T cell recognition of the A2 domain of coagulation factor VIII in hemophilia patients and healthy subjects.
Hemophilia A patients treated with coagulation factor VIII (FVIII), and also some healthy subjects, may develop anti-FVIII antibodies (Ab), whose synthesis is driven by FVIII-specific CD4+ T cells. Some Ab block the procoagulant function of FVIII (inhibitors). Many inhibitors recognize epitopes on the FVIII A2 domain. Here, we have sought to identify A2 epitopes recognized by CD4+ T cells. We tested the proliferative response of CD4+ blood lymphocytes (BL) from hemophilia patients and healthy subjects, to overlapping synthetic peptides spanning the A2 domain sequence. Many A2 peptides induced proliferative responses of CD4+ BL from one or more subjects. The peptide-induced responses were strongest in hemophilia patients with inhibitors, weakest in healthy subjects. A2 peptides comprising residues 371-400, 621-650 and 671-690 elicited frequent and strong responses in hemophilia A patients, and especially in those with inhibitors. Healthy subjects recognized frequently only the sequence 371-400. A three-dimensional model of the A2 domain suggests that these CD4+ epitope sequences have structural features typical of 'universal' CD4+ T epitopes.
Hu
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GL
Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, Minnesota 55455, USA. huxxx057@umn.edu
Okita
D K
DK
Conti-Fine
B M
BM
D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D016022:Case-Control Studies; D049109:Cell Proliferation; D018604:Epitope Mapping; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005169:Factor VIII / Q000276:immunology*; D006467:Hemophilia A / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000276:immunology / Q000494:pharmacology; D017434:Protein Structure, Tertiary
D018984:Epitopes, T-Lymphocyte; D010446:Peptide Fragments; D005169:Factor VIII