Tyrosine and glycine constitute 40% of complementarity determining region 3 of the immunoglobulin heavy chain (CDR-H3), the center of the classic antigen-binding site. To assess the role of DH RF1-encoded tyrosine and glycine in regulating CDR-H3 content and potentially influencing B cell function, we created mice limited to a single DH encoding asparagine, histidine, and arginines in RF1. Tyrosine and glycine content in CDR-H3 was halved. Bone marrow and spleen mature B cell and peritoneal cavity B-1 cell numbers were also halved, whereas marginal zone B cell numbers increased. Serum immunoglobulin G subclass levels and antibody titers to T-dependent and T-independent antigens all declined. Thus, violation of the conserved preference for tyrosine and glycine in DH RF1 alters CDR-H3 content and impairs B cell development and antibody production.
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12 June 2006
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June 05 2006
Forced usage of positively charged amino acids in immunoglobulin CDR-H3 impairs B cell development and antibody production
Gregory C. Ippolito,
Gregory C. Ippolito
1Department of Microbiology, Department of Pediatrics, Department of Medicine, Department of Pediatric Dentistry, and Department of Genetics, University of Alabama at Birmingham, SHEL 401, Birmingham, AL 35294
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Robert L. Schelonka,
Robert L. Schelonka
1Department of Microbiology, Department of Pediatrics, Department of Medicine, Department of Pediatric Dentistry, and Department of Genetics, University of Alabama at Birmingham, SHEL 401, Birmingham, AL 35294
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Michael Zemlin,
Michael Zemlin
1Department of Microbiology, Department of Pediatrics, Department of Medicine, Department of Pediatric Dentistry, and Department of Genetics, University of Alabama at Birmingham, SHEL 401, Birmingham, AL 35294
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Ivaylo I. Ivanov,
Ivaylo I. Ivanov
1Department of Microbiology, Department of Pediatrics, Department of Medicine, Department of Pediatric Dentistry, and Department of Genetics, University of Alabama at Birmingham, SHEL 401, Birmingham, AL 35294
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Ryoki Kobayashi,
Ryoki Kobayashi
1Department of Microbiology, Department of Pediatrics, Department of Medicine, Department of Pediatric Dentistry, and Department of Genetics, University of Alabama at Birmingham, SHEL 401, Birmingham, AL 35294
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Cosima Zemlin,
Cosima Zemlin
1Department of Microbiology, Department of Pediatrics, Department of Medicine, Department of Pediatric Dentistry, and Department of Genetics, University of Alabama at Birmingham, SHEL 401, Birmingham, AL 35294
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G. Larry Gartland,
G. Larry Gartland
1Department of Microbiology, Department of Pediatrics, Department of Medicine, Department of Pediatric Dentistry, and Department of Genetics, University of Alabama at Birmingham, SHEL 401, Birmingham, AL 35294
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Lars Nitschke,
Lars Nitschke
2Department of Genetics, University of Erlangen, 91058 Erlangen, Germany
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Jukka Pelkonen,
Jukka Pelkonen
3Department of Clinical Microbiology, University of Kuopio, POB 1627, 70211 Kuopio, Finland
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Kohtaro Fujihashi,
Kohtaro Fujihashi
1Department of Microbiology, Department of Pediatrics, Department of Medicine, Department of Pediatric Dentistry, and Department of Genetics, University of Alabama at Birmingham, SHEL 401, Birmingham, AL 35294
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Klaus Rajewsky,
Klaus Rajewsky
4The Center for Blood Research, Harvard Medical School, Boston, MA 02115
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Harry W. Schroeder, Jr.
Harry W. Schroeder, Jr.
