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Prepublished online as a Blood First Edition Paper on October 17, 2002; DOI 10.1182/blood-2002-05-1369. This Article Full Text (PDF) All Versions of this Article: 2002-05-1369v1 101/4/1351    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Jacquemin, M. G Articles by Saint-Remy, J.-M. Search for Related Content PubMed PubMed Citation Articles by Jacquemin, M. G Articles by Saint-Remy, J.-M. Social Bookmarking                   What's this? Submitted May 10, 2002 Accepted September 6, 2002 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 Marc G Jacquemin*, Valerie Vantomme, Cecile Buhot, Renaud Lavend'homme, Wivine Burny, Nathalie Demotte, Pascal Chaux, Kathelijne Peerlinck, Jos Vermylen, Bernard Maillere, Pierre van der Bruggen, and Jean-Marie Saint-Remy Center for Molecular and Vascular Biology, Katholieke Universiteit Leuven, Leuven, Belgium Ludwig Institute for Cancer Research, Brussels, Belgium Departement d'Ingenierie et d'Etudes des proteines, CEA-Saclay, Gif-sur-Yvette, France * Corresponding author; email: marc.jacquemin{at}med.kuleuven.ac.be. Mild/moderate haemophilia A patients carrying certain mutations in the C1 domain of factor VIII (FVIII) have a higher risk of inhibitor occurence. To analyse the mechanisms responsible for inhibitor development in such patients, we characterised 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 titre inhibitor towards normal but not self FVIII. All T cell clones recognised 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 MHC class II molecules expressed in more than 60% of the population. None of the T cell clones recognised recombinant FVIII carrying the substitution Arg2150His, even when FVIII was presented by a FVIII-specific B cell line. The mutation likely alters T cell recognition of the mutated peptide associated to MHC molecules, since 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 occurence of an inhibitor in patients carrying this substitution. A similar phenomenon may occur with other mutations associated to an increased incidence of inhibitor formation. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: R. A. Ettinger, E. A. James, W. W. Kwok, A. R. Thompson, and K. P. Pratt 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, August 13, 2009; 114(7): 1423 - 1428. [Abstract] [Full Text] [PDF] S. Dasgupta, A. M. Navarrete, S. Andre, B. Wootla, S. Delignat, Y. Repesse, J. Bayry, A. Nicoletti, E. L. Saenko, R. d'Oiron, et al. Factor VIII bypasses CD91/LRP for endocytosis by dendritic cells leading to T-cell activation Haematologica, January 1, 2008; 93(1): 83 - 89. [Abstract] [Full Text] [PDF] S. Dasgupta, A.-M. Navarrete, J. Bayry, S. Delignat, B. Wootla, S. Andre, O. Christophe, M. Nascimbeni, M. Jacquemin, L. Martinez-Pomares, et al. A role for exposed mannosylations in presentation of human therapeutic self-proteins to CD4+ T lymphocytes PNAS, May 22, 2007; 104(21): 8965 - 8970. [Abstract] [Full Text] [PDF] S. Dasgupta, Y. Repesse, J. Bayry, A.-M. Navarrete, B. Wootla, S. Delignat, T. Irinopoulou, C. Kamate, J.-M. Saint-Remy, M. Jacquemin, et al. VWF protects FVIII from endocytosis by dendritic cells and subsequent presentation to immune effectors Blood, January 15, 2007; 109(2): 610 - 612. [Abstract] [Full Text] [PDF] E. T. Parker, J. F. Healey, R. T. Barrow, H. N. Craddock, and P. Lollar Reduction of the inhibitory antibody response to human factor VIII in hemophilia A mice by mutagenesis of the A2 domain B-cell epitope Blood, August 1, 2004; 104(3): 704 - 710. [Abstract] [Full Text] [PDF]

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