title: Commensal microbiota influence systemic autoimmune responses.
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.
authors.affiliation: Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Ghent University Hospital, Ghent, Belgium.
authors.forename: Jens T
authors.initials: JT
authors.lastname: Van Praet
authors.affiliation: Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Ghent University Hospital, Ghent, Belgium.
authors.forename: Erin
authors.initials: E
authors.lastname: Donovan
authors.affiliation: Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Ghent University Hospital, Ghent, Belgium.
authors.forename: Inge
authors.initials: I
authors.lastname: Vanassche
authors.affiliation: Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Ghent University Hospital, Ghent, Belgium.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Drennan
authors.affiliation: Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Ghent University Hospital, Ghent, Belgium.
authors.forename: Fien
authors.initials: F
authors.lastname: Windels
authors.affiliation: Department of Pathology, University Medical Center, Utrecht, the Netherlands.
authors.forename: Amélie
authors.initials: A
authors.lastname: Dendooven
authors.affiliation: Department of Pathology, Ghent University Hospital, Ghent, Belgium.
authors.forename: Liesbeth
authors.initials: L
authors.lastname: Allais
authors.affiliation: Department of Pathology, Ghent University Hospital, Ghent, Belgium.
authors.forename: Claude A
authors.initials: CA
authors.lastname: Cuvelier
authors.affiliation: Department of Rheumatology, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Fons
authors.initials: F
authors.lastname: van de Loo
authors.affiliation: Infectious and Inflammatory Disease Center, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA.
authors.forename: Paula S
authors.initials: PS
authors.lastname: Norris
authors.affiliation: German Rheumatism Research Center (DRFZ), A Leibniz Institute, Berlin, Germany Belozersky Institute of Physico-Chemical Biology and Biological Faculty, Lomonosov Moscow State University, Moscow, Russia.
authors.forename: Andrey A
authors.initials: AA
authors.lastname: Kruglov
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, and Lomonosov Moscow State University, Moscow, Russia.
authors.forename: Sergei A
authors.initials: SA
authors.lastname: Nedospasov
authors.affiliation: INRA, UMR1319 Micalis, Jouy-en-Josas, France AgroParisTech Micalis, Jouy-en-Josas, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Rabot
authors.affiliation: Bioinformatics and (eco-)systems Biology Laboratory, Department of Microbiology and Immunology, Rega Institute VIB Center for the Biology of Disease, KU Leuven, Belgium.
authors.forename: Raul
authors.initials: R
authors.lastname: Tito
authors.affiliation: Bioinformatics and (eco-)systems Biology Laboratory, Department of Microbiology and Immunology, Rega Institute VIB Center for the Biology of Disease, KU Leuven, Belgium.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Raes
authors.affiliation: INRA, UMR1319 Micalis, Jouy-en-Josas, France INSERM UMR1163, Laboratory of Intestinal Immunity, Université Paris Descartes-Sorbonne Paris Cité and Institut Imagine, Paris, France.
authors.forename: Valerie
authors.initials: V
authors.lastname: Gaboriau-Routhiau
authors.affiliation: INSERM UMR1163, Laboratory of Intestinal Immunity, Université Paris Descartes-Sorbonne Paris Cité and Institut Imagine, Paris, France.
authors.forename: Nadine
authors.initials: N
authors.lastname: Cerf-Bensussan
authors.affiliation: Laboratory of Microbial Ecology and Technology, Ghent University, Ghent, Belgium.
authors.forename: Tom
authors.initials: T
authors.lastname: Van de Wiele
authors.affiliation: Lymphoid Tissue Development Group, Institut Pasteur, Paris, France.
authors.forename: Gérard
authors.initials: G
authors.lastname: Eberl
authors.affiliation: Infectious and Inflammatory Disease Center, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA.
authors.forename: Carl F
authors.initials: CF
authors.lastname: Ware
authors.affiliation: Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Ghent University Hospital, Ghent, Belgium VIB Inflammation Research Center Ghent University, Ghent, Belgium Dirk.Elewaut@ugent.be.
authors.forename: Dirk
authors.initials: D
authors.lastname: Elewaut
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000235:genetics / Q000276:immunology; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D008233:Lymphotoxin-alpha / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D064307:Microbiota / Q000276:immunology*; D011247:Pregnancy; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000974:Antibodies, Antinuclear; D008233:Lymphotoxin-alpha; D011518:Proto-Oncogene Proteins
keywords: antinuclear antibodies; commensal microbiota; systemic autoimmunity