title: Anti-factor VIII antibodies in brothers with haemophilia A share similar characteristics.
abstract: BACKGROUND
  The development of neutralizing antibodies (inhibitors) against coagulation factor VIII (FVIII) is currently the most serious complication for patients with haemophilia A undergoing FVIII replacement therapy. Several genetic factors have been acknowledged as risk factors for inhibitor development.
  
  
  OBJECTIVE
  To analyze the influence of genetic factors on the nature of the humoral immune response to FVIII in eight brother pairs with inhibitors.
  
  
  METHODS
  The domain specificity of FVIII-specific IgG was analysed by antibody binding to FVIII fragments and homologue-scanning mutagenesis (HSM). The FVIII-specific IgG subclasses were measured by direct ELISA.
  
  
  RESULTS
  Of the 16 patient analysed with both methods, 12 had A2- and 13 had C2-specific IgG. The presence of A1-, A3- or C1-specific IgG was identified in nine of 14 patients analysed by HSM. IgG1, IgG2 and IgG4 subclasses contributed to the anti-FVIII IgG response, and the amount of FVIII-specific IgG1 (r = 0.66) and IgG4 (r = 0.69) correlated significantly with inhibitor titres. Patients with high concentrations of total anti-FVIII IgG (r = 0.69) or high inhibitor titres (r = 0.52) had a high proportion of FVIII-specific IgG4. Statistical analysis revealed trends/evidence that the subclass distribution (P = 0.0847) and domain specificity to HC/LC (P = 0.0883) and A2/C2 (P = 0.0011) of anti-FVIII IgG were more similar in brothers compared to unrelated subjects.
  
  
  CONCLUSIONS
  Overall, our data provide a first hint that anti-FVIII IgG characteristics are comparable among haemophilic brothers with inhibitors. Whether genetic factors also influence the nature of patients' antibodies needs to be confirmed in a larger study population.
authors.affiliation: Department of Paediatrics, Clinical and Molecular Haemostasis and Immunodeficiency, University Hospital Frankfurt, Frankfurt am Main, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Kahle
authors.affiliation: Department of Paediatrics, Clinical and Molecular Haemostasis and Immunodeficiency, University Hospital Frankfurt, Frankfurt am Main, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Orlowski
authors.affiliation: Department of Paediatrics, Clinical and Molecular Haemostasis and Immunodeficiency, University Hospital Frankfurt, Frankfurt am Main, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Stichel
authors.affiliation: Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta and Emory University, Atlanta, GA, USA.
authors.forename: J F
authors.initials: JF
authors.lastname: Healey
authors.affiliation: Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta and Emory University, Atlanta, GA, USA.
authors.forename: E T
authors.initials: ET
authors.lastname: Parker
authors.affiliation: Department of Biostatistics, Rho Inc., Chapel Hill, NC, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Donfield
authors.affiliation: Centre for Thrombosis and Haemostasis, Lund University, Skåne University Hospital, Malmö, Sweden.
authors.forename: J
authors.initials: J
authors.lastname: Astermark
authors.affiliation: Centre for Thrombosis and Haemostasis, Lund University, Skåne University Hospital, Malmö, Sweden.
authors.forename: E
authors.initials: E
authors.lastname: Berntorp
authors.affiliation: Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta and Emory University, Atlanta, GA, USA.
authors.forename: P
authors.initials: P
authors.lastname: Lollar
authors.affiliation: Department of Paediatrics, Clinical and Molecular Haemostasis and Immunodeficiency, University Hospital Frankfurt, Frankfurt am Main, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Schwabe
authors.affiliation: Department of Paediatrics, Clinical and Molecular Haemostasis and Immunodeficiency, University Hospital Frankfurt, Frankfurt am Main, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Königs
mesh_terms: D000906:Antibodies / Q000097:blood*; D005169:Factor VIII / Q000008:administration & dosage / Q000627:therapeutic use*; D006467:Hemophilia A / Q000188:drug therapy* / Q000276:immunology; D006801:Humans; D008297:Male; D035781:Siblings
chemical_list: D000906:Antibodies; D005169:Factor VIII
keywords: IgG subclasses; anti-factor VIII antibodies; epitope mapping; factor VIII inhibitors; haemophilia A