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HLA‐DR‐restricted T‐cell responses to factor VIII epitopes in a mild haemophilia A family with missense substitution A2201P
Author(s) -
ETTINGER R. A.,
JAMES E. A.,
KWOK W. W.,
THOMPSON A. R.,
PRATT K. P.
Publication year - 2010
Publication title -
haemophilia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.213
H-Index - 92
eISSN - 1365-2516
pISSN - 1351-8216
DOI - 10.1111/j.1365-2516.2008.01905.x
Subject(s) - epitope , haemophilia a , missense mutation , antigen , microbiology and biotechnology , human leukocyte antigen , immunology , medicine , t cell , virology , biology , mutation , immune system , genetics , haemophilia , gene , pediatrics
Summary. An HLA‐DRA‐DRB1*0101‐restricted T‐cell epitope in the factor VIII (FVIII) C2 domain occurred in a mild haemophilia A patient with missense substitution FVIII‐A2201P. His T cells responded to synthetic peptides FVIII 2186–2205 and FVIII 2194–2213 ( J Thromb Haemost 2007; 5: 2399). T cells from family members with genotype FVIII‐A2201P were analysed to determine if FVIII‐specific T cells occur in individuals with a haemophilic mutation but no clinically significant inhibitor response. Fluorescent MHC class II tetramers corresponding to subjects’ HLA‐DRB1 types were loaded with 20‐mer peptides and utilized to label antigen‐specific CD4+ T cells. T‐cell responses to peptides spanning the FVIII‐C2 sequence were evaluated. T cells recognizing specific peptides were cloned, and antigen specificity was verified by proliferation assays. Plasma and/or purified IgG samples were tested for FVIII inhibitory activity. CD4+ T cells and T‐cell clones from two brothers who shared the DRB1*0101 allele responded to FVIII 2194–2213 . A haemophilic cousin’s HLA‐DRA‐DRB1*1104‐restricted response to FVIII 2202–2221 was detected only when CD4+CD25+ cells were depleted. A great uncle and two obligate carriers had no detectable FVIII‐C2‐specific T cells. Concentrated IgG from the brother without a clinical inhibitor response showed a low‐titre FVIII inhibitor. FVIII‐specific T cells and inhibitory IgG were found in a previously infused, haemophilic subject who had a sub‐clinical FVIII inhibitor. CD4+CD25+ depleted T cells from a non‐infused haemophilic cousin recognized an overlapping FVIII epitope, indicating a latent HLA‐DRA‐DRB1*1104‐restricted T‐cell response to FVIII. Specific T‐cell responses to FVIII can occur without clinically significant inhibitors.