Defective Lymphatics in Crohn’s Disease: Tertiary Lymphoid Follicles Plug the Gap

The gut-associated lymphoid tissues are the guardians of the enteric immune system and integrate dietary and microbial stimuli to maintain immunologic tolerance. However, during periods of persistent chronic inflammation, such as in Crohn’s disease (CD), a dysfunctional lymphatic system is a pathologic hallmark. Indeed, the predominant histopathologic features of CD are lymphocytic lymphangitis, occluded lymphatic vessels, and inflammatory granulomas. These trademark features of chronic disease are found in or around ectopic tertiary lymphoid tissues (TLT) in the inflamed lamina propria (Gut 2008;57:1-4). In addition, the presence of TLT at the base of aphthous ulcers is the earliest endoscopically evident lesion in CD and their appearance heralds recurrent disease within the neoterminal ileum after ilectomy (Gut 1984;25:665-672). To date, the function of intestinal TLT and their impact on the etiology and pathogenesis of CD remains enigmatic, with limited experimental evidence as to their role. How TLT integrate into the pathophysiology of CD remains a critical question, yet clinical investigation into their development and function remains limited. Randolph et al aimed to assess the integrity of mesenteric lymphatic vasculature in CD. First, they confirmed the previous findings generated from immunopathologic studies of intestinal mucosa, indicating defective lymphatic function during active disease. To achieve this, patent blue dye was injected into the serosa of ileal loops before surgical resection, highlighting afferent lymphatic vessels draining the lamina propria. This technique nicely demonstrated a deviation of normal lymphatic vessels in active CD, compared with non-CD counterparts and indicated a remodeling of the vasculature in the mesentery. Next, they used a 3-dimensional system to image whole mount sections from a patient cohort undergoing ilectomy for stricturing CD (to obtain cm3 tissue coverage). Surprisingly, this work revealed advanced remodeling of the lymphatic vascular tracks, with the presence of ectopic lymphoid follicles within the collecting vessel line. A border of adipocytes and no evident capsule, suggesting that these organized structures were not sentinel lymph nodes but TLT instead. The work by Randolph et al highlights that, although most studies have reported on lymphatic capillaries in the intestinal wall, where collecting vessels remove solutes and immune cells, the primary functional site of lymphatic dysfunction may be the larger vessels in the mesentery, which interface with sentinel lymph nodes

Cell-Specific Inhibition of p38α as a Therapeutic Strategy for Inflammatory Bowel Disease

The abstract is included in the text

Microbial-Driven Immunological Memory and Its Potential Role in Microbiome Editing for the Prevention of Colorectal Cancer.

Over the last several years, many advances have been made in understanding the role of bacteria in the pathogenesis of gastrointestinal cancers. Beginning with Helicobacter pylori being recognized as the first bacterial carcinogen and the causative agent of most gastric cancers, more recent studies have examined the role of enteric microbes in colorectal cancer. In the digestive tract, these communities are numerous and have a complex interrelationship with local immune/inflammatory responses that impact the health of the host. As modifying the microbiome in the stomach has decreased the risk of gastric cancer, modifying the distal microbiome may decrease the risk of colorectal cancers. To date, very few studies have considered the notion that mucosal lymphocyte-dependent immune memory may confound attempts to change the microbial components in these communities. The goal of this review is to consider some of the factors impacting host-microbial interactions that affect colorectal cancer and raise questions about how immune memory responses to the local microbial consortium affect any attempt to modify the composition of the intestinal microbiome

Ectopic lymphoid tissue alters the chemokine gradient, increases lymphocyte retention and exacerbates murine ileitis

Background The earliest endoscopically-evident lesion in Crohn’s disease is the aphthous ulcer, which develops over ectopic lymphoid tissues (ie, inducible lymphoid follicles (ILF), tertiary lymphoid tissue (TLT)) in the chronically inflamed intestine. ILF/TLT are induced within effector sites by homeostatic lymphoid chemokines, but their role in the development of intestinal ILF/TLT and in the pathogenesis of Crohn’s disease is poorly understood. Design Using a mouse model of Crohn’s-like ileitis (TNFΔARE) which develops florid induction of ILF/TLT within its terminal ileum, the contribution of the CCR7/ CCL19/CCL21 chemokine axis during the development of TLT and its role in disease pathogenesis were assessed. Results Both CCL19 and CCL21 were increased within the inflamed ileum of TNFΔARE mice, which resulted in CCR7 internalisation and impaired T cell chemotaxis. ILF/ TLT were a major source of CCL19 and CCL21 and increased local synthesis, augmented recruitment/ retention of effector, naı¨ve and central memory T cell subsets within the inflamed ileum. Immunoblockade of CCR7 resulted in further effector T cell retention and exacerbation of ileitis. Conclusions Induction of ILF/TLT in the chronically inflamed intestine alters the homeostatic CCL19-CCL21 lymphoid-chemokine gradient and increases recruitment/ retention of effector CCR7+ T cell subsets within the terminal ileum, contributing to the perpetuation of chronic inflammation. Thus, blockade of CCR7 or its ligands might result in deleterious consequences for subjects with chronic inflammatory diseases