title: 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.
abstract: Mild/moderate hemophilia A patients carrying certain mutations in the C1 domain of factor VIII (FVIII) have a higher risk of inhibitor occurrence. To analyze the mechanisms responsible for inhibitor development in such patients, we characterized FVIII-specific CD4(+) T-cell clones derived from a mild hemophilia A patient carrying an Arg2150His substitution in the C1 domain and who presented with a high titer inhibitor toward normal but not self-FVIII. All T-cell clones recognized synthetic peptides encompassing Arg2150. The peptides were presented to the T-cell clones by DRB1*0401/DRB4*01 or DRB1*1501/DRB5*01. Interestingly, the latter haplotype was previously reported as being associated with an increased incidence of inhibitor formation. Peptide I2144-T2161 also bound to other DR molecules such as DRB1*0101 and DRB1*0701, indicating that the peptide binds to major histocompatibility complex (MHC) class II molecules expressed in more than 60% of the population. None of the T-cell clones recognized recombinant FVIII carrying the substitution Arg2150His, even when FVIII was presented by an FVIII-specific B-cell line. The mutation likely alters T-cell recognition of the mutated peptide associated to MHC molecules, because the mutated peptide bound to immunopurified DR molecules nearly as effectively as the native peptide. These observations demonstrate that T cells of this patient with mutation Arg2150His distinguish between self- and wild-type FVIII and provide a plausible mechanism for the frequent occurrence of an inhibitor in patients carrying this substitution. A similar phenomenon may occur with other mutations associated to an increased incidence of inhibitor formation.
authors.affiliation: Center for Molecular and Vascular Biology, University of Leuven, Belgium. marc.jacquemin@med.kuleuven.ac.be
authors.forename: Marc
authors.initials: M
authors.lastname: Jacquemin
authors.forename: Valérie
authors.initials: V
authors.lastname: Vantomme
authors.forename: Cécile
authors.initials: C
authors.lastname: Buhot
authors.forename: Renaud
authors.initials: R
authors.lastname: Lavend'homme
authors.forename: Wivine
authors.initials: W
authors.lastname: Burny
authors.forename: Nathalie
authors.initials: N
authors.lastname: Demotte
authors.forename: Pascal
authors.initials: P
authors.lastname: Chaux
authors.forename: Kathelijne
authors.initials: K
authors.lastname: Peerlinck
authors.forename: Jos
authors.initials: J
authors.lastname: Vermylen
authors.forename: Bernard
authors.initials: B
authors.lastname: Maillere
authors.forename: Pierre
authors.initials: P
authors.lastname: van der Bruggen
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Saint-Remy
mesh_terms: D000906:Antibodies / Q000276:immunology*; D017951:Antigen Presentation; D001120:Arginine; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002999:Clone Cells / Q000276:immunology; D018604:Epitope Mapping; D005169:Factor VIII / Q000235:genetics* / Q000276:immunology* / Q000627:therapeutic use; D006684:HLA-DR Antigens / Q000276:immunology; D059811:HLA-DRB1 Chains; D059845:HLA-DRB4 Chains; D006467:Hemophilia A / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology*; D006639:Histidine; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006801:Humans; D008213:Lymphocyte Activation; D008875:Middle Aged; D009154:Mutation; D010446:Peptide Fragments / Q000276:immunology; D011994:Recombinant Proteins / Q000276:immunology / Q000627:therapeutic use
chemical_list: D000906:Antibodies; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C553505:HLA-DRB1*04:01 antigen; D059845:HLA-DRB4 Chains; D000949:Histocompatibility Antigens Class II; D010446:Peptide Fragments; D011994:Recombinant Proteins; D006639:Histidine; D005169:Factor VIII; D001120:Arginine