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Differential Cytokine Production and Bystander Activation of Autoreactive B Cells in Response to CpG-A and CpG-B Oligonucleotides¹

Ana M. Avalos,^* Eicke Latz, Betty Mousseau, Sean R. Christensen, Mark J. Shlomchik, Frances Lund, and Ann Marshak-Rothstein^2*

^*Department of Microbiology, Boston University School of Medicine, Boston, MA 02118; Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605; Division of Allergy, Immunology and Rheumatology, University of Rochester Medical Center, Rochester, NY 14620; and Section of Immunology, Yale University School of Medicine, New Haven, CT 06520

Synthetic oligonucleotides containing CpG motifs have been shown to induce proliferation, differentiation, and cytokine production in B cells, macrophages, and dendritic cells through a TLR9-dependent mechanism. A class (CpG-A) and B class (CpG-B) oligonucleotides display distinct physical properties. CpG-A, but not CpG-B, can multimerize to form exceedingly large lattices. CpG-A cannot effectively activate B cells but does induce plasmacytoid dendritic cells to produce high levels of IFN, while CpG-B is a potent B cell mitogen. In this study, we report that CpG-A is internalized by B cells, and CpG-A and CpG-B accumulate in distinct intracellular compartments. When present in the form of an immune complex (CpG-A IC), CpG-A is taken up more efficiently by AM14 IgG2a-specific B cells, and elicits a robust TLR9-dependent B cell proliferative response. B cells proliferating comparably and in a TLR9-dependent fashion in response to CpG-A IC and CpG-B exhibited distinct cytokine profiles. CpG-A IC induced enhanced production of RANTES and markedly reduced levels of IL-6 when compared with CpG-B. We also found that engagement of the AM14 BCR by a protein IC, which cannot by itself induce proliferation, promoted TLR9-dependent but BCR-independent proliferation by bystander CpG-A or fragments of mammalian dsDNA. These data identify direct and indirect mechanisms by which BCR engagement facilitates access of exogenous ligands to TLR9-associated compartments and subsequent B cell activation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants AR050256 and AR35230 (to A.M.R.) and RO1 AI068056 (to F.L.).

² Address correspondence and reprint requests to Dr. Ann Marshak-Rothstein, Department of Microbiology, Boston University School of Medicine, Boston, MA 02118. E-mail address: amrothst{at}bu.edu

³ Abbreviations used in this paper: ODN, oligonucleotide; CpG-A, CpG class A; CpG-B, CpG class B; DC, dendritic cell; pDC, plasmacytoid DC; IC, immune complex; LAMP, lysosome associated membrane protein.