Neuroimmune regulation of inflammatory responses in inflammatory bowel disease

Abstract

The term inflammatory bowel disease (IBD) is used to describe chronic inflammatory conditions of the gastro-intestinal tract. Patients suffer from abdominal pain, diarrhea, rectal bleeding and a substantial personal burden. The etiology of IBD is gradually being unraveled but remains a complex interaction between environmental, immunological and genetic factors. Mast cells and nerves can be found in close association in the intestine and the connection increases during inflammation. Understanding of the interaction between mast cells and nerves in IBD could help to provide new insights in the pathophysiology of this disorder. In this thesis a murine model was setup and validated to study the role of mast cells and nerves in the development of IBD by inducing a hypersensitivity response in the colon. This reaction is accompanied with mast cell proliferation and activation, infiltration of inflammatory cells, hypertrophy of lymphoid structures and diarrhea. The importance of mast cells was established by the observation that the responses could not be induced in mast cell-deficient (WBB6F1 W/Wv) mice. Furthermore, treatment with specific antibodies directed against the mast cell-derived pro-inflammatory cytokine TNF? could also abolish the characteristics for the response. A role for nerve-derived neuropeptide substance P was established by treatment with an antagonist against its specific receptor, NK1. Traditionally, mast cells are involved in allergic reactions and get activated by cross-linking of IgE molecules bound on the mast cell surface. However, not all hypersensitivity responses are associated with increased circulating levels of IgE. It was demonstrated that antigen-specific immunoglobulin-free light chains (IgLC) was capable of inducing mast cell activation by itself providing evidence for mast cell activation in non-IgE-mediated disorders. In the newly described murine colitis model a prominent role is established for IgLC by demonstrating that treatment with the specific antagonist for IgLC led to the abrogation of the hypersensitivity response in the colon. Since mast cells and nerves are highly associated and both described to be involved in hypersensitivity reactions, a role for IgLC in inducing neuronal activation was hypothesized. In this thesis it is described that IgLC can bind specifically to mouse dorsal root ganglion (DRG) neurons. Subsequent activation with the corresponding antigen resulted in a gradual increase in intracellular Ca2+ suggesting that the neuron gets activated. These data reveal a new physiological role for IgLC in eliciting antigen-specific neuronal activation and thereby amplification of the inflammatory response. Clinical relevance for IgLC is provided by demonstrating that serum concentrations of IgLC are increased in patients suffering from IBD and another gastro-intestinal disorder, irritable bowel syndrome. The data obtained in this thesis present new insight in the mast cell-nerve interactions in gastro-intestinal disorders and the novel murine model supplies a helpful tool to elucidate on the mechanism behind this interaction.