 | IMMUNE MECHANISMS AND DISEASE
Copyright © 2003 by the New York Academy of Sciences
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Annals of the New York Academy of Sciences 987:270-273 (2003)
© 2003 New York Academy of Sciences
Molecular Mechanism of Serial VH Gene Replacement
ZHIXIN ZHANGa,
YUI-HSI WANGa,
MICHAEL ZEMLINa,
HARRY W. FINDLEYb,
S. LOUIS BRIDGESc,
PETER D. BURROWSa AND
MAX D. COOPERa,d
aDivision of Developmental and Clinical Immunology, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA
bDivision of Pediatric Hematology/Oncology/Bone Marrow Transplantation, Emory University School of Medicine, Atlanta, Georgia 30322, USA
cDivision of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA
dThe Howard Hughes Medical Institute, Birmingham, Alabama 35294, USA
Address for correspondence: Max D. Cooper, M.D., University of Alabama at Birmingham, WTI378, 1824 6th Avenue South, Birmingham, Alabama 35294-3300. Voice: 205-975-7204; fax: 205-934-1875.
max.cooper{at}ccc.uab.edu
Ann, N.Y. Acad. Sci. 987: 270-273 (2003).
The molecular mechanism of serial VH replacement was analyzed using a human B cell line, EU12, that undergoes continuous spontaneous differentiation from pro-B to pre-B and then to B cell stage. In earlier studies, we found that this cell line undergoes intraclonal V(D)J diversification. Analysis of the IgH gene sequences in EU12 cells predicted the occurrence of serial VH replacement involving the cryptic recombination signal sequences (cRSS) embedded within framework 3 regions and concurrent extension of the CDR3 region. Detection of double-stranded DNA breaks at the cRSS site and different VH replacement excision circles confirm the ongoing nature of this diversification process in the EU12 cells. In vitro binding and cleavage assays using recombinant RAG-1 and RAG-2 proteins further validated the cRSS participation in this RAG-mediated recombination process. Serial VH replacements may represent an additional mechanism for diversification of the primary B cell repertoire.
Key Words: molecular mechanism • serial VH replacement • Khuman B cell • VH gene • VL gene • double-stranded DNA
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