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Anti-factor VIII antibodies in brothers with haemophilia A share similar characteristics

Kahle, J.; Orlowski, A.; Stichel, D.; Healey, J. F.; Parker, E. T.; Donfield, S. M.; Astermark, J. LU ; Berntorp, E. LU ; Lollar, P. and Schwabe, D., et al. (2017) In Haemophilia 23(2). p.292-299
Abstract

Introduction: 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. Aim: 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... (More)

Introduction: 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. Aim: 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. Conclusion: 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.

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publication status
published
subject
keywords
Anti-factor VIII antibodies, Epitope mapping, Factor VIII inhibitors, Haemophilia A, IgG subclasses
in
Haemophilia
volume
23
issue
2
pages
292 - 299
publisher
Federation of European Neuroscience Societies and Blackwell Publishing Ltd
external identifiers
  • scopus:84998631541
  • wos:000397406000016
ISSN
1351-8216
DOI
10.1111/hae.13105
language
English
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yes
id
da4c2432-4f11-4792-9e2b-b89165aadc90
date added to LUP
2016-12-30 13:40:33
date last changed
2018-01-07 11:43:31
@article{da4c2432-4f11-4792-9e2b-b89165aadc90,
  abstract     = {<p>Introduction: 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. Aim: 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. Conclusion: 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.</p>},
  author       = {Kahle, J. and Orlowski, A. and Stichel, D. and Healey, J. F. and Parker, E. T. and Donfield, S. M. and Astermark, J. and Berntorp, E. and Lollar, P. and Schwabe, D. and Königs, C.},
  issn         = {1351-8216},
  keyword      = {Anti-factor VIII antibodies,Epitope mapping,Factor VIII inhibitors,Haemophilia A,IgG subclasses},
  language     = {eng},
  number       = {2},
  pages        = {292--299},
  publisher    = {Federation of European Neuroscience Societies and Blackwell Publishing Ltd},
  series       = {Haemophilia},
  title        = {Anti-factor VIII antibodies in brothers with haemophilia A share similar characteristics},
  url          = {http://dx.doi.org/10.1111/hae.13105},
  volume       = {23},
  year         = {2017},
}