Endocytic receptor for pro-coagulant factor VIII: Relevance to inhibitor formation

Summary

The immunogenicity of therapeutic factor VIII (FVIII) in patients with haemophilia A remains a critical issue in patient management. This review describes the immunological processes involved in the activation of the immune system against FVIII, with a particular focus on the role of endocytic receptors for the recognition of FVIII by antigen-presenting cells.

Keywords

Haemophilia A - factor VIII - antigen-presenting cells - endocytic receptors - allo-immunisation

• References

• 1 MacLennan IC. Germinal centers. Annu Rev Immunol 1994; 12: 117-139.
• 2 Fulcher CA, de Graaf Mahoney S, Zimmerman TS. Factor VIII inhibitor IgG subclass and FVIII polypeptide specificity determined by immunoblotting. Blood 1987; 69: 1475-1480.
• 3 Jacquemin MG, Desqueper BG, Benhida A. et al. Mechanism and kinetics of factor VIII inactivation: study with an IgG4 monoclonal antibody derived from a hemophilia A patient with inhibitor. Blood 1998; 92: 496-506.
• 4 Verbruggen B, Novakova I, Wessels H. et al. The Nijmegen modification of the Bethesda assay for Factor VIII: C inhibitors: improved specificity and reliability. Thromb Haemost 1995; 73: 247-251.
• 5 Scandella D, Mattingly M, de Graaf S. et al. Localization of epitopes for human factor VIII inhibitior antibodies by immunoblotting and antibody neutralization. Blood 1989; 74: 1618-1626.
• 6 Barrow R, Healey J, Jacquemin M. et al. Antigenicity of putative phospholipid membrane-binding residues in factor VIII. Blood 2001; 97: 169-174.
• 7 Fulcher CA, De Graaf Mahoney S, Roberts JR. et al. Localization of human factor VIII inhibitor epitopes to two polypeptide fragments. Proc Natl Acad Sci USA 1985; 82: 7728-7732.
• 8 Scandella D, De Graaf Mahoney S, Mattingly M. et al. Epitope mapping of human factor VIII inhibitor antibodies by deletion analysis of factor VIII fragments expressed in Escherichia coli. Proc Natl Acad Sci USA 1988; 85: 6152-6156.
• 9 Nogami K, Shima M, Nishiya K. et al. A novel mechanism of factor VIII protection by von Willebrand factor from activated protein C-catalyzed inactivation. Blood 2002; 99: 3993-3998.
• 10 Foster PA, Fulcher CA, Huoghten RA. et al. Synthetic factor VIII peptides with amino acid sequences contained within the C2 domain of factor VIII inhibit factor VIII binding to phosphatidylserine. Blood 1990; 75: 1999-2004.
• 11 Nogami K, Shima M, Giddings JC. et al. Relationship between the binding sites for von Willebrand factor, phospholipid, and human factor VIII C2 inhibitor alloantibodies within the factor VIII C2 domain. Int J Hematol 2007; 85: 317-322.
• 12 Scandella D. Epitope specificity and inactivation mechanisms of factor VIII inhibitor antibodies. Vox Sang 1999; 77 (Suppl. 01) 17-20.
• 13 Shima M, Nakai H, Scandella D. et al. Common inhibitory effects of human anti-C2 domain inhibitor alloantibodies on factor VIII binding to von Willebrand factor. Br J Haematol 1995; 91: 714-721.
• 14 Scandella D, Mattingly M, Prescott R. A recombinant Factor VIII A2 domain poly-peptide quantitatively neutralizes human inhibitor antibodies that bind to A2. Blood 1993; 82: 1767-1775.
• 15 Zhong D, Saenko EL, Shima M. et al. Some human inhibitor antibodies interfere with factor VIII binding to Factor IX. Blood 1998; 92: 136-142.
• 16 Fay PJ, Scandella D. Human inhibitor antibodies specific for the factor VIII A2 domain disrupt the interaction between the subunit and factor IXa. J Biol Chem 1999; 274: 29826-29830.
