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

Thromboembolism complicates disorders caused by 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 (FcgammaRIIa), yet 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 activity by IgG-ICs by THP-1 monocytic cells and human monocytes. Induction of factor Xa activity by ICs containing IgG antibodies to platelet factor 4 (PF4) involved in heparin-induced thrombocytopenia (HIT), b-2-glycoprotein-1 implicated in the antiphospholipid syndrome (APS), or red blood cells coated with anti-(alpha)-Rh(D) antibodies that mediate hemolysis in vivo were inhibited by a humanized monoclonal antibody (MoAb) that blocks IgG binding to human FcRn. IgG ICs that bind to FcgammaR and FcRn induced Factor Xa activity, whereas IgG-ICs with an Fc engineered to be unable to engage FcRn did not. Infusion of an alpha-FcRn MoAb prevented fibrin deposition following microvascular injury in a murine model of HIT in which human FcgRIIa is 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 anemic to lower IgG antibodies and IgG containing ICs may also reduce the risk of venous thromboembolism.