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Granulocyte Macrophage-Colony-stimulating Factor Autoantibodies and Increased Intestinal Permeability in Crohn Disease

Nylund, Cade M*; D'Mello, Sharon*; Kim, Mi-Ok*; Bonkowski, Erin*; Däbritz, Jan; Foell, Dirk; Meddings, Jon; Trapnell, Bruce C*; Denson, Lee A*

Journal of Pediatric Gastroenterology & Nutrition:
doi: 10.1097/MPG.0b013e3181fe2d93
Original Articles: Gastroenterology
Abstract

Background: Alterations in intestinal permeability have been implicated in the pathogenesis of Crohn disease (CD). We have reported that granulocyte macrophage-colony-stimulating factor (GM-CSF) is required for mucosal barrier function in mice, and elevated neutralizing GM-CSF autoantibodies (Ab) are associated with stricturing ileal disease and surgery in patients with CD. We hypothesized that children with CD with elevated GM-CSF Ab would exhibit increased intestinal permeability.

Patients and Methods: Subjects were divided into 3 groups: 15 with CD and high GM-CSF Ab (≥1.6 μg/mL, GM-CSF Ab Hi), 12 with CD and low GM-CSF Ab (<1.6 μg/mL, GM-CSF Ab Lo), and 15 healthy controls. Subjects ingested a lactulose:mannitol (L:M) solution, and urinary excretion of LM was measured by high-performance liquid chromatography. Serum GM-CSF Ab, endotoxin core Ab (EndoCAb), and lipopolysaccharide-binding protein (LBP), and fecal S100A12 were determined by enzyme-linked immunosorbent assay.

Results: The CD groups did not vary by age, sex, disease location, or activity. Neither systemic (serum LBP) nor mucosal (fecal S100A12) inflammation differed between the CD groups. Intestinal permeability as measured by the urine L:M ratio and endotoxin exposure as measured by serum EndoCAb were increased in the GM-CSF Ab Hi group compared to the GM-CSF Ab Lo group and controls.

Conclusions: Patients with CD with elevated GM-CSF Ab exhibit an increase in bowel permeability relative to patients with CD with lower levels of GM-CSF Ab in the absence of differences in systemic or intestinal inflammation. Therapies that target the mucosal barrier may be of particular benefit in this subgroup of patients with CD.

Author Information

*Department of Pediatrics, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio, USA

University of Münster, Münster, Germany

University of Alberta, Edmonton, Canada.

Received 5 June, 2010

Accepted 23 August, 2010

Address correspondence and reprint requests to Cade M. Nylund, MD, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd, Bethesda, MD 20814 (e-mail: cade.nylund@usuhs.mil).

The views expressed in this article are those of the authors and do not reflect the official policy or position of the US Air Force, the Department of Defense, or the US government.

This work was supported by the Crohn's and Colitis Foundation of America (L.A.D.), the Broad Medical Research Program (L.A.D.), the National Institutes of Health (NIH)–supported Cincinnati Children's Hospital Research Foundation Digestive Health Center (1P30DK078392-01, B.C.T.), and NIH grants R01 DK058259 and R01 DK078683 (L.A.D.).

The authors report no conflicts of interest.

Copyright 2011 by ESPGHAN and NASPGHAN