Pathogenic Autoreactive T and B Cells Cross-React with Mimotopes Expressed by a Common Human Gut Commensal to Trigger Autoimmunity

William E. Ruff, Carina Dehner, W. J. Kim, Odelya Pagovich, Cassyanne L. Aguiar, Andrew T. Yu, Alexander S. Roth, Silvio Manfredo Vieira, Christina Kriegel, Olamide Adeniyi, Melissa J. Mulla, Vikki M. Abrahams, William W. Kwok, Ruth Nussinov, D. Erkan, Andrew L. Goodman, Martin A. Kriegel

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Given the immense antigenic load present in the microbiome, we hypothesized that microbiota mimotopes can be a persistent trigger in human autoimmunity via cross-reactivity. Using antiphospholipid syndrome (APS) as a model, we demonstrate cross-reactivity between non-orthologous mimotopes expressed by a common human gut commensal, Roseburia intestinalis (R. int), and T and B cell autoepitopes in the APS autoantigen β2-glycoprotein I (β2GPI). Autoantigen-reactive CD4+ memory T cell clones and an APS-derived, pathogenic monoclonal antibody cross-reacted with R. int mimotopes. Core-sequence-dependent anti-R. int mimotope IgG titers were significantly elevated in APS patients and correlated with anti-β2GPI IgG autoantibodies. R. int immunization of mice induced β2GPI-specific lymphocytes and autoantibodies. Oral gavage of susceptible mice with R. int induced anti-human β2GPI autoantibodies and autoimmune pathologies. Together, these data support a role for non-orthologous commensal-host cross-reactivity in the development and persistence of autoimmunity in APS, which may apply more broadly to human autoimmune disease. Commensal-derived antigens may contribute to autoimmunity by coincidentally mimicking immune-targeted self-structures. Ruff et al. report that human autoreactive lymphocytes and autoantibodies cross-react with homologous regions expressed by the human gut commensal Roseburia intestinalis. Pathogenic APS-generated autoantibodies target bacterial DNA methyltransferase. Gavage of susceptible mice with R. intestinalis triggers autoimmune pathologies.

Original languageEnglish (US)
Pages (from-to)100-113.e8
JournalCell Host and Microbe
Volume26
Issue number1
DOIs
StatePublished - Jul 10 2019

Keywords

  • Bacteroides thetaiotaomicron
  • DNA methyltransferase
  • IgA-coated bacteria
  • Th1 cell clones
  • apolipoprotein H
  • calprotectin
  • microbiotme
  • molecular mimicry
  • systemic autoimmunity
  • thrombosis

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Virology

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  • Cite this

    Ruff, W. E., Dehner, C., Kim, W. J., Pagovich, O., Aguiar, C. L., Yu, A. T., Roth, A. S., Vieira, S. M., Kriegel, C., Adeniyi, O., Mulla, M. J., Abrahams, V. M., Kwok, W. W., Nussinov, R., Erkan, D., Goodman, A. L., & Kriegel, M. A. (2019). Pathogenic Autoreactive T and B Cells Cross-React with Mimotopes Expressed by a Common Human Gut Commensal to Trigger Autoimmunity. Cell Host and Microbe, 26(1), 100-113.e8. https://doi.org/10.1016/j.chom.2019.05.003