U.S. Department of Defense


Date of this Version



Cellular Immunology 301 (2016) 1


U.S. Government Work


In this special issue of Cellular Immunology, we highlight the work of researchers investigating the immune response to factor VIII (FVIII) in hemophilia. Hemophilia is a relatively rare disease with an incidence of 1/5000 males. Why is it important to investigate the immune response in a relatively rare disease? Why study any orphan monogenic disease? The answer lies in immunology!

Hemophilia A is an x-linked disease caused by a variety of mutations (deletions, inversions, missense, etc.) in the gene for the coagulation protein FVIII. Because these patients lack FVIII, this leads to bleeding issues that can have life-long morbidity consequences, e.g. joint arthropathy resulting from repeated bleeds. We know how to treat this disease with prophylactic and therapeutic injections of human recombinant or plasma-derived FVIII to restore near-normal clotting times. However, up to 30% of hemophilia A patients produce antibodies to FVIII that neutralize the efficacy of this bio-therapeutic. These antibodies are referred to by clinicians as ‘‘inhibitors” because they inhibit the pro-coagulant function of FVIII. Clearly, many severe hemophilia A patients lack central tolerance to this human protein because they most likely never saw it during the development of the immune system: a beautiful natural example of acquired self-tolerance.