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

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.