Autoreactive B cells discriminate CpG-rich and CpG-poor DNA and this response is modulated by IFN-α

MB Uccellini, L Busconi, NM Green, P Busto… - The Journal of …, 2008 - journals.aai.org
MB Uccellini, L Busconi, NM Green, P Busto, SR Christensen, MJ Shlomchik
The Journal of Immunology, 2008journals.aai.org
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 …
Abstract
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-α 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-α can contribute to the pathogenesis of systemic lupus erythematosus.
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