Rehal Sonia, von der Weid Pierre-Yves
Inflammation Research Network and Smooth Muscle Research Group, Department of Physiology & Pharmacology, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
Inflammation Research Network and Smooth Muscle Research Group, Department of Physiology & Pharmacology, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
Am J Pathol. 2017 Apr;187(4):798-807. doi: 10.1016/j.ajpath.2016.12.007. Epub 2017 Feb 6.
Chronic inflammatory diseases are associated with a persistent and enhanced response to environmental antigens. As an adaptive response to this exaggerated immune state, affected tissue typically develops tertiary lymphoid organs. Studies of Crohn disease (CD), a chronic inflammatory disease of the intestinal tract, report tertiary lymphoid organs present within the mucosal wall, along with other lymphatic diseases, such as lymphangiogenesis and obstructed lymphatic vessels. These observations suggest that downstream mesenteric lymphatic vessels and lymph drainage into mesenteric lymph nodes may be compromised. However, information is lacking on the morphologic features and functional status of mesenteric lymphatics in CD. Using confocal imaging, PCR, flow cytometry, and functional strategies, we addressed these questions in the established TNFΔARE mouse model of CD and found that this mouse model had many lymphatic abnormalities reminiscent of human CD. These abnormalities include intestinal lymphangiectasia, mesenteric lymph node lymphadenopathy, and lymphangiogenesis in both the mesentery and mucosa. Critically, TNFΔARE mice also present mesenteric tertiary lymphoid organs and have altered lymphatic transport of dendritic cells to mesenteric lymph nodes, two features likely to actively modulate immunity. Our findings provide key insights into lymphatic remodeling in the TNFΔARE mouse model. They shed light on the involvement of these lymphatic changes in immune dysfunctions observed in CD and suggest the lymphatic system as new target for therapeutic options.
慢性炎症性疾病与对环境抗原的持续且增强的反应相关。作为对这种过度免疫状态的适应性反应，受影响的组织通常会形成三级淋巴器官。对克罗恩病（CD）（一种肠道慢性炎症性疾病）的研究报告称，在粘膜壁内存在三级淋巴器官，以及其他淋巴疾病，如淋巴管生成和淋巴管阻塞。这些观察结果表明，肠系膜下游淋巴管和淋巴引流至肠系膜淋巴结可能受到损害。然而，关于CD中肠系膜淋巴管的形态学特征和功能状态的信息尚缺。我们使用共聚焦成像、聚合酶链反应、流式细胞术和功能策略，在已建立的CD的TNFΔARE小鼠模型中解决了这些问题，发现该小鼠模型有许多类似于人类CD的淋巴异常。这些异常包括肠道淋巴管扩张、肠系膜淋巴结肿大，以及肠系膜和粘膜中的淋巴管生成。至关重要的是，TNFΔARE小鼠还存在肠系膜三级淋巴器官，并且树突状细胞向肠系膜淋巴结的淋巴转运发生改变，这两个特征可能会积极调节免疫。我们的研究结果为TNFΔARE小鼠模型中的淋巴重塑提供了关键见解。它们揭示了这些淋巴变化在CD中观察到的免疫功能障碍中的作用，并表明淋巴系统是治疗选择的新靶点。
