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J Thromb Haemost. 2011 Apr;9(4):689-99. doi: 10.1111/j.1538-7836.2011.04202.x.

T-cell responses in two unrelated hemophilia A inhibitor subjects include an epitope at the factor VIII R593C missense site.

Author information

1
Benaroya Research Institute, Seattle, WA, USA.

Abstract

BACKGROUND:

Development of neutralizing anti-factor (F)VIII antibodies ('inhibitors') is a serious clinical problem in hemophilia A. Increased inhibitor risk has been associated with certain FVIII missense substitutions, including R593C in the A2 domain.

OBJECTIVES:

The aim of the present study was to identify T-cell epitopes in FVIII and characterize T-cell responses in two unrelated hemophilia A subjects sharing F8-R593C and HLA-DRB1*1101 genotypes. We hypothesized that the hemophilic substitution site coincides with an important T-cell epitope.

PATIENTS/METHODS:

The binding affinities of peptides for recombinant HLA-DR proteins were measured and compared with epitope prediction results. CD4+ T cells were stimulated using peptides and stained with fluorescent, peptide-loaded tetramers.

RESULTS:

The inhibitor subjects, but not HLA-matched controls, had high-avidity HLA-DRB1*1101-restricted T-cell responses against FVIII(589-608), which contains the hemophilic missense site. Antigen-specific T cells secreted Th1 and Th2 cytokines and proliferated in response to FVIII and FVIII(592-603). FVIII(589-608) bound with physiologically relevant (micromolar) IC(50) values to recombinant DR0101, DR1101 and DR1501 proteins.

CONCLUSIONS:

Hemophilia A patients with R593C missense substitutions and these HLA haplotypes had an increased incidence of inhibitors in our cohorts, supporting a paradigm in which presentation of FVIII epitopes containing the wild-type R593 influences inhibitor risk in this hemophilia A sub-population.

PMID:
21251204
PMCID:
PMC4323178
DOI:
10.1111/j.1538-7836.2011.04202.x
[Indexed for MEDLINE]
Free PMC Article

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