Granulocyte-Macrophage Colony-Stimulating Factor Autoantibodies in Murine Ileitis and Progressive Ileal Crohn's Disease

• Type of Material: Article
• Authors: Xiaonan Han, University of Cincinnati; Kanji Uchida, University of Cincinnati; Ingrid Jurickova, University of Cincinnati; Diana Koch, University of Cincinnati; Tara Willson, University of Cincinnati; Charles Samson, University of Cincinnati; Erin Bonkowski, University of Cincinnati; Anna Trauernicht, University of Cincinnati; Mi-Ok Kim, University of Cincinnati; Gitit Tomer, University of Cincinnati; Marla Dubinsky, Cedar-Sinai Medical Center; Scott Plevy, University of North Carolina; Subra Kugathasan, Emory University; Bruce C. Trapnell, University of Cincinnati; Lee A. Denson, University of Cincinnati
• Language: English
• Date: 2009-04-01
• Publisher: Elsevier: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2009 AGA Institute.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1053/j.gastro.2008.12.046
• Title of Journal or Parent Work: Gastroenterology
• ISSN: 0016-5085
• Volume: 136
• Issue: 4
• Start Page: 1261
• End Page: 1271
• Grant/Funding Information: This work was supported by the Crohn’s and Colitis Foundation of America, the Broad Medical Research Program, the Bioinformatics, Flow Cytometry, and Microarray cores of the National Institutes of Health (NIH)-supported Cincinnati Children’s Hospital Research Foundation Digestive Health Center (1P30DK078392-01), and NIH grants R01 DK078683 and DK068164.; This work was supported by the Crohn’s and Colitis Foundation of America (LD & XH), the Broad Medical Research Program (LD & SP), the Cincinnati Children’s Hospital Research Foundation Translational Research Institute (LD), the National Institutes of Health (NIH)-supported Cincinnati Children’s Hospital Research Foundation Digestive Health Center (1P30DK078392-01, BT), and NIH grant R01 DK058259 (LD).
• Keywords: AUTOPHAGY; PREVALENCE; Gastroenterology & Hepatology; MUTATIONS; ASSOCIATION; SUSCEPTIBILITY; EXPRESSION; Science & Technology; DYSFUNCTION; RESPONSES; Life Sciences & Biomedicine; NEUTROPHILS; VARIANTS
• Research Categories: Biology, Cell; Health Sciences, Epidemiology; Health Sciences, Medicine and Surgery

Abstract

Background & Aims: Genetic variations that affect innate immunity increase risk of ileal Crohn's disease (CD). However, the penetrance of susceptibility genes, including NOD2, is low, suggesting additional risk factors. Neutralizing autoantibodies (Ab) against granulocyte-macrophage colony-stimulating factor (GM-CSF Ab) reduce neutrophil antimicrobial function in patients with primary alveolar proteinosis (PAP). We investigated whether GM-CSF Ab regulates neutrophil function in CD. Methods: Serum samples from 354 adult and pediatric patients with inflammatory bowel disease (IBD) were analyzed for GM-CSF Ab and IBD markers. Levels of GM-CSF Ab were compared with patients' CD features and neutrophil function. Intestinal barrier function and nonsteroidal anti-inflammatory drug (NSAID)-induced injury were assessed in GM-CSF-null and NOD2-null mice. Results: Median GM-CSF Ab levels increased from 0.4 μg/mL in control serum to 2.4 μg/mL in pediatric CD and 11.7 μg/mL in adult CD serum and were associated with ileal involvement (P < .001). Ileal location, duration of disease, and increased GM-CSF Ab levels were associated with stricturing/penetrating behavior (odds ratio, 2.2; P = .018). The positive and negative predictive values of GM-CSF Ab for stricturing/penetrating behavior were comparable with that of other IBD serum markers. CD patients with increased GM-CSF Ab had reduced neutrophil phagocytic capacity and increased accumulation of pSTAT3+ neutrophils in the affected ileum. GM-CSF-null mice and NOD2-null mice in which GM-CSF was neutralized had defects in mucosal barrier function and developed a transmural ileitis following NSAID exposure. Conclusions: GM-CSF regulates ileal homeostasis in CD and in mouse models. CD patients with increases in serum GM-CSF Ab might benefit from GM-CSF administration.