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 beta 2-glycoprotein I (b2GPI). 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-?2GPI IgG autoantibodies. R. int immunization induced b2GPI-specific lymphocytes and autoantibodies. R. int oral gavage into a susceptible host induced anti-human b2GPI autoantibodies with histological evidence of pathogenicity. 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.