FcRn augments induction of tissue factor activity by ...

THROMBOSIS AND HEMOSTASIS| JUNE 4, 2020

FcRn augments induction of tissue factor activity by IgG-containing immune complexes

Douglas B. Cines, Sergei Zaitsev, Lubica Rauova, Ann H. Rux, Victoria Stepanova, Sriram Krishnaswamy, Amrita Sarkar, M. Anna Kowalska, Guohua Zhao, Alan E. Mast, Laurence J. Blumberg, Keith R. McCrae, Mortimer Poncz, Jonathan J. Hubbard, Michal Pyzik, Richard S. Blumberg

Blood (2020) 135 (23): 2085–2093.

https://doi.org/10.1182/blood.2019001133

Key PointsAbstract

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.

Subjects:

Immunobiology and Immunotherapy, Thrombosis and Hemostasis

Topics:

antibodies, antigen-antibody complex, ciliary motility disorders, immunoglobulin g, thromboplastin, fc receptors, warm antibody autoimmune hemolytic anemia, monoclonal antibodies

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