HLA-DRB1-factor VIII binding is a risk factor for inhibitor development in nonsevere hemophilia: a case-control study

Development of anti-factor VIII (FVIII) inhibitory antibodies (inhibitors) is the most significant treatment complication of hemophilia A. Characteristics of the interaction between major histocompatibility complex (MHC) class II and FVIII peptides may influence FVIII antigen presentation to T cells and subsequent inhibitor development. We analyzed predicted HLA-DRB1, a subset of MHC class II, and FVIII peptide binding and its association with inhibitor development among subjects with nonsevere hemophilia A, including 20 cases (inhibitor titer ≥ 1.0 BU/mL on 2 occasions or on 1 occasion with subsequent immune tolerance induction) and 37 controls (who had received FVIII infusions and did not develop inhibitor). Using the MHC-II Binding Predictions Tool (https://www.iedb.org), the binding affinity and core binding were determined for endogenous FVIII (eFVIII) and treatment FVIII (tFVIII). A tFVIII peptide was considered novel if it was predicted to bind and present a surface to the T-cell receptor that was unique from that presented by eFVIII. Having >10 novel HLA-DRB1 allele-tFVIII peptide combinations was associated with inhibitor development (adjusted odds ratio, 4.1; 95% confidence interval, 1.1-15.0). Cases and controls with p.Arg612Cys and p.Arg2169His demonstrated a high level of novel HLA-DRB1-tFVIII peptide combinations. Assessing the likelihood that tFVIII is presented to T cells in a novel fashion may be useful for understanding and ultimately reducing the risk for inhibitor development among patients with nonsevere hemophilia, particularly those with F8 mutations other than p.Arg612Cys and p.Arg2169His.