Elie York

All Publications

• Persistent Splenic-Derived IgM Preferentially Recognize Factor VIIIA2 and C2 Domain Epitopes but Do Not Alter Antibody Production. Journal of thrombosis and haemostasis : JTH York, E. S., Dratch, B. D., Ito, J., Horwitz, S. M., Emamian, S., Ambarian, J. A., Gill, S., Jones, J., Chonat, S., Lollar, P., Meeks, S. L., Davis, K. M., Batsuli, G. 2024

  Abstract

  The most significant treatment complication for patients with hemophilia A is the development of neutralizing immunoglobin G (IgG), termed inhibitors, against factor VIII (FVIII) which prevent FVIII replacement therapy. Low titers of FVIII-specific immunoglobin M (IgM) have been identified in hemophilia A patients with and without inhibitors, as well as healthy individuals. However, the duration and influence of IgM on the immune response to FVIII remains unclear.To characterize the binding interactions of persistently secreted FVIII-specific IgM in hemophilia A mice and assess their effect on IgG antibody development.Splenic-derived monoclonal antibodies (MAbs) from immunized FVIII knockout mice were isolated and purified using hybridoma technology. Binding interactions were assessed utilizing a novel fluid-phase ELISA and computational modeling with HADDOCK to account for weak IgM binding.Sixteen porcine cross-reactive and non-inhibitory FVIII-specific IgM MAbs were identified. RNA sequencing of FVIII-specific IgM revealed 13 unique VDJ/VJ sequences indicating derivation from 13 unique B cell clones. IgM demonstrated polyclonal and polyreactive binding to FVIII in vitro and in silico. Molecular docking studies with reconstructed IgM VDJ/VJ regions identified frequent IgM interactions with amino acid residues K376, T381, K437, R2215 or K2249 within the FVIII A2 and C2 domains. Injections of individual IgM prior to FVIII exposure and co-injection of FVIII/IgM immune complexes did not affect de novo FVIII antibody production.Persistent FVIII-specific IgM are polyclonal but preferentially bind the A2 and C2 domains and FVIII/IgM immune complex formation do not significantly alter inhibitor development.

  View details for DOI 10.1016/j.jtha.2024.10.017

  View details for PubMedID 39476969

• Investigating persistent factor VIII-specific IgM in the humoral immune response to factor VIII York, E. S., Ito, J., Batsuli, G. AMER ASSOC IMMUNOLOGISTS. 2023

  View details for Web of Science ID 001106506502443

• Factor VIII antibody immune complexes modulate the humoral response to factor VIII in an epitope-dependent manner. Frontiers in immunology Batsuli, G., Ito, J., York, E. S., Cox, C., Baldwin, W., Gill, S., Lollar, P., Meeks, S. L. 2023; 14: 1233356

  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.

  View details for DOI 10.3389/fimmu.2023.1233356

  View details for PubMedID 37720212