Lymphangiogenesis in Crohn’s disease: an immunohistochemical study using monoclonal antibody D2-40

Abstract

Crohn's disease (CD) is a chronic inflammatory bowel disorder of unknown etiology. An involvement of the intestinal lymphatic system has been suggested. Recently, monoclonal antibodies have become available to distinguish lymphatic vessels from blood vessels. The aim of the study was to examine the distribution of lymphatic vessels in ileal and colic walls of patients affected by CD and compare it with healthy controls and other inflammatory bowel diseases. Twenty-eight cases of CD, 13 cases of other inflammatory bowel diseases, and 10 normal ileal and colic walls were studied. Immunohistochemical staining was performed using the monoclonal antibody D2-40. Quantification of lymphatic vessels was performed by identifying four fields with high density of lymphatics and then counting the number of lymphatic vessels at high resolution. Lymphatic diameter was also evaluated by using an ocular micrometer. Lymphatic vessels showed the highest density in CD specimens. The median number of lymphatics was significantly higher both in ileal and colic samples of CD than the other inflammatory diseases as well as normal controls. Moreover, in patients with CD, diffuse lymphangiectasia was also observed. The present data suggest that lymphangiogenesis and lymphangiectasia probably play a role in the pathogenesis of CD.

VEGF-C–dependent stimulation of lymphatic function ameliorates experimental inflammatory bowel disease

“…These novel findings are important because, although the precise pathophysiology of IBD is unknown, LV obstruction and dysfunction are long-recognized features observed in humans with this disease (15,16), and normalizing gut lymphatics with prolymphangiogenic factors such as VEGF-C may improve disease activity. Consistent with altered lymphatic contractile function reported in an animal model of acute intestinal inflammation (19), intestinal lymphatics are known to be grossly abnormal in the gut of CD patients (10). Moreover, mucosal role in mediating post-resolution innate lymphocyte repopulation and restoring tissue homeostasis (48,68).…”

“…To assess whether lymphangiogenesis occurs in human IBD, we performed immunohistochemical staining of control and active CD-and UC-involved colons with antibodies recognizing podoplanin, a widely accepted marker of lymphatic vasculature (9,10,35). Normal colon mucosa only showed sporadic, thin LVs in the lamina propria and submucosa, whereas CD and UC tissues contained numerous, readily detectable dilated LVs ( Figure 1A).…”

“…While the study of IBD has been largely focused on the roles played by the classical components of the immune system, other reports have called attention to the significant contribution of nonimmune cells, such as epithelial, endothelial, mesenchymal, and vascular cells (4)(5)(6). In particular, there is a growing body of evidence showing that IBD is associated with the development of new blood (angiogenesis) and lymph (lymphangiogenesis) vessels from the existing vascular network (7)(8)(9)(10). Although the pathogenic role of angiogenesis in IBD is well understood (11), whether lymphangiogenesis plays a protective or pathogenic role is still unknown.…”

Is lymphatic status related to regression of inflammation in Crohn's disease?

“…A higher number of lymphatic vessels have been observed in the ileal and colonic wall in comparison to the healthy small and large bowel [14] . The diameter of the lymph vessels in the intestinal wall affected by CD was approximately ten times larger than normal controls and was significantly increased in comparison to other inflammatory bowel diseases, such as ulcerative colitis, ischemic ileitis or pseudomembranous colitis [15] . Interestingly, lymphangiogenesis and lymphangiectasia were present also in normal intestinal tract near the bowel affected by CD [15] .…”

“…The diameter of the lymph vessels in the intestinal wall affected by CD was approximately ten times larger than normal controls and was significantly increased in comparison to other inflammatory bowel diseases, such as ulcerative colitis, ischemic ileitis or pseudomembranous colitis [15] . Interestingly, lymphangiogenesis and lymphangiectasia were present also in normal intestinal tract near the bowel affected by CD [15] . These last aspects suggest that alteration of the lymphatic system could be an inducer of CD [16] .…”