Maarten Cozijnsen

13 Chapter 1 General introduction Pathogenesis of CD and the role of TNF The pathogenesis of CD is highly complex and still not fully understood. CD is a multifactorial disease in which genetic predisposition, microbial and dietary environmental pressure and susceptibilities of the immune system lead to aberrant inflammatory responses to luminal microbiota and concomitant autoimmune responses. Although a cure has not yet been found, manipulating one of these factors does alleviates disease. For example, diversion of luminal content with ileostomy, which drastically alters environmental pressure, reduces mucosal inflammation in the bowel distal to the stoma. In addition, dietary intervention with exclusive enteral nutrition (EEN), which affects luminal microbial composition, also inhibits inflammation and can restore the integrity of the mucosal layer. Lastly, inhibiting the immune response also has strong beneficial effects, as most clearly evidenced by the effect of immune suppressive and immune modulating interventions on CD. A key problem in the chronicity of CD is the development of immune memory driven by T-lymphocytes (T-cells) that reside in the intestinal lamina propria, secrete interferon-gamma and cause reactivation of the disease upon recognition of their environmental activating trigger. 7 Effective elimination or inhibition of this cell population may reduce the chance of disease re-activation and explains why T cells are an important target in CD treatment strategies. Tumor necrosis factor alfa (TNF-alfa) is an inflammatory cytokine mainly produced by macrophages although it can also be produced by many other leukocytes amongst which T cells. It is produced as a transmembrane protein (tmTNF) and a soluble form (sTNF). TNF-alfa is an important factor for orchestrating cellular immune responses and plays a crucial role in host-defense to pathogens and killing of malignant cells. TNF signals via two receptors: TNF receptor type 1 (TNFR1), expressed in almost all cell types, and TNFR2, expressed on leukocytes only. Ligation of the receptor results in a complex signaling cascade leading to the production of wide variety of proteins involved in cell survival, proliferation, differentiation, migration, and apoptosis. When TNF concentrations in blood become very high, an acute phase reaction in the liver ensues causing fever and cachexia.