Specifically, we found that approximately 20% of black American <

Specifically, we found that approximately 20% of black American LY294002 supplier HA patients carrying the H1 or H2 variation of F8, who therefore received matched (or least-mismatched) infusions with FVIII, developed inhibitors [13]; this is equivalent to the overall rate observed

in prior studies that were likely comprised of relatively few HA patients with black African heritage [31]. On the other hand, black HA patients with the H3 or H4 haplotype, which are mismatched with all currently available recombinant FVIII products, and likely with most of the FVIII contained in plasma-derived FVIII products in the US (which are typically derived from a predominantly white blood donor population), developed inhibitors at about three times the rate of black patients with the H1 or H2 haplotype [13]. As described above, differences between the infused and endogenous FVIII in patients may arise naturally, due to ns-SNPs and/or the causal F8 mutation, or from structural alterations of recombinant products, e.g. due to distinct post-translational modifications, or to sequence engineering for increasing protein expression [30] or prolonging protein half-life in patients’ circulation [32–34]. Thus, patients infused with ‘mismatched’ FVIII may be exposed to neo-epitopes

that can cause immune responses. HA patients with major Dabrafenib research buy Tolmetin F8 gene deletions or premature stop codons will obviously have the greatest degree of mismatch between their endogenous FVIII and a therapeutic FVIII product. The most common defect causing HA is the intron-22 inversion (I22-inv) that occurs in approximately 40% of all severely affected patients [35]. An intron-22 inverted F8 allele cannot be transcribed into a full-length mRNA as the promoter region and the adjacent gene region containing exons 1–22 have been inverted [36]. In I22-inv patients, exons 1 through 22 are transcribed as a polyadenylated fusion transcript in which two (or more) unrelated 3′-exons have replaced F8 exons

23 through 26. However, intron 22 of the F8 locus also contains two nested genes, F8A and F8B, which are controlled by a CpG-island containing a bidirectional promoter [37,38]. In I22-inv patients, transcription and translation of the F8B gene would be predicted to generate a polypeptide encoded almost entirely by exons 23–26; this putative protein is referred to as FVIIIB. If a partial FVIII protein encoded by the mRNA containing exons 1–22 is expressed, along with the FVIIIB protein, then one would expect that I22-inv patients would be more likely to tolerate infused FVIII, unless ‘mismatched’ amino acid sequences, e.g. at the wild-type exon-22/-23 junction region, were recognized as foreign by their immune systems.

Comments are closed.