An imbalance of the Th1/Th2 ratio contributes to various immunological disorders. The dramatic B cell response,19,22
comprehensive mRNA analysis of cytokines,21
and increased production of interleukin 5 (IL-5) by CD4 positive T cells in diseased intestine23
strongly suggest a role for the predominant Th2 response in the pathogenesis of UC. In contrast, increased numbers of interferon γ producing CD4 positive T cells and IL-12 producing macrophages in inflamed intestine7,10
have been reported in Crohn’s disease, which is now widely recognised as a typical Th1 dominant disorder.4
It is possible that activated T cells are recruited from the peripheral circulation to orchestrate the intestinal inflammation, although the primary mechanism for T cell recruitment remains unclear. Mesenteric lymph nodes and luminal lymphoid tissues are possible candidates for such recruitment.
Chemokines, which chemically attract leucocytes to inflammatory foci, are involved in particular immunoreactions.24–26
The expression of interferon inducible protein IC, IL-8, monocyte chemotactic proteins 1–3, and macrophage inflammatory proteins 1α and 1β in Crohn’s disease and UC did not differ significantly,27–32
and the differential expression of chemokines in Crohn’s disease and UC has not been reported previously. Although both SLC and ELC expressed in lymphoid tissue are known to be involved in the regulation of antigen specific T cells,15,17,18
this is the first study to reveal the expression of SLC and ELC in Crohn’s disease gut associated lymphoid tissue (GALT).
We found that SLC and ELC were mainly expressed in the GALT T cell zone, which suggests that SLC and ELC function as T cell homing chemokines in the intestine. Expression of SLC and ELC was higher in the mesenteric lymph nodes than in the intestine, and in patients with Crohn’s disease compared with controls and patients with UC.
We have reported previously that antigen presenting macrophages found in the intestinal granulomas of patients with Crohn’s disease cause a Th1 dominant immune response.5,10
In our present study, ELC was expressed in mature dendritic cells in Crohn’s disease lymph nodes, whereas SLC and ELC were not expressed in macrophages located in granulomas of mesenteric lymph nodes or in the intestine of these patients. Katou and colleagues22
reported concomitant localisation of ELC positive mature dendritic cells and CD45RA naive T cells, and ELC negative mature dendritic cells and CD45RO memory T cells in chronic inflammatory human skin lesions. Therefore, a memory T cell immune response, rather than a naive T cell response is probably involved in granuloma formation in patients with Crohn’s disease.
“We found that SLC and ELC were mainly expressed in the gut associated lymphoid tissue T cell zone, which suggests that SLC and ELC function as T cell homing chemokines in the intestine”
HEVs, lymphatic vessels, and mature dendritic cells are important in the regulation of the immune response of antigen specific T cells in lymph nodes. The number of SLC positive HEVs and lymphatic vessels, and ELC positive mature dendritic cells, was significantly higher in the mesenteric lymph nodes of patients with Crohn’s disease than in patients with UC. Furthermore, real time quantification by RT-PCR revealed increased SLC, ELC, and CCR7 mRNA in the mesenteric lymph nodes of patients with Crohn’s disease compared with those with UC. The expression of SLC and ELC, and their ligand CCR7, was higher in the mesenteric lymph nodes of patients with Crohn’s disease than in those with UC in terms of both mRNA and protein. Such a discrepancy in chemokine expression between different inflammatory bowel diseases has not been reported previously. In Crohn’s disease GALT, not only HEVs, but also lymphatic vessels, play an important role in the recruitment of memory T cells. Interestingly, the expression of these chemokines is more prominent in mesenteric lymph nodes than in the inflamed intestine. Mesenteric lymph nodes may be the primary sites of T cell recruitment to the inflamed intestine and may perpetuate the inflammatory reaction by activating memory T cells in patients with Crohn’s disease.
Take home messages
- Differential expression of SLC (secondary lymphoid tissue chemokine) ELC (EBI1 ligand chemokine), and their ligand, CCR7, in the mesenteric lymph nodes of patients with Crohn’s disease suggests that abnormal antigen processing and T helper type 1 response skewing may be involved in the pathogenesis of Crohn’s disease
- Mesenteric lymph nodes play an important role in T cell and dendritic cell recruitment in patients with this disease and may be the primary sites of T memory cell homing in this disease
- In the future, antibodies or drugs that suppress SLC and ELC may be useful in the treatment of Crohn’s disease
Dendritic cells in peripheral tissues begin maturation after phagocytosing antigens, followed by CCR6 downregulation and CCR7 upregulation, and are recruited to the lymph nodes by a reciprocal reaction with SLC, which is produced by lymphatic vessels.15,17
In addition, CCR7 is expressed on naive T cells and Th1 T cells.33
Increased expression of SLC in lymphatic vessels and HEVs triggers the recruitment of CCR7 positive dendritic cells and T cells, which leads to T cell zone hyperplasia in Crohn’s disease lymph nodes. Dendritic cells recruited in lymph nodes produce CCR7 to interact with CCR7 positive T cells and expand the Th1 immune response in Crohn’s disease. Suppression of SLC and ELC in Crohn’s disease GALT by antibodies or drugs is a possible future treatment for patients with Crohn’s disease.
In conclusion, differential expression of SLC, ELC, and CCR7 in the mesenteric lymph nodes of patients with Crohn’s disease characterises abnormal antigen processing and Th1 skewing as a pathogenetic mechanism in Crohn’s disease. Mesenteric lymph nodes play an important role in T cell and dendritic cell recruitment in patients with this disease.