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Resistance to CpG DNA–induced autoimmunity through tolerogenic B cell antigen receptor ERK signaling

Nature Immunology volume 4, pages 594–600 (2003)Cite this article

Abstract

CpG sequences in self-DNA are an important potential trigger for autoantibody secretion in systemic lupus and other systemic autoimmune disorders. It is not known how this ubiquitous threat may be controlled by active mechanisms for maintaining self tolerance. Here we show that two distinct mechanisms oppose autoantibody secretion induced by CpG DNA in anergic B cells that are constantly binding self-antigen. Uncoupling of the antigen receptor (BCR) from a calcineurin-dependent pathway prevents signals that synergize with CpG DNA for proliferation. The BCR does not become desensitized by activating the extracellular response kinase (ERK) MAP kinase pathway, however, and continuous self-antigen signaling to ERK inhibits CpG DNA–induced plasma cell differentiation. These two mechanisms seem to act as a general control against autoantibody production elicited by Toll-like receptors, and their regulation of T cell–independent responses to Toll-like receptor 9 (TLR9) is probably crucial for resistance to systemic autoimmunity.

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Figure 1: Selective responses to concurrent BCR and TLR9 in anergic B cells.
Figure 2: Self antigen–mediated inhibition of plasma cell differentiation.
Figure 3: Blockade of BCR-mediated inhibition of plasma cell differentiation by PD98059 treatment.
Figure 4: Persistent but not transient exposure to antigen inhibits plasma cell differentiation.
Figure 5: Overexpressed MEK* blocks CpG DNA–induced plasma cell differentiation.

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Acknowledgements

We thank N. Ahn for the MEK* cDNA, K. Sullivan and the staff of the Medical Genome Center for care and breeding of the transgenic mice and A. Murtagh and S. Ewing for genotyping. C.G.V. is a recipient of a Wellcome Trust International Prize Traveling Fellowship. Supported by a grant from the National Health and Medical Research Council of Australia.

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  1. ACRF Genetics Laboratory and Medical Genome Centre, John Curtin School of Medical Research, Australian National University, Canberra, ACT 2601, Australia

    Lixin Rui, Carola G Vinuesa, Julie Blasioli & Christopher C Goodnow

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Correspondence to Christopher C Goodnow.

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Rui, L., Vinuesa, C., Blasioli, J. et al. Resistance to CpG DNA–induced autoimmunity through tolerogenic B cell antigen receptor ERK signaling. Nat Immunol 4, 594–600 (2003). https://doi.org/10.1038/ni924

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