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Cell Host Microbe. 2019 Jul 10;26(1):100-113.e8. doi: 10.1016/j.chom.2019.05.003. Epub 2019 Jun 18.

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

Author information

1
Department of Immunobiology, Yale School of Medicine, New Haven, CT 06510, USA.
2
Barbara Volcker Center for Women and Rheumatic Diseases, Hospital for Special Surgery, Weill Cornell Medicine, New York, NY 10021, USA.
3
Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT 06510, USA.
4
Benaroya Research Institute at Virginia Mason, Seattle, WA 98101, USA.
5
Computational Structural Biology Section, Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA; Sackler Institute of Molecular Medicine, Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
6
Microbial Sciences Institute, Department of Microbial Pathogenesis, Yale School of Medicine, New Haven, CT 06536, USA.
7
Department of Immunobiology, Yale School of Medicine, New Haven, CT 06510, USA; Department of Medicine, Section of Rheumatology, Yale School of Medicine, New Haven, CT 06510, USA. Electronic address: martin.kriegel@yale.edu.

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.

KEYWORDS:

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

PMID:
31227334
DOI:
10.1016/j.chom.2019.05.003

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