B-cell and T-cell epitopes in anti-factor VIII immune responses.
Adequate hemostasis is achieved for many hemophilia A patients by infusion of plasma-derived or recombinant factor VIII (FVIII), but unfortunately, a significant subset of patients develop an immune response in which anti-FVIII antibodies, referred to clinically as "inhibitors," interfere with its procoagulant activity. Inhibitors are the subset of anti-FVIII antibodies that bind to surfaces on FVIII (B-cell epitopes) that are important for its proper functioning in coagulation. Less antigenic FVIII molecules may be designed by identifying and then modifying the amino acid sequences of inhibitor B-cell epitopes. Conversely, characterization of these epitopes can yield important information regarding functionally important surfaces on FVIII. The production of inhibitor antibodies is driven by T cells. T cells recognize FVIII as foreign when FVIII-derived peptides bind to major histocompatibility complex (MHC) class II molecules on the surface of antigen-presenting cells. The class II-peptide complexes must then be recognized by T-cell receptors (TCRs). T-cell stimulation requires sustained association of antigen-presenting cells and T cells through formation of a class II-peptide-TCR complex, and peptide sequences that mediate this association are termed "T-cell epitopes." MHC class II tetramers that bind FVIII-derived peptides and recognize antigen-specific TCRs are proving useful in the characterization of human leukocyte antigen-restricted T-cell responses to FVIII.
Pratt
Kathleen P
KP
Puget Sound Blood Center, 921 Terry Ave, Seattle, WA 98104-1256, USA. kathleenp@psbcresearch.org
Thompson
Arthur R
AR
D001323:Autoantibodies / Q000276:immunology* / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology; D018985:Epitopes, B-Lymphocyte / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005169:Factor VIII / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D006467:Hemophilia A / Q000097:blood / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation; D008958:Models, Molecular; D013601:T-Lymphocytes / Q000276:immunology
D001323:Autoantibodies; D018985:Epitopes, B-Lymphocyte; D018984:Epitopes, T-Lymphocyte; D007074:Immunoglobulin G; D005169:Factor VIII