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

Author:

Ruff, William E

Dehner, Carina

Kim, Woo J

Pagovich, Odelya

Aguiar, Cassyanne L

Yu, Andrew T

Roth, Alexander S

Vieira, Silvio Manfredo

Kriegel, Christina

Adeniyi, Olamide

Mulla, Melissa J

Abrahams, Vikki M

Kwok, William W

Nussinov,Ruth

Erkan, Doruk

Goodman, Andrew L

Kriegel, Martin A
Author Address

Department of Immunobiology, Yale School of Medicine, New Haven, CT 06510, USA., Barbara Volcker Center for Women and Rheumatic Diseases, Hospital for Special Surgery, Weill Cornell Medicine, New York, NY 10021, USA., Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT 06510, USA., Benaroya Research Institute at Virginia Mason, Seattle, WA 98101, USA., 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., Microbial Sciences Institute, Department of Microbial Pathogenesis, Yale School of Medicine, New Haven, CT 06536, USA., 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 ß2-glycoprotein I (ß2GPI). 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-ß2GPI IgG autoantibodies. R. int immunization of mice induced ß2GPI-specific lymphocytes and autoantibodies. Oral gavage of susceptible mice with R. int induced anti-human ß2GPI 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. Copyright © 2019 Elsevier Inc. All rights reserved.

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