Granulomas obstruct lymphatics in all layers of the intestine in Crohn's disease

Abstract

After an earlier study defining immunolabeled lymphoid follicles, obstructed lymphatics, and granulomas of the diseased ilea of 24 Crohn's disease patients, we chose to trace the lymphatics of these cases and 10 additional by serial sectioning. Particular attention was given to establishing physical continuity between granuloma-obstructed lymphatics and lymphatics with 'lymphocytic thrombi'. Formalin-fixed paraffin-embedded tissue blocks from resected diseased ilea and proximal colons from 34 patients were reviewed. Patients were 13 men and 21 women, aged 14-60 years. Duration of disease ranged from 1 month to 10 years. Immunohistochemistry employed D2-40 antibody to label lymphatics and anti-CD68 to label granulomas. Twenty-nine of the 34 (85%) resection tissues had lymphangectasia, in mucosa, submucosa, and subserosa. In 53% of the specimens, lymphatics of the various layers were obstructed by granulomas that filled the lumina. In 44%, 15/34, there were also distended lymphatics that were totally plugged with lymphocytes. In 10 of the 15, serial sections revealed continuity between the lymphocyte-plugged lymphatics and the endolymphatic granulomatous obstruction downstream. In 5 of the cases, D2-40 immunostaining revealed redundant lymphatic endothelium interwoven with the granuloma cells. Granulomas totally obstruct lymphatics in all layers of the intestine in Crohn's disease. Upstream of these obstructions, lymphatics are distended with lymphocytes. The degree and extent of this potentially irreversible 'lymphangitis nodosa' have undoubtedly confounded treatment regimens and clinical trials. There currently are no imaging methods to demonstrate the lymphangitis, nor treatments to resolve it.

Evidence for Chlamydia in Crohns Disease

“…Recently we studied the lymphatics in resection specimens from patients with Crohn's disease [1,2]. Employing serial sections of granuloma-obstructed lymphatics or of lymphatics that were distended with lymphocytes, we showed physical continuity between the former and the latter [2].…”

“…Employing serial sections of granuloma-obstructed lymphatics or of lymphatics that were distended with lymphocytes, we showed physical continuity between the former and the latter [2]. Given the importance of this lymphangitis, we began to search for viral or bacterial antigens that might be responsible [3].…”

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

“…For example, mice deficient for angiopoietin-2 show intestinal lymphatic dysplasia and exacerbated colitis in the dextran sulfate sodium (DSS) colitis model (12,13), while selective ablation of the LVs leads to distortion of the intestinal villi architecture and severe bowel inflammation (14). Although the precise pathophysiology of IBD is unknown, LV obstruction and dysfunction are long-recognized features observed in humans with this disease (15,16). The existence of an abnormal lymphatic system is further supported by a recent article describing defective drainage capacity of LVs in human CD bowel strictures (17).…”

Ano-genital Granulomatosis and Crohn’s Disease: A Case Series of Males Presenting with Genital Lymphoedema

“…12,13 In one study, 46% of granuloma found within biopsies taken from patients with intestinal CD were related to or in close proximity to lymphatic vessels. 24 These observations possibly point to a common pathway between the two clinical entities.…”

“…Certainly, a role for lymphatic insufficiency in the aetio-pathogenesis of CD has previously been proposed. 13,25 The nomenclature is confusing and it has been argued by some authors that AGG is indistinguishable from cutaneous metastatic CD. 15 However, we propose that AGG and MCD are two separate presentations of cutaneous granulomatous inflammation as a result of CD.…”