While the lymphatic system is clearly pivotal for immunity and fluid homeostasis in the entire body, it is even more closely linked with the gastrointestinal system because of its role in nutrient absorption and immune cell trafficking to this area. The relationship between the gut and the lymphatic system has also been shown to be critical during intestinal inflammation. IBD patients presenting with oedema were reported to have enlarged lymphatic vessels, which appeared obstructed [37
]. The enlarged and stenotic lymphatic vessels suggest poor lymphatic drainage, which would further exacerbate the tissue oedema. Interestingly, animal studies where mesenteric lymphatic drainage was experimentally obliterated led to Crohn’s disease-like macroscopic and microscopic patterns [40
]. These animal models of lymphatic obstruction are considered by some to best reproduce Crohn’s disease symptoms without contribution from genes, environment or bacterial makeup in the gut [31
]. Importantly, these animal models of lymphatic obstruction recapitulate transmural inflammation and intestinal fistulae characteristic of Crohn’s disease [42
Another feature seen in histological samples from IBD patients is the presence of lymphoid aggregates. Although the mechanisms surrounding the formation of these structures are not well understood, the hypothesis of lymphoid neogenesis proposes that the obstruction of lymphatic drainage promotes ectopic germinal centres to form in the tissues [43
]. Further involvement of the lymphatic system in the development of intestinal inflammation relates to lymphangiogenesis, the formation of new lymphatic vessels, which is commonly seen in biopsy samples from IBD patients [44
]. This lymphangiogenesis may function to increase the delivery of dendritic cells and antigen-presenting cells to the lymph nodes to enhance the adaptive immune response, however this has not been proven.
Whether these new lymphatic vessels improve drainage to the lymph nodes is still under debate. A study reporting that a large number of DC and proliferating T cells were found in the lamina propria of Crohn’s disease patients, suggests that they are unable to be drained away by the lymphatic system and are trapped at the site of inflammation forming lymphoid aggregates, and creating a self-perpetuating feedback loop that prolongs the local immune response [48
]. On the other hand, Jurisic et al. [49
] found a significant increase in the severity of colonic inflammation in IL-10-deficient mice (that spontaneously develop IBD-like symptoms) treated with an antibody directed against the vascular endothelial growth factor receptor 3 (VEGFR-3), a major lymphangiogenic receptor [50
]. The study demonstrated that when lymphatic function in an inflamed gut was inhibited or reduced in anti-VEGFR-3-treated mice, inflammation was exacerbated. This was attributed to the possibility that decreased lymphatic drainage promotes increased leukocyte numbers in, and poor cell transport out of, tissue. They also suggested that increased inflammatory mediators in the local tissue allow extravasation of leukocytes out of blood vessels, thus further exacerbating the tissue inflammation. It was suggested that the episodic relapsing-remitting nature of IBD might be due to the periodic dysfunction of local tissue lymphatic vessels. Data in other studies of rheumatoid arthritis (a disease characterised by chronic inflammation with flare and remission periods similar to IBD) in mice showed that inhibition of lymphangiogenesis and lymphatic drainage via VEGFR-3 blockade exacerbated the inflammatory response [50
]. Other studies have shown the relationship between dysfunctional immune responses and lymphangiogenesis in other organ systems. Lymphangiogenesis has been observed in kidney transplant rejection as well as in psoriatic skin lesions, both involving altered immune and inflammatory responses in their pathogenesis. These new studies highlight the potential importance of intact lymphatic vasculature as well as the propagation of new lymphatic vessels in the resolution of inflammation or maintenance of remission in a chronically inflamed gut.
Granulomas are a hallmark histological feature of Crohn’s disease and a recent study has found that the granulomas in Crohn’s patients show lymphangiectasia (pathological dilation of lymphatic vessels), as well as lymphocytic perilymphangitis. This supports the association between inflammation, granulomas and tertiary lymphoid follicles in the lymphatic vasculature of Crohn’s disease patients [51
]. Animal models of ileitis have shown that the contractile function of mesenteric lymphatic vessels can be altered both in vivo
and in vitro
with an increasing level of dysfunction correlated with an increasing degree of mucosal damage [52
]. This dysfunction was significantly reduced in the presence of cyclooxygenase and nitric oxide synthase inhibitors, suggesting the involvement of arachidonic acid products and nitric oxide in the inflammation-induced dysfunction [52
]. These studies lend support to the possibility that the lymphatic system is intimately involved in the pathogenesis and damage done to the tissues in patients with inflammatory bowel disease. One study has even suggested that Crohn’s disease is caused by a congenital lack of mesenteric lymphatic vessels which leads to lymph and bacterial stasis, lymphangitis and eventual inflammatory change [54
]. While this is not the currently accepted aetiology for IBD, it is important not to dismiss the lymphatic system as a potential contributor to the pathogenesis of IBD and, importantly, as a potential therapeutic target in the management of intestinal inflammation. Altogether, these studies suggest a very strong link between the integrity of lymphatic function and the exacerbation or resolution of instances of intestinal inflammation.