ena-STUDY-YALE-05-04-2019-14:46:55:691-126
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.
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.