Abstract
APS is the association of antiphospholipid antibodies (aPL) with thromboses and/or recurrent pregnancy loss (RPL). Among patients with SLE, one-third have aPL and 10–15% have a manifestation of secondary APS. Animal studies suggested that complement activation plays an important role in the pathogenesis of thrombosis and pregnancy loss in APS. We performed a cross-sectional study on complement proteins and genes in 525 patients with aPL. Among them, 237 experienced thromboses and 293 had SLE; 111 had both SLE and thromboses, and 106 had neither SLE nor thrombosis. Complement protein levels were determined by radial immunodiffusion for C4, C3 and factor H; and by functional ELISA for mannan binding lectin (MBL). Total C4, C4A and C4B gene copy numbers (GCN) were measured by TaqMan-based realtime PCR. Two to six copies of C4 genes are frequently present in a diploid genome, and each copy may code for an acidic C4A or a basic C4B protein. We observed significantly (a) higher protein levels of total C4, C4A, C4B, C3, and anticardiolipin (ACLA) IgG, (b) increased frequencies of lupus anticoagulant and males, and (c) decreased levels of complement factor H, MBL and ACLA-IgM among patients with thrombosis than those without thrombosis (N = 288). We also observed significantly lower GCNs of total C4 and C4A among aPL-positive patients with both SLE and thrombosis than others. By contrast, aPL-positive subjects with SLE had significantly reduced protein levels of C3, total C4, C4A, C4B and ACLA-IgG, and higher frequency of females than those without SLE. Patients with thrombosis but without SLE (N = 126), and patients with SLE but without thrombosis (N = 182) had the greatest differences in mean protein levels of C3 (p = 2.6 × 10−6), C4 (p = 2.2 × 10−9) and ACLA-IgG (p = 1.2 × 10−5). RPL occurred in 23.7% of female patients and thrombotic SLE patients had the highest frequency of RPL (41.0%; p = 3.8 × 10−10). Compared with non-RPL females, RPL had significantly higher frequency of thrombosis and elevated C4 protein levels. Female patients with homozygous C4A deficiency all experienced RPL (p = 0.0001) but the opposite was true for patients with homozygous C4B deficiency (p = 0.017). These results provide new insights and biomarkers for diagnosis and management of APS and SLE.
Highlights
Antiphospholipid syndrome (APS) is characterized by vascular thrombosis and/or pregnancy morbidity such as recurrent fetal loss in the persistent presence of antiphospholipid antibodies [1,2,3,4,5,6,7]. aPL are a heterogeneous group of autoantibodies that include antibodies against phospholipid binding protein β2-glycoprotein I (β2GPI), anticardiolipin antibodies (ACLA), and lupus anticoagulant (LAC) [8]
These study subjects were initially segregated into three groups: definite APS, extended APS, and non-APS based on clinical manifestations associated with APS, which included vascular thromboses and pregnancy morbidity
The greatest intergroup effect size indices are: C4, thrombosis only (To) vs. systemic lupus erythematosus (SLE) only (So): 0.709; C4B, To vs. So: 0.570; C4A, To vs. So: 0.566; ACLA-IgG, To vs. So: 0.554; complement factor H, thrombosis and SLE (TS) vs. no thrombosis and no SLE (NTS): 0.483; ACLA-IgM, To vs. NTS: 0.373; and mannan binding lectin (MBL), TS vs. So: 0.367. This is a cross-sectional study of complement protein profiles and copy number variations of C4 genes in a relatively large cohort of human subjects with aPL antibodies
Summary
Antiphospholipid syndrome (APS) is characterized by vascular thrombosis and/or pregnancy morbidity such as recurrent fetal loss in the persistent presence of antiphospholipid antibodies (aPL) [1,2,3,4,5,6,7]. aPL are a heterogeneous group of autoantibodies that include antibodies against phospholipid binding protein β2-glycoprotein I (β2GPI), anticardiolipin antibodies (ACLA), and lupus anticoagulant (LAC) [8]. Blockade of complement activation by genetic deletion of C3 or C4, or with transgenic insertion of complement regulatory protein Crry-Ig, a soluble inhibitor of mouse C3 convertase, protected mice, rats or hamsters from pregnancy complications induced by injections of human aPL [45, 47,48,49,50,51,52,53,54,55,56] These phenomena suggest that complement proteins or their activated products are engaged in the pathogenesis of APS, as they probably provide immune effectors for aPLmediated thromboses, tissue injury and/or fetal loss in mouse models. Systematic and meticulous studies on how complement proteins and genes contribute to the pathology of human APS (recurrent vascular thrombosis or pregnancy morbidity) and the concurrence of SLE and APS were scarce or limited by small sample size. When C4 was identified as a significant parameter in a model, we further asked whether C4A or C4B or both C4 isotypes were playing a major role
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