title: Granulocyte-macrophage colony-stimulating factor autoantibodies in murine ileitis and progressive ileal Crohn's disease.
abstract: OBJECTIVE
  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 microg/mL in control serum to 2.4 microg/mL in pediatric CD and 11.7 microg/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.
authors.affiliation: Department of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, USA.
authors.forename: Xiaonan
authors.initials: X
authors.lastname: Han
authors.forename: Kanji
authors.initials: K
authors.lastname: Uchida
authors.forename: Ingrid
authors.initials: I
authors.lastname: Jurickova
authors.forename: Diana
authors.initials: D
authors.lastname: Koch
authors.forename: Tara
authors.initials: T
authors.lastname: Willson
authors.forename: Charles
authors.initials: C
authors.lastname: Samson
authors.forename: Erin
authors.initials: E
authors.lastname: Bonkowski
authors.forename: Anna
authors.initials: A
authors.lastname: Trauernicht
authors.forename: Mi-Ok
authors.initials: MO
authors.lastname: Kim
authors.forename: Gitit
authors.initials: G
authors.lastname: Tomer
authors.forename: Marla
authors.initials: M
authors.lastname: Dubinsky
authors.forename: Scott
authors.initials: S
authors.lastname: Plevy
authors.forename: Subra
authors.initials: S
authors.lastname: Kugathsan
authors.forename: Bruce C
authors.initials: BC
authors.lastname: Trapnell
authors.forename: Lee A
authors.initials: LA
authors.lastname: Denson
mesh_terms: D000328:Adult; D000818:Animals; D001323:Autoantibodies / Q000097:blood*; D016022:Case-Control Studies; D002648:Child; D003424:Crohn Disease / Q000097:blood / Q000235:genetics / Q000276:immunology*; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007079:Ileitis / Q000097:blood / Q000235:genetics / Q000276:immunology*; D007082:Ileum / Q000378:metabolism / Q000473:pathology; D053208:Kaplan-Meier Estimate; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism
chemical_list: D001323:Autoantibodies; D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; D050796:STAT3 Transcription Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor