International Immunology, Vol. 11, No. 10, 1693-1700,
October 1999
© 1999 Japanese Society for Immunology
Multivalent cross-linking of membrane Ig sensitizes murine B cells to a broader spectrum of CpG-containing oligodeoxynucleotide motifs, including their methylated counterparts, for stimulation of proliferation and Ig secretion
1 Departments of Medicine and
2 Pathology, and
3 Biomedical Instrumentation Center, Uniformed Services University of the Health Sciences, Bethesda, MD 20814-4799, USA
4 Rheumatology Service, Department of Medicine, Walter Reed Army Medical Center, Washington, DC 20307, USA
5 Medical Research Service, Durham Veterans Administration Hospital, Division of Immunology, Division of Rheumatology and Immunology, Duke University Medical Center, Durham, NC 27710, USA
6 Retroviral Immunology Section, Center for Biologics Evaluation, Food and Drug Administration, Bethesda, MD 20892, USA
Correspondence to: B. E. Goeckeritz
We have previously reported that B cells that are activated by multivalent but not bivalent membrane Ig cross-linking ligands synergize with various B cell activators culminating in enhanced B cell proliferation. In this study we asked whether B cells that are activated by a multivalent mIg cross-linking agonist could respond to oligodeoxynucleotides (ODN) containing non-stimulatory motifs. Earlier reports have shown that ODN containing a CpG motif in which the cytosine is unmethylated and is flanked by two 5' purines and two 3' pyrimidines induce high levels of B cell activation, while ODN whose CpG are methylated or flanked by sequences other than the optimal two 5' purines and two 3' pyrimidines were non-stimulatory. In this manuscript we show that when B cells are stimulated in vitro with dextran-conjugated anti-IgD antibodies (anti-IgD–dex), as the multivalent mIg ligand, their proliferation is enhanced and they can be induced to secrete Ig in response to ODN containing various non-optimal motifs, both methylated and non-methylated. Furthermore we could induce synergistic levels of proliferation with concentrations of anti-IgD–dex that were in the picomolar concentration range and with concentrations of ODN that were 10- to 100-fold less than previously reported to be necessary for mitogenic activity. These data provided a model to explain how low concentrations of a multi-epitope-expressing microorganism in the context of mammalian (methylated) or microorganism (non-methylated) DNA can lead to dysregulated B cell proliferation and Ig secretion.
Keywords: antibodies, B lymphocytes, cellular activation, CpG, oligodeoxynucleotides, rodent, spleen
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  A. D. Henn, J. Rebhahn, M. A. Brown, A. J. Murphy, M. N. Coca, O. Hyrien, T. Pellegrin, T. Mosmann, and M. S. Zand Modulation of Single-Cell IgG Secretion Frequency and Rates in Human Memory B Cells by CpG DNA, CD40L, IL-21, and Cell Division J. Immunol., September 1, 2009; 183(5): 3177 - 3187. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. B. Uccellini, L. Busconi, N. M. Green, P. Busto, S. R. Christensen, M. J. Shlomchik, A. Marshak-Rothstein, and G. A. Viglianti Autoreactive B Cells Discriminate CpG-Rich and CpG-Poor DNA and This Response Is Modulated by IFN-{alpha} J. Immunol., November 1, 2008; 181(9): 5875 - 5884. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Lartigue, P. Courville, I. Auquit, A. Francois, C. Arnoult, F. Tron, D. Gilbert, and P. Musette Role of TLR9 in Anti-Nucleosome and Anti-DNA Antibody Production in lpr Mutation-Induced Murine Lupus J. Immunol., July 15, 2006; 177(2): 1349 - 1354. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. L. Fields, M. H. Metzgar, B. D. Hondowicz, S.-A. Kang, S. T. Alexander, K. D. Hazard, A. C. Hsu, Y.-Z. Du, E. L. Prak, M. Monestier, et al. Exogenous and Endogenous TLR Ligands Activate Anti-Chromatin and Polyreactive B Cells. J. Immunol., June 1, 2006; 176(11): 6491 - 6502. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Nordstrom, J. Jendholm, M. Samuelsson, A. Forsgren, and K. Riesbeck The IgD-binding domain of the Moraxella IgD-binding protein MID (MID962-1200) activates human B cells in the presence of T cell cytokines J. Leukoc. Biol., February 1, 2006; 79(2): 319 - 329. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. R. Christensen, M. Kashgarian, L. Alexopoulou, R. A. Flavell, S. Akira, and M. J. Shlomchik Toll-like receptor 9 controls anti-DNA autoantibody production in murine lupus J. Exp. Med., July 18, 2005; 202(2): 321 - 331. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. A. Trouw, S. C. Nilsson, I. Goncalves, G. Landberg, and A. M. Blom C4b-binding protein binds to necrotic cells and DNA, limiting DNA release and inhibiting complement activation J. Exp. Med., June 20, 2005; 201(12): 1937 - 1948. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Poeck, M. Wagner, J. Battiany, S. Rothenfusser, D. Wellisch, V. Hornung, B. Jahrsdorfer, T. Giese, S. Endres, and G. Hartmann Plasmacytoid dendritic cells, antigen, and CpG-C license human B cells for plasma cell differentiation and immunoglobulin production in the absence of T-cell help Blood, April 15, 2004; 103(8): 3058 - 3064. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Thyagarajan, N. Arunkumar, and W. Song Polyvalent Antigens Stabilize B Cell Antigen Receptor Surface Signaling Microdomains J. Immunol., June 15, 2003; 170(12): 6099 - 6106. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. J. Stacey, G. R. Young, F. Clark, D. P. Sester, T. L. Roberts, S. Naik, M. J. Sweet, and D. A. Hume The Molecular Basis for the Lack of Immunostimulatory Activity of Vertebrate DNA J. Immunol., April 1, 2003; 170(7): 3614 - 3620. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Wang and A. M. Krieg Synergy between CpG- or non-CpG DNA and specific antigen for B cell activation Int. Immunol., February 1, 2003; 15(2): 223 - 231. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Gursel, M. Gursel, K. J. Ishii, and D. M. Klinman Sterically Stabilized Cationic Liposomes Improve the Uptake and Immunostimulatory Activity of CpG Oligonucleotides J. Immunol., September 15, 2001; 167(6): 3324 - 3328. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Xu and K.-P. Lam B-Cell Maturation Protein, Which Binds the Tumor Necrosis Factor Family Members BAFF and APRIL, Is Dispensable for Humoral Immune Responses Mol. Cell. Biol., June 15, 2001; 21(12): 4067 - 4074. [Abstract] [Full Text]
|
|
|
|
|
|
G. J. Weiner The immunobiology and clinical potential of immunostimulatory CpG oligodeoxynucleotides J. Leukoc. Biol., October 1, 2000; 68(4): 455 - 463. [Abstract] [Full Text]
|
|