Department of Pathology and Laboratory Medicine and.
Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
Blood. 2020 Jun 4;135(23):2085-2093. doi: 10.1182/blood.2019001133.
Thromboembolism complicates disorders caused by immunoglobulin G (IgG)-containing immune complexes (ICs), but the underlying mechanisms are incompletely understood. Prior evidence indicates that induction of tissue factor (TF) on monocytes, a pivotal step in the initiation, localization, and propagation of coagulation by ICs, is mediated through Fcγ receptor IIa (FcγRIIa); however, the involvement of other receptors has not been investigated in detail. The neonatal Fc receptor (FcRn) that mediates IgG and albumin recycling also participates in cellular responses to IgG-containing ICs. Here we asked whether FcRn is also involved in the induction of TF-dependent factor Xa (FXa) activity by IgG-containing ICs by THP-1 monocytic cells and human monocytes. Induction of FXa activity by ICs containing IgG antibodies to platelet factor 4 (PF4) involved in heparin-induced thrombocytopenia (HIT), β-2-glycoprotein-1 implicated in antiphospholipid syndrome, or red blood cells coated with anti-(α)-Rh(D) antibodies that mediate hemolysis in vivo was inhibited by a humanized monoclonal antibody (mAb) that blocks IgG binding to human FcRn. IgG-containing ICs that bind to FcγR and FcRn induced FXa activity, whereas IgG-containing ICs with an Fc engineered to be unable to engage FcRn did not. Infusion of an α-FcRn mAb prevented fibrin deposition after microvascular injury in a murine model of HIT in which human FcγRIIa was expressed as a transgene. These data implicate FcRn in TF-dependent FXa activity induced by soluble and cell-associated IgG-containing ICs. Antibodies to FcRn, now in clinical trials in warm autoimmune hemolytic anemia to lower IgG antibodies and IgG containing ICs may also reduce the risk of venous thromboembolism.
血栓栓塞症使免疫球蛋白 G（IgG）包含的免疫复合物（ICs）引起的疾病复杂化，但潜在机制尚不完全清楚。先前的证据表明，单核细胞组织因子（TF）的诱导，即 ICs 引发、定位和传播凝血的关键步骤，是通过 Fcγ 受体 IIa（FcγRIIa）介导的；然而，其他受体的参与尚未详细研究。介导 IgG 和白蛋白循环的新生儿 Fc 受体（FcRn）也参与了细胞对含 IgG 的 ICs 的反应。在这里，我们询问 FcRn 是否也参与了含 IgG 的 ICs 通过 THP-1 单核细胞和人单核细胞诱导 TF 依赖性因子 Xa（FXa）活性。血小板因子 4（PF4）的 IgG 抗体、抗磷脂综合征相关的β-2-糖蛋白-1 或与体内介导溶血的抗（α）-Rh（D）抗体包被的 RBC 引起的 FXa 活性的诱导被一种阻断 IgG 与人 FcRn 结合的人源化单克隆抗体（mAb）抑制。与 FcγR 和 FcRn 结合的含 IgG 的 ICs 诱导 FXa 活性，而工程改造为无法与 FcRn 结合的含 IgG 的 ICs 则没有。在转基因表达人 FcγRIIa 的肝素诱导的血小板减少症（HIT）小鼠模型中，输注α-FcRn mAb 可防止微血管损伤后纤维蛋白沉积。这些数据表明 FcRn 参与了可溶性和细胞相关的含 IgG 的 ICs 诱导的 TF 依赖性 FXa 活性。目前正在临床试验中用于治疗温自身免疫性溶血性贫血以降低 IgG 抗体和 IgG 包含的 ICs 的 FcRn 抗体也可能降低静脉血栓栓塞的风险。
