三甲
刘颂
副主任医师
南京鼓楼医院
胃肠外科
克罗恩病的发病新机制：克罗恩病、淋巴系统、脂肪组织
10843人已读
Evidence collected allows us to propose the following working model. Compromised lymph drainage, reported in IBD, leads to oedema, lymphangiogenesis, impaired immune cell trafficking and lymph leakage. Lymph factor(s) stimulate adipose tissue to proliferate and produce cytokines, which affect immune cell functions and exacerbate inflammation.
The authors thus hypothesized that lymph leakage promotes adipose tissue accumulation in two phases: first, increased storage of leaking lipids in existing adipocytes causes adipocyte hypertrophy; and second, once the adipocytes reach maximum lipid storage capacity, the promotion of preadipocyte differentiation results in adipocyte hyperplasia. The adipogenic factor present in lymph is as yet unidentified.
目前认为，淋巴渗漏（lymph leakage）导致脂肪组织积聚的机理有以下两点：1. 随淋巴渗出的脂质在成熟脂肪细胞中逐渐堆积，造成脂肪细胞肥大。2. 当成熟脂肪细胞储存脂质的能力达到饱和时，前脂肪细胞的分化将导致脂肪细胞数量增多（增生）。
Some of the most consistent pathological featuresobserved in patients suffering from Crohn’s disease aremucosal exudation, interstitial (submucosal) oedema andextensive dilation of lacteals. Lymphatic vessel dilationand oedema suggest poor lymph drainage consequentto either lymphatic obstruction or impairedcontractile function.
克罗恩病患者的淋巴系统特征：粘膜渗出、间质（粘膜下）水肿、乳糜管扩张。
其中，淋巴管（乳糜管）扩张及水肿说明CD患者的淋巴回流存在障碍，这种障碍可能是由于淋巴管梗阻或淋巴管收缩功能异常造成的，这在动物实验中得到了证实。将硬化剂注射入狗或者
猪的淋巴管或淋巴结，造成淋巴系统梗阻后，可以发现动物出现与IBD类似的肠道损伤。
Lymphatic obstruction or impaired lymph drainagecould also be involved in the development of lymphoidaggregates, a recurrent feature in Crohn’s disease and inmost chronic inflammatory diseases. Ectopic lymphoidaggregates are lymphoid structures containing dendritic, Band T cells that are able to support germinal centre reactionsand to initiate a local, although incomplete, immuneresponse. The molecular mechanisms leading to the formationof lymphoid aggregates (referred as lymphoid neogenesis)are not clearly understood, but the hypothesis of arole for defective lymphatic drainage has been proposed.Impaired lymph drainage could favour lymphoid neogenesisby reducing the amount of antigens and antigen-loadedantigen-presenting cells that are able to leave the inflamedsite and reach the draining lymph node, thus promotingthe accumulation of immune cells and mediators.
淋巴管梗阻及淋巴回流不畅也会造成克罗恩病患者的另一个典型特征：淋巴聚集（lymphoid aggregates）。淋巴聚集是指包含有树突状细胞（DC）、B细胞、T细胞在内的淋巴结构，这种淋巴结构能够诱导局部免疫应答。淋巴聚集的具体分子学机制尚不明确，但科学家已逐渐将淋巴回流异常公认为其主导因素之一。淋巴回流异常可导致“淋巴新生”（lymphoid neogenesis），造成炎症部位抗原及其APC向淋巴结的转运受阻，从而导致抗原及其APC在炎症部位持续存在及炎性应答的持续存在。
Similarly, defective lymphatic drainage could also beevoked in the granulomatous nature of Crohn’s diseasewith granulomata developing as a consequenceof the compromised clearing of the macrophage-madeaggregates. It should be noted that a proportion ofgranulomata seen in Crohn’s disease patients wasobserved to be associated with initial lymphatic vessels,suggesting granulomatous lymphangitis as a primarylesion of Crohn’s disease, and submucosal oedema andfibrosis as the consequence of the granulomatous inflammation.
与此同时，淋巴回流受阻也会造成克罗恩病患者的另一典型特征：肉芽肿。研究证实，CD患者肉芽肿形成与淋巴管密切相关，说明肉芽肿性淋巴管炎是CD的始动因素，而粘膜下（间质）水肿及纤维化则是肉芽肿性炎的结果。
Hypertrophy of adipose tissue and fat-wrapping (or creepingfat) is another important characteristic of Crohn’s disease,initially described as changes in the appearance ofmesenteric adipose tissue.Fat wrappingwas suggested to be caused by cytokine releasefrom adjacent lymphoid tissues, further highlightingthe importance of both adipose tissue and the embeddedlymphatic vessels and nodes in the pathogenesis of Crohn’sdisease. Critically, this adipose tissue shows overexpressionof PPARc and increased TNFa production,suggesting involvement of adipose tissue in the developmentof Crohn’s disease rather than altered fat distributionas a consequence of the disease. The presence ofmacrophages, dendritic cells and T cells in the adipose tissuesuggests these cells as another likely source of cytokinesand potential contributors to inflammatory changesobserved in Crohn’s disease.
脂肪肥大增生（爬行脂肪 Creeping fat）是CD患者的另一个典型特征。目前认为，爬行脂肪是由附近淋巴组织分泌的细胞因子导致的，这也再次强调了脂肪与淋巴在克罗恩病发病机制中的重要地位。值得注意的是，爬行脂肪表达出高水平的PPAR-gama与TNF-alpha，说明爬行脂肪是CD的“因”（cause），而不是“果”（consequence）。
The hypothesis of a strong correlation between lymphaticvessels, fat deposition and transmural inflammationmay also provide a plausible explanation for thedifferences between Crohn’s disease and ulcerative colitis,where fat-wrapping, granulomas and considerableoedema are not typical; indeed, only mucosal inflammationdevelops. It is possible to speculate that because ofthe superficial nature of the ulcerative colitis inflammation,the drainage function of intestinal and mesentericlymphatic vessels is not compromised. On the otherhand, the normal function of these lymphatics may helpconfine the inflammation to the mucosa.
在克罗恩病中，淋巴系统、脂肪聚集、透壁炎症三者相互关联、相互作用，也为克罗恩病与溃疡性结肠炎的本质差异提供了合理的解释。在溃疡性结肠炎中，由于炎症仅局限于粘膜及粘膜下层，并没有侵犯损伤到淋巴系统。正是因为淋巴系统功能未出现异常，才能有助于将炎症应答局限于粘膜层中，不发展为透壁性炎症。
Aliment Pharmacol Ther 2010; 32: 697–711
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