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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Animals
  • Antibodies, Bacterial / immunology*
  • Antigens, Bacterial / immunology*
  • Antiphospholipid Syndrome / pathology
  • Autoantibodies / blood
  • Autoantibodies / immunology
  • Autoimmunity*
  • B-Lymphocytes / immunology*
  • Clostridiales / immunology*
  • Cross Reactions*
  • Female
  • Gastrointestinal Tract / microbiology
  • Humans
  • Immunoglobulin G / blood
  • Male
  • Mice
  • Middle Aged
  • Models, Animal
  • T-Lymphocytes / immunology*
  • Young Adult
  • beta 2-Glycoprotein I / immunology


  • Antibodies, Bacterial
  • Antigens, Bacterial
  • Autoantibodies
  • Immunoglobulin G
  • beta 2-Glycoprotein I