In the earliest reports in the 1990s, large deletions, nonsense mutations and inversions were defined

as high-risk mutations, as the highest percentages of inhibitor patients were observed in these subgroups [8, 9]. The risk is not, however, consistent among patients with these mutations as has been observed in family studies in which high rates of discordance have MK1775 been found between siblings with the same mutation [10, 11]. In a recent meta-analysis by Gouw et al., the inhibitor risks in patients with large deletions and nonsense mutations were higher than in patients with intron 22 inversions (pooled OR = 3.6, 95% confidence interval [95% CI], 2.3–5.7 and OR = 1.4, 95% CI, 1.1–1.8, respectively) confirming the relatively high risk for inhibitors associated with these mutation types [12]. However, a high frequency of inhibitors has also been reported

for other mutations. The current view is that, besides these null mutations, small deletions/insertions outside A-runs, splice-site mutation at conserved nucleotides at position 1/2, and certain missense mutations, e.g. Arg593>Cys, Tyr2105>Cys, Arg2150>His, Arg2163>His, selleck inhibitor Trp2229>Cys and Pro2300>Leu, will also confer a relatively high inhibitor risk [13]. The question can also be raised as to whether a cross-reactive material-negative mutation with no circulating antigen, such as the intron 22 inversion, which only causes inhibitors in 20% of patients, really should be classified as a high-risk mutation or rather a protective mutation instead. Further light on this was recently provided by Pandey et al. who described that endogenous FVIII synthesis from Casein kinase 1 the inverted F8 locus may modulate the immune response [14]. They actually found that the levels of F8 mRNA and intracellular FVIII in subjects with intron 22 inversions were similar to those of healthy subjects. They therefore suggested that most patients with intron 22 inversions were, in fact,

tolerized against FVIII, which could explain the inhibitor rate of only 20%. The importance of the HLA class II molecules is easily appreciated when considering that these molecules will determine the peptides to be presented to the T-helper cells [15]. If only peptides with sequences previously recognized by the immune system and not able to elicit an immune response are presented, then an immune reaction against the infused factor will not occur (Fig. 2). However, if this is not the case and immunogenic peptides with foreign sequences are presented, then the reaction can take place. Whether the final outcome of this will be inhibitory antibodies produced by the plasma cells or not will then depend on the levels of a variety of immune-regulatory elements. Perhaps due to the heterogeneity of the HLA system and the repertoire of peptides that can be bound, consistent associations with inhibitor development have not been observed across studies.