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J. Exp. Med.,
Volume 189, Number 11, June 7, 1999 1791-1798
By
From the * Institute of Experimental Immunology, Department of Pathology, University Hospital,
CH-8091 Zürich, Switzerland; and the Variable (V) region gene replacement was recently implicated in B cell repertoire diversification, but the contribution of this mechanism to antibody responses is still unknown. To investigate the role of V gene replacements in the generation of antigen-specific antibodies, we analyzed antiviral immunoglobulin responses of "quasimonoclonal" (QM) mice. The B cells of
QM mice are genetically committed to exclusively express the anti-(4-hydroxy-3-nitrophenyl) acetyl specificity. However, ~20% of the peripheral B cells of QM mice undergo secondary
rearrangements and thereby potentially acquire new specificities. QM mice infected with vesicular stomatitis virus (VSV), lymphocytic choriomeningitis virus, or poliovirus mounted virus-specific neutralizing antibody responses. In general, kinetics of the antiviral immunoglobulin
responses were delayed in QM mice; however, titers similar to control animals were eventually produced that were sufficient to protect against VSV-induced lethal disease. VSV neutralizing
single-chain Fv fragments isolated from phage display libraries constructed from QM mice
showed VH gene replacements and extensive hypermutation. Thus, our data demonstrate that
secondary rearrangements and hypermutation can generate sufficient B cell diversity in QM
mice to mount protective antiviral antibody responses, suggesting that these mechanisms might
also contribute to the diversification of the B cell repertoire of normal mice.
Department of Microbiology and Immunology, University of
California, San Francisco, California 94143-0670
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