Autoantibodies to GM-CSF in Crohn's
Kofi
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Granulocyte-macrophage colony-stimulating factor autoantibodies in
murine ileitis and progressive ileal Crohn's disease.
Han X, Uchida K, Jurickova I, Koch D, Willson T, Samson C, Bonkowski E,
Trauernicht A, Kim MO, Tomer G, Dubinsky M, Plevy S, Kugathsan S,
Trapnell BC, Denson LA.
Department of Gastroenterology, Hepatology, and Nutrition, Cincinnati
Children's Hospital Medical Center and the University of Cincinnati
College of Medicine, Cincinnati, Ohio 45229, USA.
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 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.
Publication Types:
* Research Support, N.I.H., Extramural
* Research Support, Non-U.S. Gov't
PMID: 19230854