Abstract
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.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Hoyer, L.W. Factor VIII inhibitors:A continuing problem. J.Lab.Clin.Med. 121:385, 1993.
Hoyer, L.W. Medical progress:Hemophilia A. N.Engl.J.Med. 330:38, 1994.
Nilsson, I.M., Berntorp, E., Zettervall, O. and Dahlbäck, B. Noncoagulation inhibitory factor VIII antibodies after induction of tolerance to factor VIII in hemophilia A patients. Blood 75:378, 1990.
Hopp, T.P. Protein surface analysis. Methods for identifying antigenic determinants and other interaction sites. J.Immunol.Meth. 88:1, 1986.
Getzoff, E.D., Geysen, H.M., Rodda, S.J., Alexander, H., Tainer, J.A. and Lerner, R.A. Mechanisms of antibody binding to a protein. Science 235:1191, 1987.
Scientific Imaging Systems, MacVector, New Haven:Eastman Kodak Company, 1994. Ed. 4th
Rothbard, J.B. and Taylor, WR. A sequence pattern common to T cell epitopes. EMBO Journal 7:93, 1988.
Margalit, H., Spouge, J.L., Cornette, J.L., Cease, K.B., DeLisi, C. and Berzofsky, J.A. Prediction of immunodominant helper T cell antigenic sites from the primary sequence. J.Biol.Chem. 138:2213, 1987.
Scandella, D., Mattingly, M. and Prescott, R. A recombinant factor VIII A2 domain polypeptide quantitatively neutralizes human inhibitor antibodies that bind to A2. Blood 82:1767, 1993.
Shima, M., Scandella, D., Yoshioka, A., et al. A factor VIII neutralizing monoclonal antibody and a human inhibitor alloantibody recognizing epitopes in the C2 domain inhibit factor VIII binding to von Willebrand factor and to phosphatidylserine. Thromb.Haemost. 69:240, 1993.
Scandella, D., Timmons, L., Mattingly, M., Trabold, N. arid Hoyer, L.W. A soluble recombinant factor VIII fragment containing the A2 domain binds to some human anti-factor VIII antibodies that are not detected by immunoblotting. Thromb.Haemost. 67:665, 1992.
Ware, J., MacDonald, MJ., Lo, M., de Graaf, S. and Fulcher, C.A. Epitope mapping of human factor VIII inhibitor antibodies by site-directed mutagenesis of a factor VIII polypeptide. Blood Coag.& Fibrinol 3:703, 1992.
Lubahn, B.C., Ware, J., Stafford, D.W. and Reisner, H.M. Identification of a F.VIII epitope recognized by a human hemophilic inhibitor. Blood 73:497, 1989.
Aalberse, R., van der Gaag, R. and van der Leeuwen, J. Serologic aspects of IgG4 antibodies. I. Prolonged immunization results in IgG4 restricted response. J.Immunol. 130:722, 1983.
Lusher, J.M., Arkin, S., Abildgaard, C.F., Schwartz, R.S. and Kogenate Prev Untreated Patient Group. Recombinant factor VIII for the treatment of previously untreated patients with hemophilia A. Safety, efficacy, and development of inhibitors. N.Engl.J.Med. 328:453, 1993.
Rosendaal, F.R., Nieuwenhuis, H.K., van den Berg, H.M., et al. A sudden increase in factor VIII inhibitor development in multitransfused hemophilia A patients in the Netherlands. Blood 81:2180, 1993.
Hironaka, T, Furukawa, K., Esmon, P.C., et al. Structural study of the sugar chains of porcine factor VIII-Tissue- and species-specific glycosylation of factor VIII. Arch.Biochem.Biophys. 307:316, 1993.
Frommel, D. and Allain, J.P. Genetic predisposition to develop Factor VIII antibody in classic hemophilia. Clin. Immunol. Immunopathol. 8:34, 1977
Frommel, D., Allain, J.P, Saint-Paul, E., et al. HLA antigens and Factor VIII antibody in classic hemophilia. Thromb.Haemostas 46:687, 1981.
Frommel, D., Muller, J.Y., Prou-Wartelle, O. and Allain, J.P. Possible linkage between the major histocompatibility complex and the immune response to Factor VIII in classic haemophilia. Vox Sang 33:270, 1977.
Lubahn, B.C. Inhibitor development in hemophilia A:Defining genetic factors that control the human immune response to F.VIII. (Ph. D. Dissertation), Chapel Hill:University of North Carolina at Chapel Hill, 1991.
Thompson, A.R. Molecular biology of the hemophilias. Prog.Hemost.Thromb. 10:175, 1991.
Millar, D.S., Steinbrecher, R.A., Wieland, K., et al. The molecular genetic analysis of haemophilia A; Characterization of six partial deletions in the factor VIII gene. Hum.Genet. 86:219, 1990.
McMillan, C.W., Shapiro, S.S., Whitehurst, D., et al. The natural history of Factor VIII:C inhibitors in patients with hemophilia A:A national cooperative study. II. Observations on the initial development of Factor VIILC inhibitors. Blood 71:344, 1988.
McMillan, C.W. Clinical patterns of hemophilic patients who develop inhibitors. In:Factor VIII Inhibitors, New York:Alan R. Liss, 1984, p. 31#x2013;44.
Clark, A. Immunogenetics of Inhibitor Response to FVIILC, (Masters Thesis), 1994.
Simonney, N., De Bosch, N., Argueyo, A., Garcia, E. and Layrisse, Z. HLA antigens in hemophiliacs A with or without Factor VIII antibodies in a Venezuelan mestizo population. Tissue Antigens 25:216, 1985.
Papasteriades, C, Economidou, J., Pappas, H., et al. Association between HLA antigens and progression of HIV infection in Greek haemophiliacs. Dis.Markers 11:131, 1993.
Reisner, H.M., Reisner, E.G., Kostyu, D.D., Lubahn, B.C., McMillan, C. and White, G.C. Possible association of HLA and Gm with the alloimmune response to FVIII Thromb.Haemostas 58:1222a, 1987. (Abstract)
Lubahn, B.C., Reisner, E.G., Dawson, D.V., et al. Genetic susceptibility to inhibitor formation in hemophilia A:Related individuals develop antibodies to similar regions of Factor VIII. In preparation, 1994.
Fulcher, CA., Lechner, K. and De Graaf Mahoney, S. Immunoblot analysis shows changes in factor VIII inhibitor chain specificty in factor VIII inhibitor patients over time. Blood 72:1348, 1988.
Gilles, J.G., Gilis, K., Arnout, J., Vermylen, J. and Saint-Remy, J-M. The serum of normal donors contains both anti-FVIII and corresponding anti-idiotype antibodies. Thromb.Haemostas 65:677, 1991. (Abstract)
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1995 Plenum Press, New York
About this chapter
Cite this chapter
Reisner, H.M., Clark, A., Levin, L. (1995). Immunogenetics of the human immune response to factor VIII. In: Aledort, L.M., Hoyer, L.W., Lusher, J.M., Reisner, H.M., White, G.C. (eds) Inhibitors to Coagulation Factors. Advances in Experimental Medicine and Biology, vol 386. Springer, Boston, MA. https://doi.org/10.1007/978-1-4613-0331-2_5
Download citation
DOI: https://doi.org/10.1007/978-1-4613-0331-2_5
Publisher Name: Springer, Boston, MA
Print ISBN: 978-1-4613-8001-6
Online ISBN: 978-1-4613-0331-2
eBook Packages: Springer Book Archive