1Department of Microbiology, Department of Pediatrics, Department of Medicine, Department of Pediatric Dentistry, and Department of Genetics, University of Alabama at Birmingham, SHEL 401, Birmingham, AL 35294
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Gregory C. Ippolito
1Department of Microbiology, Department of Pediatrics, Department of Medicine, Department of Pediatric Dentistry, and Department of Genetics, University of Alabama at Birmingham, SHEL 401, Birmingham, AL 35294
Robert L. Schelonka
1Department of Microbiology, Department of Pediatrics, Department of Medicine, Department of Pediatric Dentistry, and Department of Genetics, University of Alabama at Birmingham, SHEL 401, Birmingham, AL 35294
Michael Zemlin
1Department of Microbiology, Department of Pediatrics, Department of Medicine, Department of Pediatric Dentistry, and Department of Genetics, University of Alabama at Birmingham, SHEL 401, Birmingham, AL 35294
Ivaylo I. Ivanov
1Department of Microbiology, Department of Pediatrics, Department of Medicine, Department of Pediatric Dentistry, and Department of Genetics, University of Alabama at Birmingham, SHEL 401, Birmingham, AL 35294
Ryoki Kobayashi
1Department of Microbiology, Department of Pediatrics, Department of Medicine, Department of Pediatric Dentistry, and Department of Genetics, University of Alabama at Birmingham, SHEL 401, Birmingham, AL 35294
Cosima Zemlin
1Department of Microbiology, Department of Pediatrics, Department of Medicine, Department of Pediatric Dentistry, and Department of Genetics, University of Alabama at Birmingham, SHEL 401, Birmingham, AL 35294
G. Larry Gartland
1Department of Microbiology, Department of Pediatrics, Department of Medicine, Department of Pediatric Dentistry, and Department of Genetics, University of Alabama at Birmingham, SHEL 401, Birmingham, AL 35294
Lars Nitschke
2Department of Genetics, University of Erlangen, 91058 Erlangen, Germany
Jukka Pelkonen
3Department of Clinical Microbiology, University of Kuopio, POB 1627, 70211 Kuopio, Finland
Kohtaro Fujihashi
1Department of Microbiology, Department of Pediatrics, Department of Medicine, Department of Pediatric Dentistry, and Department of Genetics, University of Alabama at Birmingham, SHEL 401, Birmingham, AL 35294
Klaus Rajewsky
4The Center for Blood Research, Harvard Medical School, Boston, MA 02115
Harry W. Schroeder, Jr.
1Department of Microbiology, Department of Pediatrics, Department of Medicine, Department of Pediatric Dentistry, and Department of Genetics, University of Alabama at Birmingham, SHEL 401, Birmingham, AL 35294
CORRESPONDENCE Harry W. Schroeder Jr.: [email protected]
Abbreviations used: ΔD-DFL, depleted DH locus with single DFL16.1 gene segment; ΔD-iD, depleted DH locus with a single, mutated DFL16.1 gene segment containing inverted DSP 2.2 sequence; CDR-H3, complementarity determining region 3 of the immunoglobulin heavy chain; DEX, α(1→3)-dextran; i-RF, inverted DH reading frame; NP19-CGG, [4-hydroxy-3-nitrophenyl] acetyl-chicken γ globulin; RF, reading frame; TT, tetanus toxin.
Received:
November 02 2005
Accepted:
May 05 2006
Online ISSN: 1540-9538
Print ISSN: 0022-1007
The Rockefeller University Press
2006
J Exp Med (2006) 203 (6): 1567–1578.
Article history
Received:
November 02 2005
Accepted:
May 05 2006
Citation
Gregory C. Ippolito, Robert L. Schelonka, Michael Zemlin, Ivaylo I. Ivanov, Ryoki Kobayashi, Cosima Zemlin, G. Larry Gartland, Lars Nitschke, Jukka Pelkonen, Kohtaro Fujihashi, Klaus Rajewsky, Harry W. Schroeder; Forced usage of positively charged amino acids in immunoglobulin CDR-H3 impairs B cell development and antibody production . J Exp Med 12 June 2006; 203 (6): 1567–1578. doi: https://doi.org/10.1084/jem.20052217
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