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

Int Immunol. 1999 Oct;11(10):1693-700. doi: 10.1093/intimm/11.10.1693.


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.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antibodies / metabolism
  • Antibody Specificity
  • B-Lymphocytes / immunology*
  • Cell Count
  • Cells, Cultured
  • DNA Methylation
  • Dextrans / metabolism
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Immunoglobulin D / immunology
  • Immunoglobulin G / analysis
  • Immunoglobulin M / analysis
  • Immunoglobulins / biosynthesis*
  • Lymphocyte Activation*
  • Mice
  • Mice, Inbred Strains
  • Receptors, Antigen, B-Cell / metabolism*
  • Spleen / cytology


  • Antibodies
  • Dextrans
  • Immunoglobulin D
  • Immunoglobulin G
  • Immunoglobulin M
  • Immunoglobulins
  • Receptors, Antigen, B-Cell