From the, Division of Medicine, University College London, London, UK.
J Intern Med. 2019 Oct;286(4):373-388. doi: 10.1111/joim.12945. Epub 2019 Jun 27.
The fruitless search for the cause of Crohn's disease has been conducted for more than a century. Various theories, including autoimmunity, mycobacterial infection and aberrant response to food and other ingested materials, have been abandoned for lack of robust proof. This review will provide the evidence, obtained from patients with this condition, that the common predisposition to Crohn's is a failure of the acute inflammatory response to tissue damage. This acute inflammation normally attracts large numbers of neutrophil leucocytes which engulf and clear bacteria and autologous debris from the inflamed site. The underlying predisposition in Crohn's disease is unmasked by damage to the bowel mucosa, predominantly through infection, which allows faecal bowel contents access to the vulnerable tissues within. Consequent upon failure of the clearance of these infectious and antigenic intestinal contents, it becomes contained, leading to a chronic granulomatous inflammation, producing cytokine release, local tissue damage and systemic symptoms. Multiple molecular pathologies extending across the whole spectrum of the acute inflammatory and innate immune response lead to the common predisposition in which defective monocyte and macrophage function plays a central role. Family linkage and exome sequencing together with GWAS have identified some of the molecules involved, including receptors, molecules involved in vesicle trafficking, and effector cells. Current therapy is immunosuppressant, which controls the symptoms but accentuates the underlying problem, which can only logically be tackled by correcting the primary lesion/s by gene therapy or genome editing, or through the development of drugs that stimulate innate immunity.
对克罗恩病病因的徒劳探索已经进行了一个多世纪。各种理论，包括自身免疫、分枝杆菌感染和对食物和其他摄入物质的异常反应，都因缺乏确凿证据而被摒弃。这篇综述将提供来自患有这种疾病的患者的证据，即克罗恩病的共同易感性是对组织损伤的急性炎症反应的失败。这种急性炎症通常会吸引大量中性粒细胞白细胞，吞噬并清除细菌和炎症部位的自身碎片。在克罗恩病中，这种潜在的易感性通过肠黏膜损伤暴露出来，主要是通过感染，使粪便内容物进入易受伤害的组织内。由于这些感染性和抗原性肠内容物的清除失败，它们被包含在内，导致慢性肉芽肿性炎症，产生细胞因子释放、局部组织损伤和全身症状。跨越急性炎症和先天免疫反应整个范围的多种分子病理学导致了共同的易感性，其中单核细胞和巨噬细胞功能缺陷起着核心作用。家族连锁和外显子组测序以及 GWAS 已经确定了一些涉及的分子，包括受体、参与囊泡运输的分子和效应细胞。目前的治疗方法是免疫抑制，它可以控制症状，但会加重潜在的问题，而通过基因治疗或基因组编辑纠正主要病变/或通过开发刺激先天免疫的药物，才能逻辑地解决这个问题。