• 17 Fijnvandraat K, Celie PHN, Turenhout EAM. et al. A human alloantibody interferes with binding of Factor IXa to the Factor VIII light chain. Blood 1998; 108: 2347-2352.
• 18 Kazatchkine MD, Sultan Y, Burton-Kee EJ. et al. Circulating immune complexes containing anti-FVIII antibodies in multitransfused patients with haemophilia A. Clin Exp Immunol 1980; 39: 315-320.
• 19 Lacroix-Desmazes S, Moreau A. Sooryanarayana, et al. Catalytic activity of antibodies against factor VIII in patients with hemophilia A. Nat Med 1999; 5: 1044-1047.
• 20 Lacroix-Desmazes S, Bayry J, Misra N. et al. The prevalence of proteolytic antibodies against factor VIII in hemophilia A. N Engl J Med 2002; 346: 662-667.
• 21 Lacroix-Desmazes S, Wootla B, Dasgupta S. et al. Catalytic IgG from patients with hemophilia A inactivate therapeutic factor VIII. J Immunol 2006; 177: 1355-1363.
• 22 Jacquemin M, Vantomme V, Buhot C. et al. CD4+ T-cell clones specific for wild-type factor VIII: a molecular mechanism responsible for a higher incidence of inhibitor formation in mild/moderate hemophilia A. Blood 2003; 101: 1351-1358.
• 23 Singer ST, Addiego Jr JE, Reason DC. et al. T lymphocyte proliferative responses induced by recombinant factor VIII in hemophilia A patients with inhibitors. Thromb Haemost 1996; 76: 17-22.
• 24 Reding MT, Wu H, Krampf M. et al. CD4+ T cell response to factor VIII in hemophilia A, acquired hemophilia, and healthy subjects. Thromb Haemost 1999; 82: 509-515.
• 25 Reding M, Wu H, Krampf M. et al. Sensitization of CD4+ T cells to coagulation factor VIII: response in congenital and acquired hemophilia patients and in healthy subjects. Thromb Haemost 2000; 84: 643-652.
• 26 Reding MT, Lei S, Lei H. et al. Distribution of Th1– and Th2-induced Anti-factor VIII IgG Subclasses in Congenital and Acquired Hemophilia Patients. Thromb Haemost 2002; 88: 568-575.
• 27 Reding MT, Okita DK, Diethelm-Okita BM. et al. Human CD4+ T-cell epitope repertoire on the C2 domain of coagulation factor VIII. J Thromb Haemost 2003; 1: 1777-1784.
• 28 James EA, Kwok WW, Ettinger RA. et al. T-cell responses over time in a mild hemophilia A inhibitor subject: epitope identification and transient immunogenicity of the corresponding self-peptide. J Thromb Haemost 2007; 5: 2399-2407.
• 29 Ettinger RA, James EA, Kwok WW. et al. Lineages of human T-cell clones, including T helper 17/T helper 1 cells, isolated at different stages of anti-factor VIII immune responses. Blood 2009; 114: 1423-1428.
• 30 Misra N, Bayry J, Pashov A. et al. Restricted BV gene usage by factor VIII-reactive CD4+ T cells in inhibitor-positive patients with severe hemophilia A. Thromb Haemost 2003; 90: 813-822.
• 31 Leyva WH, Knutsen AP, Joist JH. Disappearance of a high response factor VIII inhibitor in a hemophiliac with AIDS. Am J Clin Pathol 1988; 89: 414-418.
• 32 Ragni MV, Bontempo FA, Lewis JH. Disappearance of inhibitor to factor VIII in HIV-infected hemophiliacs with progression to AIDS or severe ARC. Transfusion 1989; 29: 447-449.
• 33 Bray GL, Kroner BL, Arkin S. et al. Loss of high-responder inhibitors in patients with severe hemophilia A and human immunodeficiency virus type 1 infection: a report from the Multi-Center Hemophilia Cohort Study. Am J Hematol 1993; 42: 375-379.
• 34 Qian J, Burkly L, Smith E. et al. Role of CD154 in the secondary immune response: the reduction of pre-existing splenic germinal centers and anti-factor VIII inhibitor titer. Eur J Immunol 2000; 30: 2548-2554.
