However, tolerance could be broken (or not achieved in the first place) if I22-inv patients were infused with a FVIII protein containing an immunogenic sequence variation, e.g. due to one or more ‘foreign’ amino residues resulting from allelically ‘mismatched’ ns-SNPs in their F8 gene. Structural differences between endogenous and therapeutic FVIII proteins meet the first and minimal requirement for eliciting an immune response, but such differences may or may not be immunogenic in a given individual. Pexidartinib in vivo Differences in the immune system

from one person to another are also of critical importance. FVIII inhibitor responses are mediated by helper T cells [40]. Therefore, the limited collection of MHC genes (and alleles) in a given patient will determine

whether a particular ‘mismatched’ FVIII sequence can be presented by the restricted repertoire of MHC class II molecules on antigen-presenting cells (APCs). Additional genetic variations may influence events following antigen presentation, including avidity of interactions with T-cell receptors on responding T cells. These variations, plus the presence Fostamatinib cost or absence of ‘danger signals’– and the co-stimulatory interactions they induce between APCs and T cells – will influence the evolution of the immune response, e.g. along tolerogenic or immunogenic pathways [41]. CD4+ T-cell epitopes are linear stretches of at least 9 amino acid residues that bind to a specific groove on the surface of an MHC class II molecule. Foreign proteins (together with ‘self’ proteins co-internalized from

the vascular space or other extracellular compartments [Correction made after online publication 11 July 2011: Addition of text critical to article]) are broken down into peptides by enzymes in the MHC class II compartment of APCs. Although large numbers of peptide fragments are released, only about 2% of all the fragments generated have permissive structures – based on their amino acid side chain and backbone conformation – that allow them to interact strongly with the residues comprising the binding groove of a given MHC molecule. A critical determinant of ADAMTS5 immunogenicity for a T-cell epitope is the strength of its binding to one or more MHC molecules. As alluded to above, the development of an antibody response also requires a ‘danger signal’; in the case of infectious immunity this is provided by repetitive structural components of bacteria or viruses that are recognized by toll-like receptors as non-self and thus dangerous to self [41]. The nature of danger signals that may accompany intravenous infusions of FVIII and their role in inhibitor development is poorly understood and is a subject of current research. The MHC proteins, which in humans comprise the human leucocyte antigen (HLA) system, are extremely polymorphic [42].