Immunogenetics of the human immune response to factor VIII
The anti-Factor VIII (F.VIII) antibodies produced by hemophilic patients have the potential to be directed against many different epitopes on the F.VIII molecule. Although first recognized as inhibitors of coagulation factor activity these antibodies may or may not interfere with F.VIII bioactivity.1,2 Indeed, as has been suggested by Nilsson and co-workers, antibodies without inhibitory reactivity may play a critical role in the generation and/or maintenance of tolerance in hemophiliacs.3 At the same time, many individuals with severe hemophilia A may never develop inhibiting antibodies (inhibitors), even after hundreds of days of replacement therapy. What factors are important in determining which individuals with hemophilia A will have an immune response to F.VIII and become refractory to continued replacement therapy? To date, there are no clear answers. It is clear that inherited factors both at the F.VIII locus and at other loci, possibly associated with the immune response, play a role in inhibitor production. This brief review will try to summarize some of the more recent information on how 1) the structure of the F.VIII protein, 2) the nature of F.VIII mutation that results in hemophilia A, 3) additional genetic factors (at the HLA complex locus) may affect the probability of an individual with severe hemophilia (F.VIII:C >1%) developing antibodies to F.VIII, and 4) how the clonality of the immune response to F.VIII varies with time.
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