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
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