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

Summary 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 β 2 -glycoprotein I (β 2 GPI). 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-β 2 GPI IgG autoantibodies. R. int immunization of mice induced β 2 GPI-specific lymphocytes and autoantibodies. Oral gavage of susceptible mice with R. int induced anti-human β 2 GPI 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.