T-cell responses in two unrelated hemophilia A inhibitor subjects include an epitope at the factor VIII R593C missense site
| Autor: | Ruth A. Ettinger, Jan Voorberg, S. D. Van Haren, Kathleen P. Pratt, Eddie A. James, Karin Fijnvandraat, William W. Kwok, Joseph A. Liberman |
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| Přispěvatelé: | ACS - Amsterdam Cardiovascular Sciences, AII - Amsterdam institute for Infection and Immunity, Paediatric Infectious Diseases / Rheumatology / Immunology, Landsteiner Laboratory |
| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
congenital
hereditary and neonatal diseases and abnormalities T cell T-Lymphocytes Molecular Sequence Data Mutation Missense Enzyme-Linked Immunosorbent Assay Human leukocyte antigen Biology Hemophilia A Epitope Article law.invention Epitopes law hemic and lymphatic diseases medicine Missense mutation Humans Amino Acid Sequence Peptide sequence HLA-DR Antigen Cell Proliferation Factor VIII Hematology HLA-DR Antigens medicine.anatomical_structure Immunology Recombinant DNA biology.protein Antibody HLA-DRB1 Chains |
| Zdroj: | Journal of thrombosis and haemostasis, 9(4), 689-699. Wiley-Blackwell |
| ISSN: | 1538-7933 |
| Popis: | Summary. 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 FVIII589–608, which contains the hemophilic missense site. Antigen-specific T cells secreted Th1 and Th2 cytokines and proliferated in response to FVIII and FVIII592–603. FVIII589–608 bound with physiologically relevant (micromolar) IC50 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. |
| Databáze: | OpenAIRE |
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