Opposite Profiles of Complement in Antiphospholipid Syndrome (APS) and Systemic Lupus Erythematosus (SLE) Among Patients With Antiphospholipid Antibodies (aPL)
Opposite Profiles of Complement in Antiphospholipid Syndrome (APS) and Systemic Lupus Erythematosus (SLE) Among Patients With Antiphospholipid Antibodies (aPL)
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DOI：
10.3389/fimmu.2019.00885
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发表时间：
2019-05-07
影响因子：
7.3
通讯作者：
Yu, Chack-Yung
中科院分区：
文献类型：
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作者：
Savelli, Stephanie L.;Roubey, Robert A. S.;Yu, Chack-Yung
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。SLE患者中，1 / 3有aPL， 10-15%有继发性APS的表现。动物实验表明，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aPL患者的补体蛋白和基因进行了横断面研究。其中血栓237例，SLE 293例；111例同时有SLE和血栓形成，106例既没有SLE也没有血栓形成。放射免疫扩散法检测补体蛋白C4、C3和因子H水平；甘露聚糖结合凝集素（MBL）的功能ELISA检测。采用TaqMan-based real - time PCR检测C4、C4A和C4B基因拷贝数（GCN）。在二倍体基因组中，C4基因通常有2到6个拷贝，每个拷贝可能编码酸性C4A或碱性C4B蛋白。我们观察到(a)血栓患者的总C4、C4A、C4B、C3和抗心磷脂（ACLA） IgG蛋白水平明显高于无血栓患者（N = 288）， (b)狼疮抗凝血剂和男性频率增加，(c)补体因子H、MBL和ACLA- igm水平降低。我们还观察到，合并SLE和血栓形成的apl阳性患者的总C4和C4A GCNs明显低于其他患者。相比之下，apl阳性SLE患者C3、总C4、C4A、C4B和ACLA-IgG蛋白水平明显降低，且女性出现的频率高于非SLE患者。血栓形成但无SLE患者（N = 126）和SLE但无血栓形成患者（N = 182）在C3 （p = 2.6 × 10(-6)）、C4 （p = 2.2 × 10(-9)）和ACLA-IgG （p = 1.2 × 10(-5)）平均蛋白水平上差异最大。女性患者RPL发生率为23.7%，血栓性SLE患者RPL发生率最高（41.0%,p = 3.8 × 10(-1)0）。与非RPL雌性相比，RPL的血栓形成频率显著增加，C4蛋白水平升高。纯合子C4A缺乏症的女性患者均出现RPL (p = 0.0001)，而纯合子C4B缺乏症的女性患者则相反（p = 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。
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 x 10(-6)), C4 (p = 2.2 x 10(-9)) and ACLA-IgG (p = 1.2 x 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 x 10(-1)0). 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.