title: Innate dysfunction promotes linear growth failure in pediatric Crohn's disease and growth hormone resistance in murine ileitis.
abstract: BACKGROUND
  Growth failure remains a common complication of pediatric Crohn's disease (CD) and has been associated with small bowel involvement and need for surgery. We have reported that patients with elevated (≥ 1.6 μg/mL) granulocyte macrophage colony stimulating factor autoantibodies (GM-CSF Ab) are more likely to experience complicated ileal disease requiring surgery. We hypothesized that concurrent GM-CSF Ab and CARD15 risk allele carriage (C15(+) GMAb(+) ) would be associated with growth failure in CD and growth hormone (GH) resistance in murine ileitis.
  
  
  METHODS
  We enrolled 229 pediatric CD patients at two sites and determined CARD15 genotype, serum GM-CSF Ab, and GH binding protein (GHBP), and height (HTz) and weight (WTz) z-scores at diagnosis. Ileitis was induced in card15-deficient mice by GM-CSF neutralization and nonsteroidal antiinflammatory drug (NSAID) exposure. Hepatic GH receptor (GHR) abundance and GH-dependent Stat5 activation were determined by western blot and Igf-I mRNA expression by real-time polymerase chain reaction (PCR).
  
  
  RESULTS
  Mean (95% confidence interval [CI]) HTz at diagnosis was reduced to -0.48 (-4.2, 2.3) in C15(+) GMAb(+) patients, compared to -0.07 (-4.9, 3.4) in disease controls (P ≤ 0.05). Circulating GHBP, as a marker for tissue GHR abundance, was reduced in C15(+) GMAb(+) patients. Hepatic GHR abundance, GH induction of Stat5 tyrosine phosphorylation, and Igf-I mRNA expression were reduced in male card15-deficient mice with ileitis due to GM-CSF neutralization and NSAID exposure.
  
  
  CONCLUSIONS
  Innate dysfunction due to concurrent genetic variation in CARD15 and neutralizing GM-CSF Ab is associated with linear growth failure in pediatric CD, and hepatic GH resistance in murine ileitis.
authors.affiliation: Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA.
authors.forename: Sharon
authors.initials: S
authors.lastname: D'Mello
authors.forename: Anna
authors.initials: A
authors.lastname: Trauernicht
authors.forename: Anne
authors.initials: A
authors.lastname: Ryan
authors.forename: Erin
authors.initials: E
authors.lastname: Bonkowski
authors.forename: Tara
authors.initials: T
authors.lastname: Willson
authors.forename: Bruce C
authors.initials: BC
authors.lastname: Trapnell
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Frank
authors.forename: Subra
authors.initials: S
authors.lastname: Kugasathan
authors.forename: Lee A
authors.initials: LA
authors.lastname: Denson
mesh_terms: D000293:Adolescent; D000818:Animals; D001323:Autoantibodies / Q000097:blood; D001827:Body Height; D001835:Body Weight; D002352:Carrier Proteins / Q000097:blood; D002648:Child; D002675:Child, Preschool; D003424:Crohn Disease / Q000503:physiopathology*; D005183:Failure to Thrive / Q000503:physiopathology*; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology; D013006:Growth Hormone / Q000502:physiology*; D006801:Humans; D007079:Ileitis / Q000139:chemically induced / Q000503:physiopathology*; D007223:Infant; D008099:Liver / Q000737:chemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics; D011986:Receptors, Somatotropin / Q000032:analysis; D012189:Retrospective Studies; D050799:STAT5 Transcription Factor / Q000502:physiology
chemical_list: D001323:Autoantibodies; D002352:Carrier Proteins; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; D011986:Receptors, Somatotropin; D050799:STAT5 Transcription Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D013006:Growth Hormone; C051815:somatotropin-binding protein