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Fc Gamma Receptors and Complement Component 3 Facilitate Anti-fVIII Antibody Formation.
Zerra, Patricia E; Arthur, Connie M; Chonat, Satheesh; Maier, Cheryl L; Mener, Amanda; Shin, Sooncheon; Allen, Jerry William L; Baldwin, W Hunter; Cox, Courtney; Verkerke, Hans; Jajosky, Ryan P; Tormey, Christopher A; Meeks, Shannon L; Stowell, Sean R.
Afiliación
  • Zerra PE; Department of Pathology and Laboratory Medicine, Center for Transfusion Medicine and Cellular Therapies, Emory University School of Medicine, Atlanta, GA, United States.
  • Arthur CM; Aflac Cancer and Blood Disorders Center at Children's Healthcare of Atlanta and Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, United States.
  • Chonat S; Department of Pathology and Laboratory Medicine, Center for Transfusion Medicine and Cellular Therapies, Emory University School of Medicine, Atlanta, GA, United States.
  • Maier CL; Aflac Cancer and Blood Disorders Center at Children's Healthcare of Atlanta and Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, United States.
  • Mener A; Department of Pathology and Laboratory Medicine, Center for Transfusion Medicine and Cellular Therapies, Emory University School of Medicine, Atlanta, GA, United States.
  • Shin S; Department of Pathology and Laboratory Medicine, Center for Transfusion Medicine and Cellular Therapies, Emory University School of Medicine, Atlanta, GA, United States.
  • Allen JWL; Department of Pathology and Laboratory Medicine, Center for Transfusion Medicine and Cellular Therapies, Emory University School of Medicine, Atlanta, GA, United States.
  • Baldwin WH; Department of Pathology and Laboratory Medicine, Center for Transfusion Medicine and Cellular Therapies, Emory University School of Medicine, Atlanta, GA, United States.
  • Cox C; Aflac Cancer and Blood Disorders Center at Children's Healthcare of Atlanta and Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, United States.
  • Verkerke H; Aflac Cancer and Blood Disorders Center at Children's Healthcare of Atlanta and Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, United States.
  • Jajosky RP; Department of Pathology and Laboratory Medicine, Center for Transfusion Medicine and Cellular Therapies, Emory University School of Medicine, Atlanta, GA, United States.
  • Tormey CA; Department of Pathology and Laboratory Medicine, Center for Transfusion Medicine and Cellular Therapies, Emory University School of Medicine, Atlanta, GA, United States.
  • Meeks SL; Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT, United States.
  • Stowell SR; Pathology and Laboratory Medicine Service, VA Conneciticut Healthcare System, West Haven, CT, United States.
Front Immunol ; 11: 905, 2020.
Article en En | MEDLINE | ID: mdl-32582142
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 (FcγRs) 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 FcγRs in anti-fVIII antibody formation remains unknown. In order to define the influence of FcγRs on the development of anti-fVIII antibodies, fVIII was injected into WT or FcγR knockout recipients, followed by evaluation of anti-fVIII antibodies. Anti-fVIII antibodies were readily observed following fVIII injection into FcγR knockouts, with similar anti-fVIII antibody levels occurring in FcγR 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 FcγRs, fVIII was also injected into complement component 3 (C3) knockout recipients in parallel. Similar to FcγR knockouts, C3 knockout recipients developed a robust response to fVIII, which was likewise similar to that observed in WT recipients. As FcγRs or C3 may compensate for each other in recipients only deficient in FcγRs or C3 alone, we generated mice deficient in both FcγRs and C3 to test for potential antibody effector redundancy in anti-fVIII antibody formation. Infusion of fVIII into FcγRs and C3 (FcγR × C3) double knockouts likewise induced anti-fVIII antibodies. However, unlike individual knockouts, anti-fVIII antibodies in FcγRs × 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 FcγRs, C3 or FcγR × 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 FcγRs and C3 can differentially impact antibody formation following exposure to distinct alloantigens and that FcγRs and C3 work in concert to facilitate early anti-fVIII antibody formation.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Complemento C3 / Factor VIII / Receptores de IgG / Hemofilia A / Isoanticuerpos / Isoantígenos Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Front Immunol Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Complemento C3 / Factor VIII / Receptores de IgG / Hemofilia A / Isoanticuerpos / Isoantígenos Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Front Immunol Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos