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Molecular mimicry mediated by MHC class Ib molecules after infection with Gram-negative pathogens

Abstract

The development of many autoimmune diseases has been etiologically linked to exposure to infectious agents1. For example, a subset of patients with a history of Salmonella infection develop reactive arthritis2,3,4,5,6. The persistence of bacterial antigen in arthritic tissue and the isolation of Salmonella or Yersinia reactive CD8+ T cells from the joints of patients with reactive arthritis support the etiological link between Gram-negative bacterial infection and autoimmune disease7,8. Models proposed to account for the link between infection and autoimmunity include inflammation-induced presentation of cryptic self-epitopes, antigen persistence and molecular mimicry1. Several studies support molecular mimicry as a mechanism for the involvement of class II epitopes in infectious disease-induced self-reactivity9,10,11,12. Here, we have identified an immunodominant epitope derived from the S. typhimurium GroEL molecule. This epitope is presented by the mouse H2-T23-encoded class Ib molecule Qa-1 and was recognized by CD8+ cytotoxic T lymphocytes induced after natural infection. S. typhimurium-stimulated cytotoxic T lymphocytes recognizing the GroEL epitope cross-reacted with a peptide derived from mouse heat shock protein 60 and recognized stressed macrophages. Our results indicate involvement of MHC class Ib molecules in infection-induced autoimmune recognition and indicate a mechanism for the etiological link between Gram-negative bacterial infection and autoimmunity.

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Figure 1: Identification of Salmonella-derived epitopes presented by Qa-1b.
Figure 2: Recognition of bacterial GroEL192-200 and self homolog hsp60216-224 by Qa-1b-restricted CTLs.
Figure 3: Qa-1b-restricted CTLs recognize uninfected stressed macrophages.

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Acknowledgements

We thank R. Siliciano, D. Pardoll, M. Schlissel and A. Rosen for their critical reading of the manuscript and suggestions. This work was supported by National Institutes of Health grants RO1AI20922 and RO1AI42287 and by an Award from the Maryland Chapter of the National Arthritis Foundation (M.J.S.) and by National Institutes of Health grants RO1AI32951 and USUHS R07FE (E.S.M.) and RO1GM54882 (R.J.C.).

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Correspondence to Mark J. Soloski.

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Lo, WF., Woods, A., DeCloux, A. et al. Molecular mimicry mediated by MHC class Ib molecules after infection with Gram-negative pathogens. Nat Med 6, 215–218 (2000). https://doi.org/10.1038/72329

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