Actis Giovanni C, Rosina Floriano
Giovanni C Actis, Floriano Rosina, Division of Gastro-Hepatology, Ospedale Gradenigo, 10153 Torino, Italy.
World J Gastrointest Pharmacol Ther. 2013 Aug 6;4(3):41-6. doi: 10.4292/wjgpt.v4.i3.41.
The pathogenesis of the two inflammatory bowel diseases (IBDs) phenotypes ulcerative colitis (UC) and Crohn's disease (CD) has remained elusive, thus frustrating attempts at defining a cure. IBD often presents as a complex inflammatory process wherein colon lesions (UC) or widespread ulceration and fissure (CD) might be accompanied by ancillary extra-intestinal manifestations involving the eye, skin, joints or liver, but also by full-blown "autoimmune" disorders from psoriasis and multiple sclerosis to rheumatoid arthritis; attempts at unraveling a link or a hierarchical order in these entities have proven almost fruitless. More recently, the input of genetics has suggested that the IBDs might be multi-organ inflammatory processes, elicited by a large number of low-penetrance susceptibility genes, with environmental factors needed to induce full-blown disease. At a noteworthy exception to this rule, the description of the nucleotide-oligomerization domain (NOD) gene mutations in CD came at the beginning of the 2000s: the NOD-LRR are part of a highly conserved microbial sensor system which respond to bacterial peptidoglycans by mounting an inflammatory response. At least in Caucasian patients, the prevalently loss-of-function mutation of NOD permitted to unexpectedly define CD as an immune deficiency state, and upon its recent description in apparently unrelated disorders such as the Blau syndrome (a granulomatous pediatric syndrome), and perhaps in psoriasis and chronic obstructive pulmonary disorders, has contributed to revolutionize our view of IBD and CD in particular. The latter affection, together with psoriasis and chronic pulmonary disease can now be included into a newly identified category named "barrier organ disease", wherein a barrier organ is defined as a large mucosal or epithelial surface with an abundant metagenomic microbial population and an underneath reactive tissue, the whole structure being in contact with the outer environment and capable to react to it. Personalized treatments and empowerment of research across different disease phenotypes should be the advantages of this novel mindset.
两种炎症性肠病（IBD）表型，即溃疡性结肠炎（UC）和克罗恩病（CD）的发病机制一直难以捉摸，因此阻碍了治愈方法的确定。IBD通常表现为复杂的炎症过程，其中结肠病变（UC）或广泛的溃疡和裂隙（CD）可能伴有眼部、皮肤、关节或肝脏等肠外表现，还可能伴有从银屑病、多发性硬化症到类风湿性关节炎等全面的“自身免疫”疾病；在这些疾病之间寻找联系或层级顺序的尝试几乎毫无结果。最近，遗传学研究表明，IBD可能是由大量低外显率易感基因引发的多器官炎症过程，还需要环境因素诱发全面发病。作为这条规则的一个显著例外，21世纪初发现了CD中的核苷酸寡聚化结构域（NOD）基因突变：NOD样受体（NOD-LRR）是高度保守的微生物传感系统的一部分，通过引发炎症反应来应对细菌肽聚糖。至少在白种人患者中，NOD普遍存在的功能丧失突变意外地将CD定义为一种免疫缺陷状态，并且在最近在诸如布劳综合征（一种肉芽肿性儿科综合征）等明显不相关的疾病中发现该突变，或许还在银屑病和慢性阻塞性肺疾病中发现后，尤其有助于彻底改变我们对IBD，特别是对CD的看法。后一种疾病，连同银屑病和慢性肺病现在可以被纳入一个新确定的类别，称为“屏障器官疾病”，其中屏障器官被定义为具有丰富宏基因组微生物群体和下方反应性组织的大粘膜或上皮表面，整个结构与外部环境接触并能够对其做出反应。个性化治疗以及针对不同疾病表型加强研究应该是这种新思维方式的优势所在。