• 35 Qian J, Collins M, Sharpe AH. et al. Prevention and treatment of factor VIII inhibitors in murine hemophilia A. Blood 2000; 95: 1324-1329.
• 36 Reipert BM, Sasgary M, Ahmad RU. et al. Blockade of CD40/CD40 ligand interactions prevents induction of factor VIII inhibitors in hemophilic mice but does not induce lasting immune tolerance. Thromb Haemost 2001; 86: 1345-1352.
• 37 Rossi G, Sarkar J, Scandella D. Long-term induction of immune tolerance after blockade of CD40-CD40L interaction in a mouse model of hemophilia A. Blood 2001; 97: 2750-2757.
• 38 Hausl C, Ahmad RU, Schwarz HP. et al. Preventing restimulation of memory B cells in hemophilia A: a potential new strategy for the treatment of antibody-dependent immune disorders. Blood 2004; 104: 115-122.
• 39 Banchereau J, Briere F, Caux C. et al. Immunobiology of dendritic cells. Annu Rev Immunol 2000; 18: 767-811.
• 40 Park CS, Choi YS. How do follicular dendritic cells interact intimately with B cells in the germinal centre?. Immunology 2005; 114: 2-10.
• 41 van Nierop K, de Groot C. Human follicular dendritic cells: function, origin and development. Semin Immunol 2002; 14: 251-257.
• 42 Navarrete A, Dasgupta S, Delignat S. et al. Splenic marginal zone antigen-presenting cells are critical for the primary allo-immune response to therapeutic factor VIII in hemophilia A. J Thromb Haemost 2009; 7: 1816-1823.
• 43 van Schooten CJ, Shahbazi S, Groot E. et al. Macrophages contribute to the cellular uptake of von Willebrand factor and factor VIII in vivo. Blood 2008; 112: 1704-1712.
• 44 Lacroix-Desmazes S, Navarrete AM, Andre S. et al. Dynamics of factor VIII interactions determine its immunologic fate in hemophilia A. Blood 2008; 112: 240-249.
• 45 Herz J, Strickland DK. LRP: a multifunctional scavenger and signaling receptor. J Clin Invest 2001; 108: 779-784.
• 46 Bovenschen N, van Dijk KW, Havekes LM. et al. Clearance of coagulation factor VIII in very low-density lipoprotein receptor knockout mice. Br J Haematol 2004; 126: 722-725.
• 47 Ananyeva NM, Lee TK, Jain N. et al. Inhibitors in hemophilia A: advances in elucidation of inhibitory mechanisms and in inhibitor management with bypassing agents. Semin Thromb Hemost 2009; 35: 735-751.
• 48 Lenting P, Neels J, van den Berg B. et al. The light chain of factor VIII comprises a binding site for low density lipoprotein receptor-related protein. J Biol Chem 1999; 274: 23734-23739.
• 49 Saenko E, Yakhyaev A, Mikhailenko I. et al. Role of the low density lipoprotein-related protein receptor in mediation of factor VIII catabolism. J Biol Chem 1999; 274: 37685-37692.
• 50 Bovenschen N, Herz J, Grimbergen JM. et al. Elevated plasma factor VIII in a mouse model of low-density lipoprotein receptor-related protein deficiency. Blood 2003; 101: 3933-3939.
• 51 Sarafanov A, Ananyeva N, Shima M. et al. Cell surface heparan sulfate proteoglycans participate in factor viii catabolism mediated by low density lipoprotein receptor-related protein. J Biol Chem 2001; 276: 11970-11979.
• 52 Srivastava P. Interaction of heat shock proteins with peptides and antigen presenting cells: chaperoning of the innate and adaptive immune responses. Annu Rev Immunol 2002; 20: 395-425.
• 53 Dasgupta S, Navarrete AM, Andre S. et al. Factor VIII bypasses CD91/LRP for endocytosis by dendritic cells leading to T-cell activation. Haematologica 2008; 93: 83-89.
