B-cell and T-cell epitopes in anti-factor VIII immune responses
- PMID: 19184559
- DOI: 10.1007/s12016-009-8120-7
B-cell and T-cell epitopes in anti-factor VIII immune responses
Abstract
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.
Similar articles
-
CD4+ T-cell epitopes associated with antibody responses after intravenously and subcutaneously applied human FVIII in humanized hemophilic E17 HLA-DRB1*1501 mice.Blood. 2012 Apr 26;119(17):4073-82. doi: 10.1182/blood-2011-08-374645. Epub 2012 Mar 6. Blood. 2012. PMID: 22394599 Free PMC article.
-
Engineering less immunogenic and antigenic FVIII proteins.Cell Immunol. 2016 Mar;301:12-7. doi: 10.1016/j.cellimm.2015.10.008. Epub 2015 Nov 2. Cell Immunol. 2016. PMID: 26566286 Free PMC article. Review.
-
In silico prediction of FVIII epitopes recognised by natural autoantibodies in polyvalent immunoglobulin concentrates.Mol Immunol. 2007 Mar;44(8):1903-13. doi: 10.1016/j.molimm.2006.09.034. Epub 2006 Nov 17. Mol Immunol. 2007. PMID: 17113150
-
T cells from hemophilia A subjects recognize the same HLA-restricted FVIII epitope with a narrow TCR repertoire.Blood. 2016 Oct 20;128(16):2043-2054. doi: 10.1182/blood-2015-11-682468. Epub 2016 Jul 28. Blood. 2016. PMID: 27471234 Free PMC article. Clinical Trial.
-
Dangerous liaisons: how the immune system deals with factor VIII.J Thromb Haemost. 2013 Jan;11(1):47-55. doi: 10.1111/jth.12065. J Thromb Haemost. 2013. PMID: 23140211 Review.
Cited by
-
Progress toward inducing immunologic tolerance to factor VIII.Blood. 2013 May 30;121(22):4449-56. doi: 10.1182/blood-2013-01-478669. Epub 2013 Mar 15. Blood. 2013. PMID: 23502223 Free PMC article. Review.
-
Phospholipid binding lowers immunogenicity of human recombinant factor VIII in von Willebrand factor knockout mice.Thromb Haemost. 2011 Jun;105(6):1115-8. doi: 10.1160/TH10-09-0628. Epub 2011 Apr 7. Thromb Haemost. 2011. PMID: 21475771 Free PMC article. No abstract available.
-
Phenotypes of allo- and autoimmune antibody responses to FVIII characterized by surface plasmon resonance.PLoS One. 2013 May 8;8(5):e61120. doi: 10.1371/journal.pone.0061120. Print 2013. PLoS One. 2013. PMID: 23667433 Free PMC article.
-
Factor VIII gene variants and inhibitor risk in African American hemophilia A patients.Blood. 2015 Aug 13;126(7):895-904. doi: 10.1182/blood-2014-09-599365. Epub 2015 Jan 23. Blood. 2015. PMID: 25617427 Free PMC article.
-
High-resolution mapping of epitopes on the C2 domain of factor VIII by analysis of point mutants using surface plasmon resonance.Blood. 2014 Apr 24;123(17):2732-9. doi: 10.1182/blood-2013-09-527275. Epub 2014 Mar 3. Blood. 2014. PMID: 24591205 Free PMC article.
References
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Research Materials