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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. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2007-06-096842v1 110/13/4234    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Meeks, S. L. Articles by Lollar, P. Search for Related Content PubMed PubMed Citation Articles by Meeks, S. L. Articles by Lollar, P. Related Collections Hemostasis, Thrombosis, and Vascular Biology Immunobiology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Antihuman 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. Meeks1, John F. Healey1, Ernest T. Parker1, Rachel T. Barrow1, and Pete Lollar1 1 Aflac Cancer Center and Blood Disorders Service, Children's Healthcare of Atlanta, Department of Pediatrics, Emory University, Atlanta, GA The diversity of factor VIII (fVIII) C2 domain antibody epitopes was investigated by competition enzyme-linked immunosorbent assay (ELISA) using a panel of 56 antibodies. The overlap patterns produced 5 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 β-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 β-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 von Willebrand factor (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]

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