Abstract
Antiphospholipid syndrome (APS) is a chronic and disabling condition characterized by recurrent thrombosis and miscarriages mediated by antibodies against phospholipid-binding proteins (aPL), such as beta2glycoprotein I (β2GPI). Complement is involved in APS animal models and complement deposits have been documented in placenta and thrombotic vessels despite normal serum levels. Analysis of circulating blood cells coated with C4d displays higher sensitivity than the conventional assays that measure soluble native complement components and their unstable activation products in systemic lupus erythematosus (SLE). As C4d-coated blood cell count has been reported to be more sensitive than serum levels of complement components and their activation products in systemic lupus erythematosus (SLE) patients, we decided to evaluate the percentage of C4d positive B lymphocytes (BC4d), erythrocytes (EC4d), and platelets (PC4d) in primary APS patients and asymptomatic aPL positive carriers as marker of complement activation in APS. We assessed by flow cytometry the percentages of BC4d, EC4d, and PC4d in primary APS (PAPS; n. 23), 8 asymptomatic aPL positive carriers, 11 APS-associated SLE (SAPS), 17 aPL positive SLE, 16 aPL negative SLE, 8 aPL negative patients with previous thrombosis, 11 immune thrombocytopenia (ITP) patients, and 26 healthy subjects. In addition, we used an in vitro model to evaluate the ability of a monoclonal anti-β2GPI antibody (MBB2) to bind to normal resting or activated platelets and fix complement. EC4d and PC4d percentages were significantly higher in PAPS and aPL carriers as well as aPL positive SLE and SAPS than in aPL negative controls. The highest values were found in PAPS and in SAPS. The EC4d and PC4d percentages were significantly correlated with serum C3/C4 and anti-β2GPI/anti-cardiolipin IgG. In vitro studies showed that MBB2 bound to activated platelets only and induced C4d deposition. The detection of the activation product C4d on circulating erythrocytes and platelets supports the role of complement activation in APS. Complement may represent a new therapeutic target for better treatment and prevention of disability of APS patients.
Highlights
Antiphospholipid syndrome (APS) is a chronic autoimmune disease characterized by recurrent thrombotic events and pregnancy morbidity, in the presence of antibodies targeting anti-phospholipid binding proteins [1]
C3 and C4 Serum Levels anti-phospholipid binding proteins (aPL) positive carriers and primary APS (PAPS) patients displayed lower serum levels of C3 and C4 than normal healthy subjects, albeit their values fell in the normal range (Table 1)
Higher percentages of both EC4d and PC4d were found in aPL positive systemic lupus erythematosus (SLE), SAPS and PAPS patients compared to normal healthy subjects (NHS), immune thrombocytopenia (ITP) patients, and aPL negative thrombotic patients; higher percentages of EC4d and PC4d were detected in aPL negative SLE and asymptomatic healthy aPL positive carriers (Figures 1A,B)
Summary
Antiphospholipid syndrome (APS) is a chronic autoimmune disease characterized by recurrent thrombotic events and pregnancy morbidity, in the presence of antibodies targeting anti-phospholipid binding proteins (aPL) [1]. APS can be found in patients with no evidence of associated diseases (primary APS, PAPS) or with other autoimmune disorders, mainly systemic lupus erythematosus (SLE) (SAPS) [1]. The major aPL antigenic target is β2-glycoprotein I (β2GPI), a phospholipid binding plasma protein of 50 kDa [2]. There is sound evidence from in vitro and in vivo models that β2GPI-dependent aPL play a pathogenic role both in thrombosis and pregnancy complications [3, 4]. Epidemiological data support a strong diagnostic/prognostic value of anti-D1 antibodies in APS patients [5]
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