Commensal microbiota influence systemic autoimmune responses |
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| Authors: | Inge Vanassche Michael B Drennan Fien Windels Amélie Dendooven Liesbeth Allais Claude A Cuvelier Fons van de Loo Paula S Norris Andrey A Kruglov Sergei A Nedospasov Sylvie Rabot Raul Tito Jeroen Raes Valerie Gaboriau‐Routhiau Nadine Cerf‐Bensussan Tom Van de Wiele Gérard Eberl Carl F Ware Dirk Elewaut |
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| Institution: | 1. Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Ghent University Hospital, Ghent, Belgium;2. Department of Pathology, University Medical Center, Utrecht, the Netherlands;3. Department of Pathology, Ghent University Hospital, Ghent, Belgium;4. Department of Rheumatology, Radboud University Medical Center, Nijmegen, the Netherlands;5. Infectious and Inflammatory Disease Center, Sanford‐Burnham Medical Research Institute, La Jolla, CA, USA;6. German Rheumatism Research Center (DRFZ), A Leibniz Institute, Berlin, Germany;7. Belozersky Institute of Physico‐Chemical Biology and Biological Faculty, Lomonosov Moscow State University, Moscow, Russia;8. Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, and Lomonosov Moscow State University, Moscow, Russia;9. INRA, UMR1319 Micalis, Jouy‐en‐Josas, France;10. AgroParisTech, Micalis, Jouy‐en‐Josas, France;11. Bioinformatics and (eco‐)systems Biology Laboratory, Department of Microbiology and Immunology, Rega Institute, VIB Center for the Biology of Disease, KU Leuven, Belgium;12. INSERM UMR1163, Laboratory of Intestinal Immunity, Université Paris Descartes‐Sorbonne Paris Cité and Institut Imagine, Paris, France;13. Laboratory of Microbial Ecology and Technology, Ghent University, Ghent, Belgium;14. Lymphoid Tissue Development Group, Institut Pasteur, Paris, France;15. VIB Inflammation Research Center, Ghent University, Ghent, Belgium |
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| Abstract: | Antinuclear antibodies are a hallmark feature of generalized autoimmune diseases, including systemic lupus erythematosus and systemic sclerosis. However, the processes underlying the loss of tolerance against nuclear self‐constituents remain largely unresolved. Using mice deficient in lymphotoxin and Hox11, we report that approximately 25% of mice lacking secondary lymphoid organs spontaneously develop specific antinuclear antibodies. Interestingly, we find this phenotype is not caused by a defect in central tolerance. Rather, cell‐specific deletion and in vivo lymphotoxin blockade link these systemic autoimmune responses to the formation of gut‐associated lymphoid tissue in the neonatal period of life. We further demonstrate antinuclear antibody production is influenced by the presence of commensal gut flora, in particular increased colonization with segmented filamentous bacteria, and IL‐17 receptor signaling. Together, these data indicate that neonatal colonization of gut microbiota influences generalized autoimmunity in adult life. |
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| Keywords: | antinuclear antibodies commensal microbiota systemic autoimmunity |
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