|
|
Blood, 15 December 2007, Vol. 110, No. 13, pp. 4234-4242.
Prepublished online as a Blood First Edition Paper on September 11, 2007; DOI 10.1182/blood-2007-06-096842.
 Previous Article | Next Article 
Submitted June 19, 2007
Accepted August 27, 2007
Anti-human factor VIII C2 domain antibodies in hemophilia A mice recognize a functionally complex continuous spectrum of epitopes dominated by inhibitors of factor VIII activation
Shannon L. Meeks, John F Healey, Ernest T Parker, Rachel T. Barrow, and Pete Lollar*
Aflac Cancer Center and Blood Disorders Service, Children's Healthcare of Atlanta; the Department of Pediatrics, Emory University, Atlanta, GA, United States
* Corresponding author; email: jlollar{at}emory.edu.
The diversity of factor VIII (fVIII) C2 domain antibody epitopes was investigated by competition ELISA using a panel of 56 antibodies. The overlap patterns produced five groups of monoclonal antibodies (MAbs), designated A, AB, B, BC and C, and yielded a set of 18 distinct epitopes. Group-specific loss of antigenicity was associated with mutations at the Met2199/Phe2200 phospholipid binding  -hairpin (Group AB MAbs) and at Lys2227 (Group BC MAbs), which allowed orientation of the epitope structure as a continuum that covers one face of the C2 -sandwich. MAbs from Groups A, AB, and B inhibit the binding of fVIIIa to phospholipid membranes. Group BC was the most common group and displayed the highest specific fVIII inhibitor activities. MAbs in this group are Type II inhibitors that inhibit the activation of fVIII by either thrombin or factor Xa and poorly inhibit the binding of fVIII to phospholipid membranes or vWf. Group BC MAbs are epitopically and mechanistically distinct from the extensively studied Group C MAb, ESH8. These results reveal the structural and functional complexity of the anti-C2 domain antibody response and indicate that interference with fVIII activation is a major attribute of the inhibitor landscape.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
J. C. Lin, J. T. Schuman, S. L. Meeks, J. F. Healey, A. R. Thompson, and K. P. Pratt
B-Cell Epitope Mapping of Monoclonal Anti-Factor VIII C2 Domain Inhibitors: Identification of Amino Acids That Contribute Significant Antigen-Antibody Binding Affinity.
Blood (ASH Annual Meeting Abstracts),
November 16, 2008;
112(11):
1211 - 1211.
[Abstract]
|
|
|
|
|
|
|
S. L. Meeks, J. F. Healey, E. T. Parker, R. T. Barrow, and P. Lollar
Nonclassical anti-C2 domain antibodies are present in patients with factor VIII inhibitors
Blood,
August 15, 2008;
112(4):
1151 - 1153.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
