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Factor VIII antibody immune complexes modulate the humoral response to factor VIII in an epitope-dependent manner

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Last modified
  • 06/25/2025
Type of Material
Authors
    Glaivy Batsuli, Emory UniversityJasmine Ito, Emory UniversityElizabeth S. York, Emory UniversityCourtney L. Cox, Emory UniversityWallace Baldwin, Emory UniversitySurinder Gill, Emory UniversityPete Lollar, Emory UniversityShannon Meeks, Emory University
Language
  • English
Date
  • 2023-08-31
Publisher
  • Frontiers
Publication Version
Copyright Statement
  • © 2023 Batsuli, Ito, York, Cox, Baldwin, Gill, Lollar and Meeks
License
Final Published Version (URL)
Title of Journal or Parent Work
Volume
  • 14
Start Page
  • 1233356
Grant/Funding Information
  • This research was supported by the Atlanta Pediatric Scholars Program K12 HD072245 (GB), 2016 Hemostasis and Thrombosis Research Society/Novo Nordisk Mentored Research Award in Hemophilia and Rare Bleeding Disorders from the Hemostasis and Thrombosis Research Society supported by an educational grant from Novo Nordisk Inc. (GB), the Hemophilia of Georgia Clinical Scientist Development Award (GB), NHLBI grant K99HL150595 (GB), NHLBI grant U54HL141981 (SM and PL), and Hemophilia of Georgia, Inc. (SM and PL).
Supplemental Material (URL)
Abstract
  • Introduction Soluble antigens complexed with immunoglobulin G (IgG) antibodies can induce robust adaptive immune responses in vitro and in animal models of disease. Factor VIII immune complexes (FVIII-ICs) have been detected in individuals with hemophilia A and severe von Willebrand disease following FVIII infusions. Yet, it is unclear if and how FVIII-ICs affect antibody development over time. Methods In this study, we analyzed internalization of FVIII complexed with epitope-mapped FVIII-specific IgG monoclonal antibodies (MAbs) by murine bone marrow-derived dendritic cells (BMDCs) in vitro and antibody development in hemophilia A (FVIII-/-) mice injected with FVIII-IC over time. Results FVIII complexed with 2-116 (A1 domain MAb), 2-113 (A3 domain MAb), and I55 (C2 domain MAb) significantly increased FVIII uptake by BMDC but only FVIII/2-116 enhanced antibody titers in FVIII-/- mice compared to FVIII alone. FVIII/4A4 (A2 domain MAb) showed similar FVIII uptake by BMDC to that of isolated FVIII yet significantly increased antibody titers when injected in FVIII-/- mice. Enhanced antibody responses observed with FVIII/2-116 and FVIII/4A4 complexes in vivo were abrogated in the absence of the FVIII carrier protein von Willebrand factor. Conclusion These findings suggest that a subset of FVIII-IC modulates the humoral response to FVIII in an epitope-dependent manner, which may provide insight into the antibody response observed in some patients with hemophilia A.
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Research Categories
  • Health Sciences, Immunology

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