期刊
BLOOD
卷 135, 期 23, 页码 2085-2093出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood.2019001133
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资金
- National Institutes of Health (NIH) National Heart, Lung, and Blood Institute [ROHL142122, R01 HL139448, R01 HL128895, R01 HL141462, R01 HL068835, R01 HL125422, P01 HL139420, R01 HL123098]
- NIH National Institute of Diabetes and Digestive and Kidney Diseases [R01 DK053056]
- Syntimmune/Alexion
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 Fc gamma receptor IIa (Fc gamma RIIa); 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), beta-2-glycoprotein-1 implicated in antiphospholipid syndrome, or red blood cells coated with anti-(alpha)-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 Fc gamma R and FcRn induced FXa activity, whereas IgG-containing ICs with an Fc engineered to be unable to engage FcRn did not. Infusion of an alpha-FcRn mAb prevented fibrin deposition after microvascular injury in a murine model of HIT in which human Fc gamma RIIa 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.
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