Figure 1.

Schematic diagram showing how side-chain differences may, or may not, lead to novel peptide-MHC surfaces. (A) If a tFVIII peptide spanning the location of the F8 missense mutation is a non-binder, it poses no risk of forming a novel pMHC surface capable of inducing an immune response. Otherwise, one needs to consider the position of the F8 missense mutation within the MHC groove of the tFVIII peptide and the corresponding endogenous peptide. For most HLA class II isoforms, positions 1,4 6 and 9 are MHC-facing, and positions 2, 3, 5, 7 and 8 are TCR-facing. Where the F8 missense mutation is at a downward, MHC-facing position (top row of A, denoted by a diamond), there are two scenarios: both tFVIII and endogenous peptides are binders, implying no risk; or the tFVIII peptide is a binder and the endogenous peptide is a non-binder, implying a potential risk. Where the F8 missense mutation is at an upward, TCR-facing position (bottom row of A, denoted by a diamond) and both peptides are binders, there is a potential risk. (B) Where a tFVIII peptide is associated with a potential risk according to the preceding assessment, a peptide from elsewhere in the human proteome that (i) has the same TCR-facing residues and (ii) is a binder, will militate against this risk, as no novel pMHC surface will be formed. FVIII: factor VIII; tFVIII: therapeutic factor VIII; TCR: T-cell receptor; MHC: major histocompatibility complex; pMHC: peptide-major histocompatibility complex.