• 54 Lenting PJ, van Mourik JA, Mertens K. The life cycle of coagulation factor VIII in view of its structure and function. Blood 1998; 92: 3983-3996.
• 55 Vehar GA, Keyt B, Eaton DH. et al. Structure of human factor VIII. Nature 1984; 312: 337-342.
• 56 Kaufman RJ, Wasley LC, Dorner AJ. Synthesis, processing, and secretion of recombinant human factor VIII expressed in mammalian cells. J Biol Chem 1988; 263: 6352-6362.
• 57 Hironaka T, Furukawa K, Esmon PC. et al. Comparative study of the sugar chains of factor VIII purified from human plasma and from the culture media of recombinant baby hamster kidney cells. J Biol Chem 1992; 267: 8012-8020.
• 58 Medzihradszky KF, Besman MJ, Burlingame AL. Structural characterization of site-specific N-glycosylation of recombinant human factor VIII by reversed-phase high-performance liquid chromatography-electrospray ionization mass spectrometry. Anal Chem 1997; 69: 3986-3994.
• 59 Bovenschen N, Rijken DC, Havekes LM. et al. The B domain of coagulation factor VIII interacts with the asialoglycoprotein receptor. J Thromb Haemost 2005; 3: 1257-1265.
• 60 Dasgupta S, Navarrete AM, Bayry J. et al. A role for exposed mannosylations in presentation of human therapeutic self-proteins to CD4+ T lymphocytes. Proc Natl Acad Sci USA 2007; 104: 8965-8970.
• 61 Lusher JM, Lee CA, Kessler CM. et al. The safety and efficacy of B-domain deleted recombinant factor VIII concentrate in patients with severe haemophilia A. Haemophilia 2003; 9: 38-49.
• 62 Delignat S, Dasgupta S, Andre S. et al. Comparison of the immunogenicity of different therapeutic preparations of human factor VIII in the murine model of hemophilia A. Haematologica 2007; 92: 1423-1426.
• 63 Dasgupta S, Repesse Y, Bayry J. et al. VWF protects FVIII from endocytosis by dendritic cells and subsequent presentation to immune effectors. Blood 2007; 109: 610-612.
• 64 Sallusto F, Cella M, Danieli C. et al. Dendritic cells use macropinocytosis and the mannose receptor to concentrate macromolecules in the major histocompatibility complex class II compartment: down-regulation by cytokines and bacterial products. J Exp Med 1995; 182: 389-400.
• 65 Kosloski MP, Miclea RD, Balu-Iyer SV. Role of glycosylation in conformational stability, activity, macromolecular interaction and immunogenicity of recombinant human factor VIII. AAPS J 2009; 11: 424-431.
• 66 Shen BW, Spiegel PC, Chang CH. et al. The tertiary structure and domain organization of coagulation factor VIII. Blood 2008; 111: 1240-1247.
• 67 Pontow SE, Kery V, Stahl PD. Mannose receptor. Int Rev Cytol 1992; 137B: 221-244.
• 68 Ezekowitz RA, Sastry K, Bailly P. et al. Molecular characterization of the human macrophage mannose receptor: demonstration of multiple carbohydrate recognition-like domains and phagocytosis of yeasts in Cos-1 cells. J Exp Med 1990; 172: 1785-1794.
• 69 Taylor ME, Conary JT, Lennartz MR. et al. Primary structure of the mannose receptor contains multiple motifs resembling carbohydrate-recognition domains. J Biol Chem 1990; 265: 12156-12162.
• 70 Stahl PD, Ezekowitz RA. The mannose receptor is a pattern recognition receptor involved in host defense. Curr Opin Immunol 1998; 10: 50-55.
• 71 Lee SJ, Evers S, Roeder D. et al. Mannose receptor-mediated regulation of serum glycoprotein homeostasis. Science 2002; 295: 1898-1901.
• 72 Bovenschen N, Mertens K, Hu L. et al. LDL receptor cooperates with LDL receptor-related protein in regulating plasma levels of coagulation factor VIII in vivo. Blood 2005; 106: 906-912.