Antiphospholipid Antibodies to Domain I of Beta-2-Glycoprotein I Show Different Subclass Predominance in Comparison to Antibodies to Whole Beta-2-glycoprotein I.
Antiphospholipid Antibodies to Domain I of Beta-2-Glycoprotein I Show Different Subclass Predominance in Comparison to Antibodies to Whole Beta-2-glycoprotein I.
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DOI：
10.3389/fimmu.2018.02244
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发表时间：
2018
影响因子：
7.3
通讯作者：
Pericleous C
中科院分区：
文献类型：
--
作者：
McDonnell T;Artim-Esen B;Wincup C;Ripoll VM;Isenberg D;Giles IP;Rahman A;Pericleous C
抗磷脂抗体（aPL）是抗磷脂综合征（APS）的血清学标志，是一组针对循环血液蛋白的异质性自身抗体。在这些蛋白质中，磷脂结合β 2糖蛋白I（β2GPI）被认为是APS中的主要自身抗原。事实上，靶向b2 GPI（ab 2GPI）的IgG抗体在几种小鼠模型中直接引起血栓形成和妊娠发病率。虽然已经报道了针对b2 GPI的所有五个结构域产生的抗体，但是针对b2 GPI的第一结构域（DI）（aDI）产生的IgG ab 2GPI的亚组与血栓性APS强烈相关，并且在体内驱动血栓形成和妊娠丢失。很少有研究集中于确定aPL的IgG亚类的类型。抗体的亚类很重要，因为这决定了抗体的潜在活性;例如，与IgG 2和IgG 4相比，IgG 1和IgG 3可以更好地固定补体，并且能够穿过胎盘。目前尚不清楚IgG aDI是什么亚类，以及它们是否与ab 2GPI相同。为了确定ab 2GPI和aDI的IgG亚类分布，我们从19名具有已知ab 2GPI和aDI活性的APS患者的血清中纯化总IgG。使用亚类特异性结合抗体，我们修改了我们建立的内部ab 2GPI和aDI ELISA，以单独测量IgG 1、IgG 2、IgG 3和IgG 4。我们发现，虽然IgG 1、IgG 2和IgG 3 ab 2GPI水平相似，但在IgG亚类aDI水平中观察到显著差异。具体地，与IgG 1、IgG 2或IgG 4相比，检测到显著更高水平的IgG 3 aDI（对于所有比较，p < 0.05）。亚类特异性ab 2GPI与aDI的相关性分析表明，与IgG 1（r = 0.61，p = 0.0001）和IgG 2（r = 0.81，p = 0.0001）相比，IgG 3显示出最弱的相关性（r = 0.45，p = 0.0023）。重要的是，从APS和健康血清（n = 10 HC n = 12 APS）纯化的IgG中的总亚类水平没有差异，表明在APS衍生的IgG中观察到的增加的IgG 3 aDI信号是抗原特异性的。总之，我们的数据表明aDI显示出与ab 2GPI不同的IgG亚类分布。我们的研究结果强调了aDI检测对患者分层的重要性，并可能指向可能受亚类限制的差异性潜在aPL驱动的致病过程。
Antiphospholipid antibodies (aPL), the serological hallmark of antiphospholipid syndrome (APS), are a heterogeneous group of autoantibodies raised against circulating blood proteins. Of these proteins, the phospholipid-binding b2-glycoprotein I (β2GPI) is considered to be the main autoantigen in APS. Indeed, IgG antibodies targeting b2GPI (ab2GPI) directly cause both thrombosis and pregnancy morbidity in several mouse models. While antibodies raised against all five domains of b2GPI have been reported, a subgroup of IgG ab2GPI raised against the first domain (DI) of b2GPI (aDI), strongly correlate with thrombotic APS, and drive thrombosis and pregnancy loss in vivo. Few studies have focused on determining the type of IgG subclass(es) for aPL. The subclass of an antibody is important as this dictates the potential activity of an antibody; for example, IgG1 and IgG3 can fix complement better and are able to cross the placenta compared to IgG2 and IgG4. It is unknown what subclass IgG aDI are, and whether they are the same as ab2GPI. To determine IgG subclass distribution for ab2GPI and aDI, we purified total IgG from the serum of 19 APS patients with known ab2GPI and aDI activity. Using subclass-specific conjugated antibodies, we modified our established in-house ab2GPI and aDI ELISAs to individually measure IgG1, IgG2, IgG3, and IgG4. We found that while IgG1, IgG2, and IgG3 ab2GPI levels were similar, a marked difference was seen in IgG subclass aDI levels. Specifically, significantly higher levels of IgG3 aDI were detected compared to IgG1, IgG2, or IgG4 (p < 0.05 for all comparisons). Correlation analysis of subclass-specific ab2GPI vs. aDI demonstrated that IgG3 showed the weakest correlation (r = 0.45, p = 0.0023) compared to IgG1 (r = 0.61, p = 0.0001) and IgG2 (r = 0.81, p = 0.0001). Importantly, total subclass levels in IgG purified from APS and healthy serum (n = 10 HC n = 12 APS) did not differ, suggesting that the increased IgG3 aDI signal seen in APS-derived IgG is antigen-specific. To conclude, our data suggests that aDI show a different IgG subclass distribution to ab2GPI. Our results highlight the importance of aDI testing for patient stratification and may point toward differential underlying aPL-driven pathogenic processes that may be subclass restricted.
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影响因子：
9
作者：
Bourke LT;McDonnell T;McCormick J;Pericleous C;Ripoll VM;Giles I;Rahman A;Stephanou A;Ioannou Y
通讯作者：
Ioannou Y
影响因子：
--
作者：
通讯作者：
--
影响因子：
3.7
作者：
Mineo, Chieko;Lanier, Lane;Shaul, Philip W.
通讯作者：
Shaul, Philip W.
影响因子：
39.2
作者：
GINSBURG, KS;LIANG, MH;STAMPFER, MJ
通讯作者：
STAMPFER, MJ
影响因子：
5.5
作者：
Ravirajan, CT;Rowse, L;Isenberg, DA
通讯作者：
Isenberg, DA