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Autoreactive B Cells Discriminate CpG-Rich and CpG-Poor DNA and This Response Is Modulated by IFN-¹

Melissa B. Uccellini^*, Liliana Busconi^*, Nathaniel M. Green^*, Patricia Busto^*, Sean R. Christensen, Mark J. Shlomchik, Ann Marshak-Rothstein^2,* and Gregory A. Viglianti^2,3,*

^* Department of Microbiology and Immunology Training Program, Boston University School of Medicine, Boston, MA 02118; and Section of Immunology, Yale University School of Medicine, New Haven, CT 06520

Autoreactive B cells are activated by DNA, chromatin, or chromatin-containing immune complexes (ICs) through a mechanism dependent on dual engagement of the BCR and TLR9. We examined the contribution of endogenous DNA sequence elements to this process. DNA sequence can determine both recognition by the BCR and by TLR9. DNA fragments containing CpG islands, a natural source of unmethylated CpG dinucleotides, promote the activation of DNA-reactive B cells derived from BCR transgenic mice as well as DNA-reactive B cells present in the normal repertoire. ICs containing these CpG island fragments are potent ligands for AM14 IgG2a-reactive B cells. In contrast, ICs containing total mammalian DNA, or DNA fragments lacking immunostimulatory motifs, fail to induce B cell proliferation, indicating that BCR crosslinking alone is insufficient to activate low-affinity autoreactive B cells. Importantly, priming B cells with IFN- lowers the BCR activation threshold and relaxes the selectivity for CpG-containing DNA. Taken together, our findings underscore the importance of endogenous CpG-containing DNAs in the TLR9-dependent activation of autoreactive B cells and further identify an important mechanism through which IFN- can contribute to the pathogenesis of systemic lupus erythematosus.

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 T32 AI07309.

² A.M.-R. and G.A.V. contributed equally as senior authors.

³ Address correspondence and reprint requests to Dr. Gregory A. Viglianti, Department of Microbiology, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118. E-mail address: gviglian{at}bu.edu

⁴ Abbreviations used in this paper: SLE, systemic lupus erythematosus; DC, dendritic cell; IC, immune complex; HEL, hen egg lysozyme; KI, knock-in; LINE, long interspersed nuclear elements; ODN, oligonucleotide; PD, phosphodiester; PS, phosphorothioate; Pu, purine; Py, pyrimidine; PLC, phospholipase C; RF, rheumatoid factor; Senp, sentrin-specific peptidase; Sumo, small ubiquitin-related modifier; TNP, trinitrophenol; Tg, transgenic.