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Dangerous liaisons: how the immune system deals with factor VIII.
MedLine Citation:
PMID:  23140211     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Only a fraction of hemophilia A patients develops a neutralizing antibody (inhibitor) response to therapeutic infusions of factor VIII (FVIII). Our present understanding of the underlying causes of the immunogenicity of this protein is limited. In the past few years, insights into the uptake and processing of FVIII by antigen presenting cells (APCs) have expanded significantly. While the mechanism of endocytosis remains unclear, current data indicate that FVIII enters APCs via its C1 domain. Its subsequent processing within endolysosomes allows for presentation of a heterogeneous collection of FVIII peptides on MHC class II, and this peptide-MHC class II complex may then be recognized by cognate effector CD4(+) T cells, leading to anti-FVIII antibody production. Here we aim to summarize recent knowledge gained on FVIII processing and presentation by APCs, as well as the diversity of the FVIII-specific T-cell repertoire in mice and men. Moreover, we discuss possible factors that can drive FVIII immunogenicity. We believe that increasing understanding of immune recognition of FVIII and the cellular mechanisms of anti-FVIII antibody production will lead to novel therapeutic approaches to prevent inhibitor formation in patients with hemophilia A. © 2012 International Society on Thrombosis and Haemostasis.
Authors:
A Wroblewska; B M Reipert; K P Pratt; J Voorberg
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-11-12
Journal Detail:
Title:  Journal of thrombosis and haemostasis : JTH     Volume:  -     ISSN:  1538-7836     ISO Abbreviation:  J. Thromb. Haemost.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-11-12     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101170508     Medline TA:  J Thromb Haemost     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
© 2012 International Society on Thrombosis and Haemostasis.
Affiliation:
Department of Plasma Proteins, Sanquin-AMC Landsteiner Laboratory and Van Creveld Laboratory, Amsterdam, Netherlands Baxter BioScience, Vienna, Austria Puget Sound Blood Center Research Institute and Division of Hematology, University of Washington, Seattle, WA, USA.
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