The Research Institute at Nationwide Children's Hospital, Columbus, OH, United States.
Division of Hematology/Oncology, Nationwide Children's Hospital, Columbus, OH, United States.
Front Immunol. 2019 May 7;10:885. doi: 10.3389/fimmu.2019.00885. eCollection 2019.
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 and gene copy numbers (GCN) were measured by TaqMan-based realtime PCR. Two to six copies of 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) 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 ( = 288). We also observed significantly GCNs of total and 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 SLE ( = 126), and patients with SLE but thrombosis ( = 182) had the greatest differences in mean protein levels of C3 ( = 2.6 × 10), C4 ( = 2.2 × 10) and ACLA-IgG ( = 1.2 × 10). RPL occurred in 23.7% of female patients and thrombotic SLE patients had the highest frequency of RPL (41.0%; = 3.8 × 10). Compared with non-RPL females, RPL had significantly higher frequency of thrombosis and elevated C4 protein levels. Female patients with homozygous C4A deficiency experienced RPL ( = 0.0001) but the opposite was true for patients with homozygous C4B deficiency ( = 0.017). These results provide new insights and biomarkers for diagnosis and management of APS and SLE.
APS 是抗磷脂抗体 (aPL) 与血栓形成和/或复发性妊娠丢失 (RPL) 的关联。在 SLE 患者中，有三分之一的患者存在 aPL，有 10-15%的患者表现为继发性 APS。动物研究表明，补体激活在 APS 血栓形成和妊娠丢失的发病机制中起重要作用。我们对 525 例有 aPL 的患者的补体蛋白和基因进行了横断面研究。其中，237 例发生血栓形成，293 例患有 SLE；111 例既有 SLE 又有血栓形成，106 例既没有 SLE 也没有血栓形成。通过放射免疫扩散法测定 C4、C3 和因子 H 的补体蛋白水平；通过甘露聚糖结合凝集素 (MBL) 的功能性 ELISA 测定。通过基于 TaqMan 的实时 PCR 测量总基因和基因拷贝数 (GCN)。二至六个拷贝的基因经常存在于二倍体基因组中，每个拷贝可能编码酸性 C4A 或碱性 C4B 蛋白。我们观察到（a）总 C4、C4A、C4B、C3 和抗心磷脂 (ACLA) IgG 的 C4 蛋白水平显著升高，（b）狼疮抗凝剂和男性的频率增加，以及（c）血栓形成患者的补体因子 H、MBL 和 ACLA-IgM 水平低于无血栓形成患者（=288）。我们还观察到，与其他患者相比，同时患有 SLE 和血栓形成的 aPL 阳性患者的总和基因的 GCN 显著增加。相比之下，SLE 患者的 aPL 阳性患者的 C3、总 C4、C4A、C4B 和 ACLA-IgG 的蛋白水平显著降低，女性频率高于无 SLE 的患者。患有血栓形成但无 SLE 的患者（=126），以及患有 SLE 但无血栓形成的患者（=182）的 C3（=2.6×10）、C4（=2.2×10）和 ACLA-IgG（=1.2×10）的平均蛋白水平差异最大。23.7%的女性患者发生 RPL，血栓性 SLE 患者的 RPL 频率最高（41.0%；=3.8×10）。与非 RPL 女性相比，RPL 患者的血栓形成频率更高，C4 蛋白水平升高。纯合性 C4A 缺乏的女性患者发生 RPL（=0.0001），但纯合性 C4B 缺乏的患者则相反（=0.017）。这些结果为 APS 和 SLE 的诊断和治疗提供了新的见解和生物标志物。
