Abstract
It remains unclear how and why autoimmunity occurs. Here we show evidence for a previously unrecognized and possibly general mechanism of autoimmunity. This new finding was discovered serendipitously using material from patients with inflammatory vascular disease caused by antineutrophil cytoplasmic autoantibodies (ANCA) with specificity for proteinase-3 (PR-3). Such patients harbor not only antibodies to the autoantigen (PR-3), but also antibodies to a peptide translated from the antisense DNA strand of PR-3 (complementary PR-3, cPR-3) or to a mimic of this peptide. Immunization of mice with the middle region of cPR-3 resulted in production of antibodies not only to cPR-3, but also to the immunogen's sense peptide counterpart, PR-3. Both human and mouse antibodies to PR-3 and cPR-3 bound to each other, indicating idiotypic relationships. These findings indicate that autoimmunity can be initiated through an immune response against a peptide that is antisense or complementary to the autoantigen, which then induces anti-idiotypic antibodies (autoantibodies) that cross-react with the autoantigen.
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Acknowledgements
This work was supported by National Institutes of Health grant NIHDK-58335-01. The authors wish to thank M. Gaido for her contributions to the initial epitope mapping studies that provided clues for future direction; S.L. Hogan for statistical analysis of the data; M. Segelmark, T. Hellmark and J. Wieslander of the Department of Nephrology at the Lund University Hospital for the pcDNA3/his plasmid, purified proteinase-3, rabbit anti-PR-3 serum and guidance with the technical aspects of the PR-3-ANCA affinity purification; R.J. Preston for recommending the antisense transcript studies and for helpful comments on the manuscript; B.M. Pressler for technical assistance, discussions and comments regarding the antisense transcripts; T. Vision for help with searches for complementary proteins in sequence databases; J.J. Yang for technical assistance with antibody purification and animal handling; H. Xiao for assistance with animal immunizations; B. Siaton and E.H. Rudolph for technical assistance; and A.S. Wilkman and B.D. Phillips for assistance with human material acquisition.
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Pendergraft, W., Preston, G., Shah, R. et al. Autoimmunity is triggered by cPR-3(105–201), a protein complementary to human autoantigen proteinase-3. Nat Med 10, 72–79 (2004). https://doi.org/10.1038/nm968
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DOI: https://doi.org/10.1038/nm968
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