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Innate dysfunction promotes linear growth failure in pediatric Crohn's disease and growth hormone resistance in murine ileitis.

ABSTRACT: 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 ?g/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.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).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.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.

SUBMITTER: D'Mello S

PROVIDER: S-EPMC3057426 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Innate dysfunction promotes linear growth failure in pediatric Crohn's disease and growth hormone resistance in murine ileitis.

D'Mello Sharon S Trauernicht Anna A Ryan Anne A Bonkowski Erin E Willson Tara T Trapnell Bruce C BC Frank Stuart J SJ Kugasathan Subra S Denson Lee A LA

Inflammatory bowel diseases 20110218 2

<h4>Background</h4>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 ...[more]

PMID: 21337672

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Project description:BackgroundObesity has been associated with a more severe disease course in inflammatory bowel disease (IBD) and epidemiological data identified dietary fats but not obesity as risk factors for the development of IBD. Crohn's disease is one of the two major IBD phenotypes and mostly affects the terminal ileum. Despite recent observations that high fat diets (HFD) impair intestinal barrier functions and drive pathobiont selection relevant for chronic inflammation in the colon, mechanisms of high fat diets in the pathogenesis of Crohn's disease are not known. The aim of this study was to characterize the effect of HFD on the development of chronic ileal inflammation in a murine model of Crohn's disease-like ileitis.MethodsTNF(?ARE/WT) mice and wildtype C57BL/6 littermates were fed a HFD compared to control diet for different durations. Intestinal pathology and metabolic parameters (glucose tolerance, mesenteric tissue characteristics) were assessed. Intestinal barrier integrity was characterized at different levels including polyethylene glycol (PEG) translocation, endotoxin in portal vein plasma and cellular markers of barrier function. Inflammatory activation of epithelial cells as well as immune cell infiltration into ileal tissue were determined and related to luminal factors.ResultsHFD aggravated ileal inflammation but did not induce significant overweight or typical metabolic disorders in TNF(?ARE/WT). Expression of the tight junction protein Occludin was markedly reduced in the ileal epithelium of HFD mice independently of inflammation, and translocation of endotoxin was increased. Epithelial cells showed enhanced expression of inflammation-related activation markers, along with enhanced luminal factors-driven recruitment of dendritic cells and Th17-biased lymphocyte infiltration into the lamina propria.ConclusionsHFD feeding, independently of obesity, accelerated disease onset of small intestinal inflammation in Crohn's disease-relevant mouse model through mechanisms that involve increased intestinal permeability and altered luminal factors, leading to enhanced dendritic cell recruitment and promoted Th17 immune responses.

Project description:Background and aimsIt is unclear whether pre-pouch ileitis heralds an aggressive inflammatory pouch disease in patients with ileal pouch-anal anastomosis [IPAA]. We compared outcomes of patients with pouchitis and concomitant pre-pouch ileitis with those with pouchitis alone.MethodsPatients undergoing IPAA surgery for inflammatory bowel disease, who subsequently developed pouchitis with concomitant pre-pouch ileitis [pre-pouch ileitis group], were matched by year of IPAA surgery and preoperative diagnosis [ulcerative colitis or inflammatory bowel disease-unclassified] with patients who developed pouchitis alone [pouchitis group]. Primary outcomes were development of Crohn's disease [CD]-like complications [non-anastomotic strictures or perianal disease >6 months after ileostomy closure] and pouch failure. Secondary outcomes were need for surgical/endoscopic interventions and immunosuppressive therapy. Log-rank testing was used to compare outcome-free survival, and Cox regression was performed to identify predictors of outcomes.ResultsThere were 66 patients in each group. CD-like complications and pouch failure developed in 36.4% and 7.6% patients in the pre-pouch ileitis group and 10.6% and 1.5% in pouchitis group, respectively. CD-like complications-free survival [log-rank p = 0.0002] and pouch failure-free survival [log-rank p = 0.046] were significantly lower in the pre-pouch ileitis group. The pre-pouch ileitis group had a higher risk of requiring surgical/endoscopic interventions [log-rank p = 0.0005] and immunosuppressive therapy [log-rank p <0.0001]. Pre-pouch ileitis was independently associated with an increased risk of CD-like complications (hazard ratio [HR] 3.8; p = 0.0007), need for surgical/endoscopic interventions [HR 4.1; p = 0.002], and immunosuppressive therapy [HR 5.0; p = 0.0002].ConclusionsPre-pouch ileitis is associated with a higher risk of complicated disease and pouch failure than pouchitis. It should be considered a feature of CD.

Project description:Fibrostenosis and stricture are well-recognized endpoints in Crohn's disease (CD). We hypothesized that stricturing CD is characterized by eosinophilia and epithelial IL-33. We proposed that eosinophil exposure to IL-33 would perpetuate inflammatory chronicity and subsequent fibrostenosis.We performed a retrospective study of 74 children with inflammatory and stricturing ileal CD comparing clinicopathological features to immunohistochemical measures of eosinophilia and IL-33. To scrutinize eosinophil patterns, we developed a novel eosinophil peroxidase score encompassing number, distribution, and degranulation. Human eosinophils and intestinal fibroblasts were cultured with IL-33 and IL-13, and inflammatory and remodeling parameters were assessed. Antieosinophil therapy was also administered to the Crohn's-like ileitis model (SAMP1/SkuSlc).Our novel eosinophil peroxidase score was more sensitive than H&E staining, revealing significant differences in eosinophil patterns, comparing inflammatory and stricturing pediatric CD. A significant relationship between ileal eosinophilia and complicated clinical/histopathological phenotype including fibrosis was determined. IL-33 induced significant eosinophil peroxidase secretion and IL-13 production. Exposure to eosinophils in the presence of IL-33, "primed" fibroblasts to increase proinflammatory cytokines (TNF-?, IL-1?, and IL-6), eosinophil-associated chemokines (CCL24 and CCL26), and IL-13R?2 production. Production of fibrogenic molecules (collagen 1A2, fibronectin, and periostin) increased after exposure of "primed" fibroblasts to IL-13. Epithelial-IL-33 was increased in pediatric Crohn's ileitis and strongly associated with clinical and histopathological activity, ileal eosinophilia, and complicated fibrostenotic disease. SAMP1/SkuSlc eosinophil-targeted treatment resulted in significant improvements in inflammation and remodeling.Our study of specimens from pediatric patients with ileal CD linked eosinophil patterns and IL-33 to fibrosis and suggested that these may contribute to the perpetuation of inflammation and subsequent stricture in pediatric CD.

Dataset Information

Innate dysfunction promotes linear growth failure in pediatric Crohn's disease and growth hormone resistance in murine ileitis.

Publications

Innate dysfunction promotes linear growth failure in pediatric Crohn's disease and growth hormone resistance in murine ileitis.

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