Resistance to CpG DNA-induced autoimmunity through tolerogenic B cell antigen receptor ERK signaling.
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.
Rui
Lixin
L
ACRF Genetics Laboratory and Medical Genome Centre, John Curtin School of Medical Research, Australian National University, Canberra ACT 2601, Australia.
Vinuesa
Carola G
CG
Blasioli
Julie
J
Goodnow
Christopher C
CC
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology*; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D019703:Calcineurin / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D018899:CpG Islands / Q000276:immunology*; D004247:DNA / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000276:immunology / Q000378:metabolism; D005786:Gene Expression Regulation / Q000276:immunology; D008177:Lupus Vulgaris / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000276:immunology* / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000276:immunology* / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D051217:Toll-Like Receptor 9
D004268:DNA-Binding Proteins; D011947:Receptors, Antigen, B-Cell; D011956:Receptors, Cell Surface; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D004247:DNA; D020928:Mitogen-Activated Protein Kinases; D019703:Calcineurin