Journal
BLOOD
Volume 135, Issue 23, Pages 2085-2093Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood.2019001133
Keywords
-
Categories
Funding
- 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
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available