Granulocyte-macrophage colony-stimulating factor autoantibodies in murine ileitis and progressive ileal Crohn's disease.
Granulocyte-macrophage colony-stimulating factor autoantibodies in murine ileitis and progressive ileal Crohn's disease.
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DOI：
10.1053/j.gastro.2008.12.046
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发表时间：
2009-04
期刊：
影响因子：
29.4
通讯作者：
Denson LA
中科院分区：
文献类型：
--
作者：
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
影响先天免疫的基因变异会增加回肠克罗恩病(CD)的风险。然而，包括NOD2在内的易感基因的外显率很低，这表明还有其他危险因素。抗粒细胞巨噬细胞集落刺激因子(GM-CSF)中和抗体可降低PAP患者的中性粒细胞抗菌功能。我们研究了GM-CSF单抗对CD中性粒细胞功能的调节作用。对354例成人和儿童炎症性肠病(IBD)患者的血清标本进行了GM-CSF抗体和IBD标志物检测。比较患者CD表现和中性粒细胞功能与GM-CSF抗体水平的关系。检测GM-CSF基因缺失和NOD2基因缺失小鼠的肠屏障功能和非甾体抗炎药(NSAID)损伤的严重程度。儿童CD组和成人CD组GM-CSFAb的中位数分别为2.4mgg/ml和11.7mgmgL，与回肠受累有关(p<；0.001)。回肠位置、病程和GM-CSFAb水平升高与狭窄/穿透行为相关(优势比：2.2p=0.018)。GM-CSF抗体对IBD狭窄/穿透行为的阳性和阴性预测价值与其他IBD血清标志物相当。GM-CSF抗体升高的CD患者中性粒细胞吞噬能力降低，pSTAT3+中性粒细胞在回肠积聚增加。GM-CSF缺失和NOD2缺失的小鼠在NSAID暴露后出现黏膜屏障功能缺陷和跨壁回肠炎。GM-CSF对CD模型和小鼠模型回肠内环境的调节作用血清GM-CSF抗体升高的CD患者可能受益于治疗性GM-CSF治疗。
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 regulates neutrophil function in CD. Serum samples from 354 adult and pediatric patients with inflammatory bowel disease (IBD) were analyzed for GM-CSF Abs and IBD markers. Levels of GM-CSF Ab were compared with patients’ CD features and neutrophil function. Intestinal barrier function and severity of non-steroidal anti-inflammatory drug (NSAID)-induced injury were assessed in GM-CSF-null and Nod2-null mice. 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 Abs for stricturing/penetrating behavior was comparable to that of other IBD serum markers. CD patients with increased GM-CSF Abs 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. GM-CSF regulates ileal homeostasis in CD and in mouse models. CD patients with increases in serum GM-CSF Ab might benefit from therapeutic GM-CSF administration.
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