Identification of a F.VIII epitope recognized by a human hemophilic inhibitor.
Hemophilia A, one of the most common of the inherited bleeding disorders, results from a deficiency or abnormality of factor VIII (F.VIII). In approximately 15% of persons with hemophilia, treatment with exogenous F.VIII is complicated by the development of anti-F.VIII antibodies which block F.VIII coagulant activity. These antibodies have been termed inhibitors. To localize epitopes recognized by inhibitors, we used a lambda gt11 library which expresses small random fragments of F.VIII as fusion proteins. One epitope has been mapped to the 25-amino acid sequence lys-338 through asp-362 of F.VIII (E338-362). Immunoaffinity-purified antibodies that react with this epitope neutralize F.VIII:C activity. E338-362 is adjacent to an enzymatic cleavage site at arg-372 which is important in F.VIII activation. Hence, an antibody binding to E338-362 would probably block this cleavage and thereby block activation of F.VIII.
Lubahn
B C
BC
Department of Biology, University of North Carolina, Chapel Hill 27599.
Ware
J
J
Stafford
D W
DW
Reisner
H M
HM
D000595:Amino Acid Sequence; D000937:Antigen-Antibody Reactions; D000941:Antigens / Q000032:analysis* / Q000276:immunology; D001780:Blood Coagulation Tests; D003001:Cloning, Molecular; D000939:Epitopes / Q000032:analysis* / Q000276:immunology; D005169:Factor VIII / Q000032:analysis / Q000276:immunology*; D006801:Humans; D007518:Isoantibodies / Q000276:immunology*; D007519:Isoantigens / Q000032:analysis* / Q000276:immunology; D008969:Molecular Sequence Data; D013329:Structure-Activity Relationship; D014841:von Willebrand Factor
D000941:Antigens; D000939:Epitopes; D007518:Isoantibodies; D007519:Isoantigens; D014841:von Willebrand Factor; D005169:Factor VIII