Innate dysfunction promotes linear growth failure in pediatric Crohn's disease and growth hormone resistance in murine ileitis
✍ Scribed by Sharon D'Mello; Anna Trauernicht; Anne Ryan; Erin Bonkowski; Tara Willson; Bruce C. Trapnell; Stuart J. Frank; Subra Kugasathan; Lee A. Denson
- Publisher
- John Wiley and Sons
- Year
- 2012
- Tongue
- English
- Weight
- 424 KB
- Volume
- 18
- Category
- Article
- ISSN
- 1078-0998
No coin nor oath required. For personal study only.
✦ Synopsis
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 lg/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 þ GMAb þ ) 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 À0.48 (À4.2, 2.3) in C15 þ GMAb þ patients, compared to À0.07 (À4.9, 3.4) in disease controls (P 0.05). Circulating GHBP, as a marker for tissue GHR abundance, was reduced in C15 þ GMAb þ 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.