications have been thought to be a consequence of a unique aPLA-mediated pathogenic mechanism. However, the immunohistochemical similarity (increased complement and decreased AnxA5 staining) observed in placentas from patients with APLS, PEC, and SLE suggests that aPLA-associated pregnancy complications may reflect a more general autoimmune mechanism.

The Complement System in the Pathophysiology of Pregnancy and in Systemic Autoimmune Rheumatic Diseases During Pregnancy

“…In the PROMISSE cohort, these markers of C activation (Bb and SC5b-9) were detected in the circulation in early gestation among those SLE/aPL + women who later developed pregnancy complications (53). Analysis of placentae from aPL-negative SLE patients by Matrai and colleagues revealed signs of tissue malperfusion, infarction and intervillous thrombi and increased deposits of C4d and C5b-9 on syncytiotrophoblasts and extravillous trophoblasts compared to controls (56). The extent of C4d deposition was found to be inversely correlated with low placental and birth weight (91).…”

“…More convincing evidence supporting the role of C in inducing aPLdependent placental damage and pregnancy failure has been obtained from the immunohistochemical analysis of placental tissue for C deposits. The presence of C4d in placentae from APS women has been documented at the fetal-maternal interface, in particular on syncytiotrophoblast basement membrane, and to some extent also on extravillous trophoblasts of the basal plate by three groups (55)(56)(57). C4 deposits were found to be associated with intrauterine fetal death (55) and placental abnormalities including decidual vasculopathy, increased syncytial knots, and villous infarcts (57).…”

“…C4 deposits were found to be associated with intrauterine fetal death (55) and placental abnormalities including decidual vasculopathy, increased syncytial knots, and villous infarcts (57). Two groups have documented deposits of C5b-9 mainly localized on extravillous trophoblasts of placentae from aPL-positive women and observed no difference in the staining intensity between APS and control groups (56,57). These findings are in contrast with the data obtained by Scambi et al who reported higher levels of C5b-9 solubilized from APS placentae compared to controls, in particular in APS patients who experienced a pregnancy complication (54).…”

Low Preconception Complement Levels Are Associated with Adverse Pregnancy Outcomes in a Multicenter Study of 260 Pregnancies in 197 Women with Antiphospholipid Syndrome or Carriers of Antiphospholipid Antibodies

“…If animal models have clearly shown that activation of complement is required to produce aPL-mediated pregnancy loss and inflammation and complement deposition at trophoblast and placental level was described [10], histopathological data from human disease are not consistent. In fact, human placenta analysis does not unanimously show complement deposition, and inflammation (chorioamnionitisis or villitis) does not seem always associated with aPL-mediated pregnancy loss [24,25].…”

Design, Preparation, and Bioactivity Study of New Fusion Protein HB-NC4 in the Treatment of Osteoarthritis

“…Complement activation final product, membrane attack complex (MAC,, can form on the cell and directly cause the chondrocyte death by osmotic flux (Heinen et al, 2009). Also, MAC can promote the production of matrix metalloproteinases (MMPs) and cyclooxygenase which induces the formation of OA (Matrai et al, 2019). Therefore, how to block the complement activation, especially MAC, will become a potential strategy for OA treatment (Evans, 2005;Fortier et al, 2011).…”