7th Annual BMRP Investigator Meeting - Abstract

 

Xiaonan Han^{1^}, Kanji Uchida^{2^},, Ingrid Jurickova¹, Diana Koch², Tara Willson^1,4, Charles Samson¹, Erin Bonkowski¹, Anna Trauernicht¹, Mi-Ok Kim³, Gitit Tomer¹, Marla Dubinsky⁵, Scott Plevy⁶, Subra Kugathsan⁷, Bruce C. Trapnell² and Lee A. Denson^{a,1,4^}

 

¹Gastroenterology, Hepatology, and Nutrition, ²Pulmonary Biology, and ³Center for Epidemiology and Biostatistics, Cincinnati Children’s Hospital Medical Center and the University of Cincinnati College of Medicine, ⁴ Department of Cancer and Cell Biology, University of Cincinnati (Cincinnati, Ohio, U.S.A.); Department of Pediatrics, Cedar-Sinai Medical Center (Los Angeles, California, U.S.A.); ⁶Department of Medicine, University of North Carolina School of Medicine (Chapel Hill, North Carolina, U.S.A.); ⁷Department of Pediatrics, Emory University School of Medicine (Atlanta, Georgia, U.S.A.)

 

^these authors contributed equally to this work

Background: 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 auto-antibodies 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 regulate neutrophil function in CD. Methods: Serum samples from354 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 non-steroidal 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 mcg/mL in control serum to 2.4 mcg/mL in pediatric CD and 11.7 mcg/mL in adult CD serum and were associated with ileal involvement (p<0.001). Ileal location, duration of disease and increased GM-CSF Ab levels were associated with stricturing/penetrating behavior (Odds Ratio: 2.2, p=0.018). The positive and negative predictive value of GM-CSF Ab for stricturing/penetrating behavior was comparable to 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.

^aPrincipal Investigator