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Early events in lupus humoral autoimmunity suggest initiation through molecular mimicry

Abstract

The origins of autoimmunity in systemic lupus erythematosus (SLE) are thought to involve both genetic and environmental factors. To identify environmental agents that could potentially incite autoimmunity, we have traced the autoantibody response in human SLE back in time, prior to clinical disease onset, and identified the initial autoantigenic epitope for some lupus patients positive for antibodies to 60 kDa Ro. This initial epitope directly cross-reacts with a peptide from the latent viral protein Epstein-Barr virus nuclear antigen-1 (EBNA-1). Animals immunized with either the first epitope of 60 kDa Ro or the cross-reactive EBNA-1 epitope progressively develop autoantibodies binding multiple epitopes of Ro and spliceosomal autoantigens. They eventually acquire clinical symptoms of lupus such as leukopenia, thrombocytopenia and renal dysfunction. These data support the hypothesis that some humoral autoimmunity in human lupus arises through molecular mimicry between EBNA-1 and lupus autoantigens and provide further evidence to suspect an etiologic role for Epstein-Barr virus in SLE.

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Figure 1: Serial development of Ro autoantibodies.
Figure 2: Purified Ro169–180 antibodies cross-react with EBNA-1.
Figure 3: Ro peptide–immunized animals develop cross-reactive autoimmunity.
Figure 4: Immunization with the EBNA-158–72 peptide results in human lupus–like autoimmunity.

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Acknowledgements

The authors thank J. Vaughan for the infectious mononucleosis sera, M. Reichlin and the Oklahoma Clinical Immunology Laboratory for SLE patient sera, T. Gross, Y. Akbarali, B. Bruner and T. Bruner for their technical assistance, and X. Kim for statistical analysis. This work has been supported by the US National Institutes of Health grants (AI31584, AR45451, AI47575, AR48045, AI53747, AI54117, AR45084, AR45231, AR42460, AR48940, AI24717, RR20143, RR15577, RR14467, and DE015223), the Presbyterian Health Foundation and the US Department of Veterans Affairs. The opinions and assertions contained herein are private views of the authors and are not to be construed as official or as reflecting the views of the US Army, Navy or the Department of Defense.

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Correspondence to Judith A James.

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McClain, M., Heinlen, L., Dennis, G. et al. Early events in lupus humoral autoimmunity suggest initiation through molecular mimicry. Nat Med 11, 85–89 (2005). https://doi.org/10.1038/nm1167

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