Immunological mechanisms underlying inflammatory bowel disease

Ulcerative colitis (UC) and Crohn‘s disease (CD), collectively referred to as inflammatory bowel diseases (IBD), are characterized by aberrant immune responses in the gut, resulting in chronic intestinal inflammation. There is no cure for IBD, and the disease is increasing world-wide. The pathogenic mechanisms that drive disease onset and chronicity are currently unclear but seem to include a complex mixture of heritable pre-disposition and acquired factors.

The inflammation during IBD is characterized by a large influx of immune cells from the circulation to the inflamed intestine. This is mediated by the expression of chemokine receptors on the surface of the leukocytes, allowing them to migrate towards gradients of chemokines produced in the intestinal tissues. However, the mechanisms behind chemokine receptor-mediated leukocyte infiltration to the gut are poorly understood. The papers included in this thesis investigate the roles of CD4+ T helper cells and monocytes, focusing on chemokine receptor interactions, in mediating intestinal inflammation during IBD.

Whereas the inductive mechanisms of chemokine receptors during colitis have mainly been studied in murine T cells, we set out to investigate blood monocytes in IBD patients. We found that the chemokine receptor CCR9, important for gut-homing in T cells, is expressed on a subset of monocytes that is increased during active IBD. Furthermore, we could show that a large number of chemokine receptors are up-regulated on IBD monocytes compared to healthy controls, as well as being differentially expressed between ulcerative colitis and Crohn’s disease. As UC and CD may be clinically similar, they are often difficult to distinguish. However, as optimal therapy choices for the respective disorders differ, correctly diagnosing IBD is crucial and thus, chemokine receptor profiling on blood monocytes constitutes a potential diagnostic approach.

In T cells, murine data suggests that CCR9 interactions are important for small intestinal homing whereas their role during colitis remains unclear. We have investigated CD4+ T helper cells infiltrating the colonic mucosa during inflammation, and found that CCR9 is widely expressed on these cells, indicating importance role during human colitis. Furthermore, CCR9 expression levels were higher on T cells derived from un-affected compared to inflamed specimens, which might suggest that CCR9-positive cells have a regulatory function.

In conclusion, we have shown that chemokine receptor interactions are important for colonic immune responses during IBD. Understanding the complexity of the chemokine receptor system is fundamental to successfully targeting leukocyte migration pathways for therapeutic purposes.

List of scientific papers

I. Linton L, Karlsson M, Grundström J, Hjalmarsson E, Lindberg A, Lindh E, Glise H, Befrits R, Janczewska I, Karlén P, Winqvist O, Eberhardson M. HLA-DR(hi) and CCR9 Define a Pro-Inflammatory Monocyte Subset in IBD. Clin Transl Gastroenterol. 2012 Dec 20;3:e29.
https://doi.org/10.1038/ctg.2012.23

II. Linton L, Jonsson Rolandsdotter H, Jones M, Jones P, Glise H, Eberhardson M, Finkel Y, Winqvist O. Chemokine receptor expression profiling of human blood monocytes in juvenile patients with inflammatory bowel disease. [Manuscript]

III. Janson PC, Linton LB, Bergman EA, Marits P, Eberhardson M, Piehl F, Malmström V, Winqvist O. Profiling of CD4+ T cells with epigenetic immune lineage analysis. J Immunol. 2011 Jan 1;186(1):92-102.
https://doi.org/10.4049/jimmunol.1000960

IV. Linton L, Jonsson Rolandsdotter H, Glise H, Finkel Y, Eberhardson M, Winqvist O. Promoter demethylation is associated with CCR9 expression on colon-infiltrating CD4+ T cells during juvenile inflammatory bowel disease. [Manuscript]