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EMBO J. 2015 Feb 12;34(4):466-74. doi: 10.15252/embj.201489966. Epub 2015 Jan 19.

Commensal microbiota influence systemic autoimmune responses.

Author information

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 Belozersky Institute of Physico-Chemical Biology and Biological Faculty, Lomonosov Moscow State University, Moscow, Russia.
7
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, and Lomonosov Moscow State University, Moscow, Russia.
8
INRA, UMR1319 Micalis, Jouy-en-Josas, France AgroParisTech Micalis, Jouy-en-Josas, France.
9
Bioinformatics and (eco-)systems Biology Laboratory, Department of Microbiology and Immunology, Rega Institute VIB Center for the Biology of Disease, KU Leuven, Belgium.
10
INRA, UMR1319 Micalis, Jouy-en-Josas, France INSERM UMR1163, Laboratory of Intestinal Immunity, Université Paris Descartes-Sorbonne Paris Cité and Institut Imagine, Paris, France.
11
INSERM UMR1163, Laboratory of Intestinal Immunity, Université Paris Descartes-Sorbonne Paris Cité and Institut Imagine, Paris, France.
12
Laboratory of Microbial Ecology and Technology, Ghent University, Ghent, Belgium.
13
Lymphoid Tissue Development Group, Institut Pasteur, Paris, France.
14
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.

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.

KEYWORDS:

antinuclear antibodies; commensal microbiota; systemic autoimmunity

PMID:
25599993
PMCID:
PMC4331001
DOI:
10.15252/embj.201489966
[Indexed for MEDLINE]
Free PMC Article

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