@article{5dff3166627a48b0807203c6ab7c574d,
title = "Pathogenic Autoreactive T and B Cells Cross-React with Mimotopes Expressed by a Common Human Gut Commensal to Trigger Autoimmunity",
abstract = "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.",
keywords = "Bacteroides thetaiotaomicron, DNA methyltransferase, IgA-coated bacteria, Th1 cell clones, apolipoprotein H, calprotectin, microbiotme, molecular mimicry, systemic autoimmunity, thrombosis",
author = "Ruff, {William E.} and Carina Dehner and Kim, {W. J.} and Odelya Pagovich and Aguiar, {Cassyanne L.} and Yu, {Andrew T.} and Roth, {Alexander S.} and Vieira, {Silvio Manfredo} and Christina Kriegel and Olamide Adeniyi and Mulla, {Melissa J.} and Abrahams, {Vikki M.} and Kwok, {William W.} and Ruth Nussinov and D. Erkan and Goodman, {Andrew L.} and Kriegel, {Martin A.}",
note = "Funding Information: The authors would like to thank all study subjects for their participation, all current and former lab members for helpful discussions, Lieping Chen and Jun Wang for antibody expression vectors, Lesley Devine for assistance with FACS sorting, Roger Albesa and Inova Diagnostics for performing the anti-domain I β 2 GPI CIA assay, David Schatz for the use of the bio-layer interferometer, Noah Palm for use of an anaerobic chamber and advice on IgA-seq, Emine Guven-Maiorov (NIH) for in silico structural modeling, and John Sterpka for technical assistance. The authors also thank Kristin DeFrancesco and Irene Matos for patient recruitment at the Yale Center for Clinical Investigation. This work was supported by grants from the National Institutes of Health (NIH) ( K08AI095318 , R01AI118855 , T32AI07019 , and T32DK007017-39 ), Yale Rheumatic Diseases Research Core (NIH P30 AR053495 ), Women{\textquoteright}s Health Research at Yale, O{\textquoteright}Brien Center at Yale (NIH P30DK079310 ), Arthritis National Research Foundation , Arthritis Foundation , and Lupus Research Alliance (to M.A.K.) as well as the American Heart Association ( 15GRNT24480140 ) and Lupus Research Institute (to V.M.A.). This project has been funded in whole or in part with federal funds from the National Cancer Institute , National Institutes of Health, under contract number HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does the mention of trade names, commercial products, or organizations imply endorsement by the US Government. This research was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",
year = "2019",
month = jul,
day = "10",
doi = "10.1016/j.chom.2019.05.003",
language = "English (US)",
volume = "26",
pages = "100--113.e8",
journal = "Cell Host and Microbe",
issn = "1931-3128",
publisher = "Cell Press",
number = "1",
}