Effects of polyclonal IgG derived from patients with different clinical types of the antiphospholipid syndrome on monocyte signaling pathways.
Effects of polyclonal IgG derived from patients with different clinical types of the antiphospholipid syndrome on monocyte signaling pathways.
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DOI：
10.4049/jimmunol.0902765
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发表时间：
2010-06-15
期刊：
影响因子：
--
通讯作者：
Giles IP
中科院分区：
文献类型：
--
作者：
Lambrianides A;Carroll CJ;Pierangeli SS;Pericleous C;Branch W;Rice J;Latchman DS;Townsend P;Isenberg DA;Rahman A;Giles IP
抗磷脂抗体（aPL）通过激活Toll样受体（TLR）、p38丝裂原活化蛋白激酶（MAPK）和核因子（NF）κB通路，介导单核细胞上组织因子（TF）的上调，是抗磷脂综合征（APS）高凝状态的主要机制。我们研究了是否单核细胞信号转导通路的差异激活IgG从血管血栓形成（VT）患者单独与IgG从妊娠发病率（PM）患者单独相比。我们从49名受试者中纯化了IgG。用100μg/ml IgG处理人单核细胞细胞系和离体健康单核细胞6小时，并使用针对p38 MAPK和NFκB的抗体通过免疫印迹检查细胞提取物。为了进一步研究这些IgG诱导的细胞内信号传导途径，使用p38 MAPK、NFκB、TLR 4和TLR 2的特异性抑制剂来确定它们对TF活性的影响。只有VT患者的IgG而非PM（VT+/PM-）引起单核细胞NFκB、p38 MAPK磷酸化和TF活性上调。这些效应在来自单独PM患者（VT-/PM+）、无APS的aPL阳性患者或健康对照的IgG中未观察到。由VT+/PM−样品引起的TF上调被p38 MAPK、NFkB和TLR 4的抑制剂降低。VT+/PM− IgG对信号传导和TF上调的影响集中在结合B-2-糖蛋白I的部分。我们的研究结果表明，不同临床表现的APS患者的IgG对NF κ B磷酸化、p38 MAPK和TF活性具有不同的影响，这可能是由TLR 4的差异活化介导的。
A major mechanism of hypercoagulability in the antiphospholipid syndrome (APS) is antiphospholipid antibody (aPL)-mediated up-regulation of tissue factor (TF) on monocytes via activation of toll-like receptors (TLR), p38 mitogen activated protein kinase (MAPK) and nuclear factor (NF) κB pathways. We examined whether monocyte signalling pathways are differentially activated by IgG from patients with vascular thrombosis (VT) alone compared with IgG from patients with pregnancy morbidity (PM) alone. We purified IgG from 49 subjects. A human monocyte cell line and ex vivo healthy monocytes were treated with 100μg/ml IgG for 6 hours and cell extracts examined by immunoblot using antibodies to p38MAPK and NFκB. To further investigate intracellular signalling pathways induced by these IgG, specific inhibitors of p38MAPK, NFκB, TLR4 and TLR2 were used to determine their effect on TF activity. Only IgG from patients with VT but no PM (VT+/PM−) caused phosphorylation of NFκB, p38MAPK and up-regulation of TF activity in monocytes. These effects were not seen with IgG from patients with PM alone (VT−/PM+), aPL-positive patients without APS or healthy controls. TF up-regulation caused by the VT+/PM− samples was reduced by inhibitors of p38MAPK, NFkB, and TLR4. The effects of VT+/PM− IgG on signalling and TF up-regulation were concentrated in the fraction that bound b-2-glycoprotein I. Our findings demonstrate that IgG from patients with diverse clinical manifestations of APS have differential effects upon phosphorylation of NFkB, p38MAPK and TF activity which may be mediated by differential activation of TLR4.
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影响因子：
5.9
作者：
Schulman, S;Svenungsson, E;Granqvist, S
通讯作者：
Granqvist, S
影响因子：
--
作者：
Cervera, R;Piette, JC;Ingelmo, M
通讯作者：
Ingelmo, M
影响因子：
--
作者：
Cuadrado, MJ;LopezPedrera, C;Velasco, F
通讯作者：
Velasco, F
影响因子：
37.8
作者：
Pierangeli, SS;Colden-Stanfield, M;Harris, EN
通讯作者：
Harris, EN
影响因子：
--
作者：
López-Pedrera, C;Buendía, P;Velasco, F
通讯作者：
Velasco, F