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Common inhibitory effects of human anti-C2 domain inhibitor alloantibodies on factor VIII binding to von Willebrand factor. 1995

M Shima, and H Nakai, and D Scandella, and I Tanaka, and Y Sawamoto, and S Kamisue, and S Morichika, and T Murakami, and A Yoshioka
Department of Paediatrics, Nara Medical University, Kashihara City, Japan.

Factor VIII (FVIII) inhibitor alloantibodies obtained from seven severe haemophilia A patients were examined for their binding regions and their effects on FVIII binding to von Willebrand factor (vWF). Immunoblotting analysis with a panel of recombinant fragments demonstrated that the binding regions of antibodies in cases 1-5 were contained in the C2 domain of the light chain. Antibodies from cases 1 and 2, which recognized an epitope within residues 2248-2312, completely inhibited FVIII/vWF binding in an ELISA (IC50: 5.0 and 9.0 micrograms/ml, respectively). Antibodies from case 3 recognizing 2170-2312 and case 5 recognizing 2170-2327 also inhibited FVIII/vWF binding (IC50: 110 and 400 micrograms/ml, respectively). Case 4 antibodies recognizing 2218-2307 showed barely detectable inhibition and cases 6 and 7 antibodies recognizing the 44 kD heavy chain, did not inhibit. Our results demonstrate that all anti-C2 alloantibodies with epitopes that extend to the residue 2312 inhibit vWF binding and that an overlap of the inhibitor epitope with residues 2308-2312 is critical for maximal inhibition of vWF binding. Prevention of FVIII/vWF binding appears to be a common property of anti-C2 domain inhibitor alloantibodies.

UI MeSH Term Description Entries
D007518 Isoantibodies Antibodies from an individual that react with ISOANTIGENS of another individual of the same species. Alloantibodies
D004797 Enzyme-Linked Immunosorbent Assay An immunoassay utilizing an antibody labeled with an enzyme marker such as horseradish peroxidase. While either the enzyme or the antibody is bound to an immunosorbent substrate, they both retain their biologic activity; the change in enzyme activity as a result of the enzyme-antibody-antigen reaction is proportional to the concentration of the antigen and can be measured spectrophotometrically or with the naked eye. Many variations of the method have been developed. ELISA,Assay, Enzyme-Linked Immunosorbent,Assays, Enzyme-Linked Immunosorbent,Enzyme Linked Immunosorbent Assay,Enzyme-Linked Immunosorbent Assays,Immunosorbent Assay, Enzyme-Linked,Immunosorbent Assays, Enzyme-Linked
D005169 Factor VIII Factor VIII of blood coagulation. Antihemophilic factor that is part of the factor VIII/von Willebrand factor complex. Factor VIII is produced in the liver and acts in the intrinsic pathway of blood coagulation. It serves as a cofactor in factor X activation and this action is markedly enhanced by small amounts of thrombin. Coagulation Factor VIII,Factor VIII Clotting Antigen,Factor VIII Coagulant Antigen,Factor VIII Procoagulant Activity,Thromboplastinogen,Blood Coagulation Factor VIII,F VIII-C,Factor 8,Factor 8 C,Factor Eight,Factor VIIIC,Hyate-C,Hyatt-C,F VIII C,Hyate C,HyateC,Hyatt C,HyattC
D006467 Hemophilia A The classic hemophilia resulting from a deficiency of factor VIII. It is an inherited disorder of blood coagulation characterized by a permanent tendency to hemorrhage. Factor VIII Deficiency,Hemophilia,Autosomal Hemophilia A,Classic Hemophilia,Deficiency, Factor VIII,Factor 8 Deficiency, Congenital,Factor VIII Deficiency, Congenital,Haemophilia,Hemophilia A, Congenital,Hemophilia, Classic,As, Autosomal Hemophilia,Autosomal Hemophilia As,Classic Hemophilias,Congenital Hemophilia A,Congenital Hemophilia As,Hemophilia A, Autosomal,Hemophilia As,Hemophilia As, Autosomal,Hemophilia As, Congenital,Hemophilias, Classic
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000939 Epitopes Sites on an antigen that interact with specific antibodies. Antigenic Determinant,Antigenic Determinants,Antigenic Specificity,Epitope,Determinant, Antigenic,Determinants, Antigenic,Specificity, Antigenic
D014841 von Willebrand Factor A high-molecular-weight plasma protein, produced by endothelial cells and megakaryocytes, that is part of the factor VIII/von Willebrand factor complex. The von Willebrand factor has receptors for collagen, platelets, and ristocetin activity as well as the immunologically distinct antigenic determinants. It functions in adhesion of platelets to collagen and hemostatic plug formation. The prolonged bleeding time in VON WILLEBRAND DISEASES is due to the deficiency of this factor. Factor VIII-Related Antigen,Factor VIIIR-Ag,Factor VIIIR-RCo,Plasma Factor VIII Complex,Ristocetin Cofactor,Ristocetin-Willebrand Factor,von Willebrand Protein,Factor VIII Related Antigen,Factor VIIIR Ag,Factor VIIIR RCo,Ristocetin Willebrand Factor
D015328 Gene Rearrangement, B-Lymphocyte, Light Chain Ordered rearrangement of B-lymphocyte variable gene regions coding for the kappa or lambda IMMUNOGLOBULIN LIGHT CHAINS, thereby contributing to antibody diversity. It occurs during the second stage of differentiation of the IMMATURE B-LYMPHOCYTES. B-Cell Light Chain Gene Rearrangement,B-Lymphocyte Light Chain Gene Rearrangement,B-Lymphocyte kappa-Chain Gene Rearrangement,B-Lymphocyte lambda-Chain Gene Rearrangement,B Cell Light Chain Gene Rearrangement,B Cell kappa-Chain Gene Rearrangement,B Cell lambda-Chain Gene Rearrangement,B Lymphocyte Light Chain Gene Rearrangement,B Cell kappa Chain Gene Rearrangement,B Cell lambda Chain Gene Rearrangement,B Lymphocyte kappa Chain Gene Rearrangement,B Lymphocyte lambda Chain Gene Rearrangement
D018604 Epitope Mapping Methods used for studying the interactions of antibodies with specific regions of protein antigens. Important applications of epitope mapping are found within the area of immunochemistry. Epitope Mappings,Mapping, Epitope,Mappings, Epitope

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