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

Abstract

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.

FcRn is a CD32a coreceptor that determines susceptibility to IgG immune complex–driven autoimmunity

“…In summary, we show that CD32a and FcRn directly cooperate through formation of a ternary complex on an IgG Fc scaffold under acidic conditions, as occurs in intracellular organelles ( Baker et al, 2011 ). This ternary complex formation could impact a wide range of FcγR-mediated processes, including IgG IC induction of thrombosis, which has been previously recognized as a FcγRIIa-mediated process that is regulated by and dependent upon FcRn ( Cines et al, 2020 ). Furthermore, we demonstrate that FcRn can independently execute adaptive cellular immune responses to IgG ICs when FcRn can engage IgG on the cell surface, but that the presence of an FcγR coreceptor for IgG ICs significantly augments these responses.…”

Neonatal Fc receptor in human immunity: Function and role in therapeutic intervention

“…Two recent studies have proposed a potential further role for FcRn, demonstrating that circulating IgG-ICs may bind to FcRn in conjunction with FcgRIIa (CD32a) on the cell surface and may have a role in tissue factor expression. 27,28 This may be important for induction of thrombosis and could clinically be relevant for autoimmune conditions such as warm autoimmune hemolytic anemia and antiphospholipid syndrome, both of which are not only antibody-mediated but highly prothrombotic.…”

Structural Features and PF4 Functions that Occur in Heparin-Induced Thrombocytopenia (HIT) Complicated by COVID-19

“…TF is the high-affinity receptor and cofactor for Factor VII/VIIa (FVII/F VIIa), and the TF-FVIIa complex is the primary initiator of blood coagulation cascade that generates coagulation proteases, such as FXa, and thrombin [ 50 ]. Although the FcγRIIA on monocytes is critical for the HIT immune complexes to bind monocytes [ 51 ], Cines and colleagues have recently pointed out that FcRn, which is commonly involved in the recycling of IgGs, augments the induction of TF activity by the HIT immune complexes [ 52 ].…”