The long-standing puzzle of why nuclear antigens are targeted in systemic autoimmune diseases might have been resolved. Elizabeth Leadbetter and co-workers, reporting in Nature, show that autoreactive B cells can be triggered by self-antigens that look foreign to innate receptors.

All of us have potentially autoreactive B cells in our circulation, but these are normally kept in check. When tolerance breaks down, antibodies that are specific for DNA, RNA, nucleoproteins and immunoglobulins dominate the autoimmune response. But, it has never been clear why these specificities are selected.

Previous studies had indicated that transgenic B cells that are specific for IgG2a (a common autoantigen in systemic lupus erythematosus; SLE) can be activated by immune complexes but not monomeric antibodies. The authors have now shown that only certain immune complexes are effective — IgG2a–nucleosome complexes stimulate the B cells, but IgG2a–hapten complexes do not . Moreover, digestion with DNAse ablated the activating potential of IgG2a–nucleosome complexes, which showed that DNA was the key. It was predicted that the immune complexes activate B cells by simultaneously engaging the B-cell receptor (BCR) and a co-receptor.

Complement receptors — the most obvious co-receptor candidates — were ruled out, so the authors looked to the Toll-like receptors (TLRs). TLRs recognize conserved molecular signatures that are characteristic of microorganisms, such as hypomethylated CpG motifs in DNA. Importantly, mammalian DNA contains some CpG motifs, so it is possible that IgG2a–nucleosome immune complexes might co-ligate the IgG2a-specific BCR and a TLR.

To test this idea, the transgenic mice were crossed with mice that were deficient in Myd88, an adaptor molecule that is essential for most Tlr signalling pathways. Strikingly, Myd88−/− transgenic B cells were unresponsive to IgG2a–chromatin immune complexes.

The receptor that recognizes CpG motifs, Tlr9, is unique in that it requires endosome acidification for signalling, and specific inhibitors of endosome acidification, such as chloroquine, were shown to block the transgenic B-cell responses to IgG2a–chromatin complexes.

Co-ligation of the BCR and a TLR is an attractive mechanism to explain how autoreactive B cells that are specific for immunoglobulin or nuclear components become activated in autoimmunity. It might explain also why SLE patients benefit from chloroquine treatment.