Age-of-diagnosis dependent ileal immune intensification and reduced alpha-defensin in older versus younger pediatric Crohn Disease patients despite already established dysbiosis View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2018-12-12

AUTHORS

Yael Haberman, Melanie Schirmer, Phillip J. Dexheimer, Rebekah Karns, Tzipi Braun, Mi-Ok Kim, Thomas D. Walters, Robert N. Baldassano, Joshua D. Noe, Joel Rosh, James Markowitz, Wallace V. Crandall, David R. Mack, Anne M. Griffiths, Melvin B. Heyman, Susan S. Baker, Richard Kellermayer, Dedrick Moulton, Ashish S. Patel, Ajay S. Gulati, Steven J. Steiner, Neal LeLeiko, Anthony Otley, Maria Oliva-Hemker, David Ziring, Barbara S Kirschner, David J. Keljo, Stephen L. Guthery, Stanley A. Cohen, Scott Snapper, Jonathan Evans, Marla Dubinsky, Bruce Aronow, Jeffrey S. Hyams, Subra Kugathasan, Curtis Huttenhower, Ramnik J. Xavier, Lee A. Denson

ABSTRACT

Age-of-diagnosis associated variation in disease location and antimicrobial sero-reactivity has suggested fundamental differences in pediatric Crohn Disease (CD) pathogenesis. This variation may be related to pubertal peak incidence of ileal involvement and Peyer’s patches maturation, represented by IFNγ-expressing Th1 cells. However, direct mucosal evidence is lacking. We characterize the global pattern of ileal gene expression and microbial communities in 525 treatment-naive pediatric CD patients and controls (Ctl), stratifying samples by their age-of-diagnosis. We show a robust ileal gene signature notable for higher expression of specific immune genes including GM-CSF and INFγ, and reduced expression of antimicrobial Paneth cell α-defensins, in older compared to younger patients. Reduced α-defensin expression in older patients was associated with higher IFNγ expression. By comparison, the CD-associated ileal dysbiosis, characterized by expansion of Enterobacteriaceae and contraction of Lachnospiraceae and Ruminococcaceae, was already established within the younger group and did not vary systematically with increasing age-of-diagnosis. Multivariate analysis considering individual taxa, however did demonstrate negative associations between Lachnospiraceae and IFNγ, and positive associations between Bacteroides and α-defensin expression. These data provide evidence for maturation of mucosal Th1 immune responses and loss of epithelial antimicrobial α-defensins which are associated with specific taxa with increasing age-of-diagnosis in pediatric CD. More... »

PAGES

491-502

References to SciGraph publications

Journal

TITLE

Mucosal Immunology

ISSUE

2

VOLUME

12

Author Affiliations

  • Sheba Medical Center, Tel-HaShomer, affiliated with the Tel-Aviv University, Tel-Aviv, Israel
  • Harvard T.H. Chan School of Public Health, Boston, MA, USA
  • Cincinnati Children’s Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH, USA
  • Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
  • The Children’s Hospital of Philadelphia, Philadelphia, PA, USA
  • Medical College of Wisconsin, Milwaukee, WI, USA
  • Goryeb Children’s Hospital/Atlantic Health, Morristown, NJ, USA
  • Cohen Children’s Medical Center of New York, New Hyde Park, New York, NY, USA
  • Nationwide Children’s Hospital, Columbus, OH, USA
  • Children’s Hospital of Eastern Ontario, University of Ottawa, Ottawa, ON, Canada
  • University of California San Francisco, San Francisco, CA, USA
  • University at Buffalo, Buffalo, NY, USA
  • Texas Children’s Hospital, Baylor College School of Medicine, Houston, TX, USA
  • Vanderbilt Children’s Hospital, Nashville, TN, USA
  • UT Southwestern Medical Center at Dallas, Dallas, TX, USA
  • University of North Carolina, Chapel Hill, NC, USA
  • Riley Children’s Hospital, Indiannapolis, IN, USA
  • Hasbro Children’s Hospital, Providence, RI, USA
  • IWK Health Centre, Halifax, NS, Canada
  • John Hopkins University, Baltimore, MD, USA
  • Cedars-Sinai Medical Center, Los Angeles, CA, USA
  • University of Chicago Comer Children’s Hospital, Chicago, IL, USA
  • Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA
  • University of Utah, Salt Lake City, UT, USA
  • Children’s Center for Digestive HealthMedicine, Atlanta, GA, USA
  • Children’s Hospital - Boston, Boston, MA, USA
  • Nemours Children’s Clinic, Jacksonville, FL, USA
  • Mount Sinai Hospital New York, New York, NY, USA
  • Connecticut Children’s Medical Center, Hartford, CT, USA
  • Emory University, Atlanta, GA, USA
  • Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/s41385-018-0114-4

    DOI

    http://dx.doi.org/10.1038/s41385-018-0114-4

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1110559546

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/30542108


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