| First Author | Cines DB | Year | 2020 |
| Journal | Blood | Volume | 135 |
| Issue | 23 | Pages | 2085-2093 |
| PubMed ID | 32187355 | Mgi Jnum | J:289655 |
| Mgi Id | MGI:6432429 | Doi | 10.1182/blood.2019001133 |
| Citation | Cines DB, et al. (2020) FcRn augments induction of tissue factor activity by IgG-containing immune complexes. Blood 135(23):2085-2093 |
| abstractText | 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 Fcgamma receptor IIa (FcgammaRIIa); 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 FcgammaR 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 FcgammaRIIa 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. |
