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Prepublished online as a Blood First Edition Paper on October 17, 2002; DOI 10.1182/blood-2002-05-1369.
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Blood, 15 February 2003, Vol. 101, No. 4, pp. 1351-1358
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
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 Jacquemin,
Valérie Vantomme,
Cécile 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
From the Center for Molecular and Vascular Biology,
University of Leuven, Belgium; Département
d'Ingénierie et d'Etudes des protéines, CEA-Saclay,
Gif-sur-Yvette, France; and Ludwig Institute for Cancer
Research, Brussels, Belgium.
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.
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