Marks Daniel J B, Harbord Marcus W N, MacAllister Raymond, Rahman Farooq Z, Young Jodi, Al-Lazikani Bissan, Lees William, Novelli Marco, Bloom Stuart, Segal Anthony W
Department of Medicine, University College London, London WC1E 6JJ, UK.
Lancet. 2006 Feb 25;367(9511):668-78. doi: 10.1016/S0140-6736(06)68265-2.
The cause of Crohn's disease has not been mechanistically proven. We tested the hypothesis that the disease is a form of immunodeficiency caused by impaired innate immunity.
We investigated inflammatory responses in patients and controls by quantifying neutrophil recruitment and cytokine production after acute trauma, interleukin 8 secretion by cultured monocyte-derived macrophages after exposure to inflammatory mediators, and local inflammatory and vascular changes in response to subcutaneous injection of heat-killed Escherichia coli.
In patients with Crohn's disease, trauma to rectum, ileum, or skin led to abnormally low neutrophil accumulation (differences from healthy individuals of 79%, n=8, p=0.0003; 57%, n=3, p=0.05; 50%, n=13, p<0.0001, respectively) and lower production of proinflammatory interleukin 8 (63%, n=7, p=0.003; 63%, n=3, p=0.05; 45%, n=8, p<0.0001) and interleukin 1beta (50%, n=8, p=0.0005). Interleukin 8 secretion by cultured macrophages was reduced after exposure to acute wound fluid (38%, n=50, p<0.0001), C5a (48%, n=41, p=0.0005), or tumour necrosis factor alpha (52%, n=27, p<0.0001). Local inflammatory reaction to inoculation with E coli was attenuated, as quantified by changes in bloodflow (ileal disease 50%, n=6, p=0.01; colonic disease 77%, n=6, p=0.0003). This response was mediated by nitric oxide in controls, was increased by sildenafil in patients, and was not related to CARD15 genotype.
In Crohn's disease, a constitutionally weak immune response predisposes to accumulation of intestinal contents that breach the mucosal barrier of the bowel wall, resulting in granuloma formation and chronic inflammation. Polymorphisms in CARD15 do not underlie this phenotype, but incapacitate the NOD2 pathway that can compensate for impairment of innate inflammation. Current treatment of secondary chronic inflammation might exaggerate the underlying lesion and promote chronic disease.
克罗恩病的病因尚未得到机制上的证实。我们检验了该病是一种由先天性免疫受损导致的免疫缺陷形式这一假说。
我们通过量化急性创伤后中性粒细胞募集和细胞因子产生、培养的单核细胞衍生巨噬细胞暴露于炎症介质后白细胞介素8的分泌，以及皮下注射热灭活大肠杆菌后局部炎症和血管变化，来研究患者和对照者的炎症反应。
在克罗恩病患者中，直肠、回肠或皮肤创伤导致中性粒细胞异常低聚集（分别与健康个体相比差异为79%，n = 8，p = 0.0003；57%，n = 3，p = 0.05；50%，n = 13，p < 0.0001）以及促炎白细胞介素8产生降低（63%，n = 7，p = 0.003；63%，n = 3，p = 0.05；45%，n = 8，p < 0.0001）和白细胞介素1β降低（50%，n = 8，p = 0.0005）。培养的巨噬细胞暴露于急性伤口液（38%，n = 50，p < 0.0001）、C5a（48%，n = 41，p = 0.0005）或肿瘤坏死因子α（52%，n = 27，p < 0.0001）后白细胞介素8分泌减少。通过血流变化量化，接种大肠杆菌后的局部炎症反应减弱（回肠疾病50%，n = 6，p = 0.01；结肠疾病77%，n = 6，p = 0.0003）。在对照者中这种反应由一氧化氮介导，在患者中由西地那非增强，且与CARD15基因型无关。
在克罗恩病中，先天性免疫反应薄弱使突破肠壁黏膜屏障的肠内容物易于积聚，导致肉芽肿形成和慢性炎症。CARD15基因多态性并非此表型的基础，但使可补偿先天性炎症受损的NOD2途径失活。目前对继发性慢性炎症的治疗可能会夸大潜在病变并促进慢性病发展。
