Fc Gamma Receptors and Complement Component 3 Facilitate Anti-fVIII Antibody Formation.

ABSTRACT: Anti-factor VIII (fVIII) alloantibodies, which can develop in patients with hemophilia A, limit the therapeutic options and increase morbidity and mortality of these patients. However, the factors that influence anti-fVIII antibody development remain incompletely understood. Recent studies suggest that Fc gamma receptors (Fc?Rs) may facilitate recognition and uptake of fVIII by recently developed or pre-existing naturally occurring anti-fVIII antibodies, providing a mechanism whereby the immune system may recognize fVIII following infusion. However, the role of Fc?Rs in anti-fVIII antibody formation remains unknown. In order to define the influence of Fc?Rs on the development of anti-fVIII antibodies, fVIII was injected into WT or Fc?R knockout recipients, followed by evaluation of anti-fVIII antibodies. Anti-fVIII antibodies were readily observed following fVIII injection into Fc?R knockouts, with similar anti-fVIII antibody levels occurring in Fc?R knockouts as detected in WT mice injected in parallel. As antibodies can also fix complement, providing a potential mechanism whereby anti-fVIII antibodies may influence anti-fVIII antibody formation independent of Fc?Rs, fVIII was also injected into complement component 3 (C3) knockout recipients in parallel. Similar to Fc?R knockouts, C3 knockout recipients developed a robust response to fVIII, which was likewise similar to that observed in WT recipients. As Fc?Rs or C3 may compensate for each other in recipients only deficient in Fc?Rs or C3 alone, we generated mice deficient in both Fc?Rs and C3 to test for potential antibody effector redundancy in anti-fVIII antibody formation. Infusion of fVIII into Fc?Rs and C3 (Fc?R × C3) double knockouts likewise induced anti-fVIII antibodies. However, unlike individual knockouts, anti-fVIII antibodies in Fc?Rs × C3 knockouts were initially lower than WT recipients, although anti-fVIII antibodies increased to WT levels following additional fVIII exposure. In contrast, infusion of RBCs expressing distinct alloantigens into Fc?Rs, C3 or Fc?R × C3 knockout recipients either failed to change anti-RBC levels when compared to WT recipients or actually increased antibody responses, depending on the target antigen. Taken together, these results suggest Fc?Rs and C3 can differentially impact antibody formation following exposure to distinct alloantigens and that Fc?Rs and C3 work in concert to facilitate early anti-fVIII antibody formation.

SUBMITTER: Zerra PE 

PROVIDER: S-EPMC7295897 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature