title: Molecular characterization of the immune response to factor VIII.
abstract: Inhibitory antibodies to factor VIII arise from an alloimmune response in patients with hemophilia A infused with factor VIII and as an autoimmune response in a variety of settings. The immune response to factor VIII is T-cell dependent. Helper T cells recognize numerous epitopes in the factor VIII molecule. B cell epitopes in both the alloimmune and autoimmune responses are much more restricted, usually involving two major epitopes in the A2 and C2 domains and apparently minor epitopes in the light chain activation peptide (ap) region and the A3 domain. Anti-C2 antibodies inhibit the binding of factor VIII to phospholipid and may also interfere with the binding of factor VIII to von Willebrand factor. Anti-A2 and anti-A3 antibodies block the binding of factor VIII to factor X and factor IXa, respectively, in the intrinsic pathway factor X activation complex. The mechanism of inhibition of anti-ap antibodies is unknown. A murine hemophilia A model has been developed to study the immunogenicity of factor VIII. This model may lead to improved approaches to prevent development of inhibitory antibodies and to reverse the immune response if it develops.
authors.affiliation: Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA. jlollar@emory.edu
authors.forename: Pete
authors.initials: P
authors.lastname: Lollar
mesh_terms: D000917:Antibody Formation / Q000187:drug effects*; D018604:Epitope Mapping; D005169:Factor VIII / Q000009:adverse effects / Q000737:chemistry / Q000276:immunology*; D006801:Humans; D007518:Isoantibodies / Q000097:blood
chemical_list: D007518:Isoantibodies; D005169:Factor VIII