Small bowel cancer risk in Lynch syndrome.

It is now evident that both forms of inflammatory bowel disease (IBD), Crohn's disease and ulcerative colitis, are highly heterogeneous, not only at the clinical and pathogenetic level, but also in regard to time of appearance. In fact, early-and late-onset IBD are increasingly recognised as distinct entities that can be differentiated in regard to the underlying mechanism of inflammation and response to therapy, both in human patients and in experimental animal models. 1–3 While this differentiation is real, early and late IBD ostensibly result from the combined action of the same factors— that is, genetic predisposition, environmental changes and a disregulated immune response. On this background scenario, Damen and collaborators (Gut 2008;57:1480) ask the very pertinent question of what determines the development of specific effector T cells involved in early gut tissue damage: the expression of specific cell surface receptors or the production of specific cytokines by anti-gen-presenting cells? Based on the study of monocyte-derived dendritic cells from children with CD and UC, they found a clear dose response between the amount of the microbial ligands used to stimulate dendritic cells and the production if interleukin 12 (IL12) and IL23, and also found that the levels of these two cytokines varied independently of each other. They concluded that production of Th1-and Th17-inducing cytokines is independent of the type or stage of IBD, and the type of effector T cells depends on the amounts of particular microbial products and the presence of cell surface receptors for IL12 or IL23. While this conclusion is reasonable and plausible, it is also likely to be only part of the answer, considering the still numerous ''unknowns'' that afflict the investigation of IBD pathogenesis. Children with CD or UC display unique phenotypic and genetic characteristics related to early-onset disease. 4 IBD at a young age is associated with a stronger family history of IBD, CD-affected children are more likely than adults to have colonic involvement, and UC-affected children are more likely than adults to have extensive colitis. With regard to genetic predisposition, genome-wide association (GWA) scans performed to date have been almost exclusively performed in adult CD patients, and the genetic variants reported so far do not account for the entire IBD genetic risk. Thus, it seems probable that future GWA scans may identify novel genes linked to early-onset IBD, as has been the case for other early-onset conditions such as Alzheimer disease, type 2 diabetes …