TY - JOUR
AU - Cominelli, Fabio
AB - The precise etiopathogenesis of Crohn's disease and ulcerative colitis, the 2 major forms of inflammatory bowel disease (IBD), remain unknown. However, in recent years much progress has been made in understanding the basic mechanisms that underlie chronic intestinal inflammation, which has led to improved therapeutic options and patient quality of life. In addition, new pathophysiological concepts have challenged the traditional paradigm in IBD and generated new directions in basic science.1 This presentation reviews the emerging areas of basic research into these important diseases being actively pursued. It is likely that this research will lead to major discoveries over the next decade, resulting in a better understanding of IBD pathogenesis and the development of a "cure" for at least a subgroup of patients affected by these sometimes devastating diseases. The role of the innate immune system in disease initiation is being actively investigated by many research groups. Several lines of evidence support the novel hypothesis that a deficit in innate immune responses may underlie the disease pathogenesis. This is in contrast to the more generally accepted hypothesis that disease pathogenesis results from an overly aggressive immune response against luminal antigens of bacterial origin. In this context, the role of the intestinal epithelium, which represents the first line of defense against luminal antigens, is an active area of investigation for many laboratories. Supporting evidence for the role of the innate immune system in IBD also comes from the recently discovered association between Crohn's disease and loss-of-function mutations in NOD2/CARD15 gene, an important component of the innate immune system.2 Identification of gene mutations that are associated with a predisposition to IBD will continue to be an active area of basic research. There are at least 7 loci that have already been associated with both CD and UC, and many others are being characterized at present. An essential component of these efforts is to identify the functional correlation that underlies the predisposition. Obviously, functional correlations after predisposing are identified is an essential component of these efforts. These may require and are frequently driven by a "bedside-to-bench" translational approach, with the use of molecular biology techniques and mouse models, including introduction of human mutations into mutant mice or targeted gene deletions.3 Characterization of the precise role of the epithelium in the pathogenesis of IBD is an important step in our understanding of the role of innate immunity. Indeed, the primary abnormality in both CD and UC may reside in the intestinal epithelium and tight junction regulation. The importance of the function of the epithelial barrier function of the intestinal epithelium has been investigated at both at the molecular level and in mouse models of chronic intestinal inflammation.4 The adaptive immune system continues to be a focus of significant research efforts. This includes investigation of the roles played by effect or T cells and their cytokines, as well as the role of T regulatory cells together with the regulation of programmed cell death or apoptosis in these mucosal cell populations. This is the area in which research has produced the most tangible, exciting, and immediate results thus far, with the translation of new findings from bench to bedside and the development of novel biological therapies such as the anti-tumor necrosis factor agents. Further characterization of the other cytokines that have been implicated, such as interleukin-6 (IL-6), IL-12, and IL-23, is therefore an extremely important direction of thebasic research efforts.5 In particular, it is crucial to develop a better understanding of the mechanism of action of the current cytokine/anti-cytokine therapies, to aid in the development of new therapies with improved efficacy and decreased side effects. Therapeutics designed to interfere with intracellular signaling molecules and transcriptional factors are also undergoing active development. It is well known that environmental factors are equally important in the pathogenesis of IBD. In particular, host-microbial interactions in IBD have been the subject of intensive study. This includes exploration of the role of the commensal flora and the search for bacterial strains with beneficial properties, such as probiotics. However, not all patients with IBD display significant reactivity against bacterial antigens, suggesting that both bacterial-dependent and bacterial-independent mechanisms underlie the pathogenesis of this disease. Alternative mechanistic hypotheses therefore warrant further investigation, including the importance of food antigens and dietary products, as well as the possible importance of autoimmune pathogenic mechanisms in at least a subgroup of patients. Finally, in the era of genomics and proteomics, gene and protein arrays arehelping us to identify and characterize novel biomarkers that can be usedto phenotypically classify different forms of IBD, as well as to predictresponse to therapy. All directions in basic IBD research must continue to focus on the final common goal, which is translating the accumulating wealth of mechanistic information into advances in prevention,diagnosis, and treatment. This will help us progress toward the ultimategoal of developing a cure for patients affected by these devastating diseases. References 1. Bamias G, Nyce MR, DeLa Rue SA, Cominelli F. New concepts in the pathophysiology of inflammatory bowel disease. Ann Intern Med . 2005; 143: 895- 904. Google Scholar CrossRef Search ADS PubMed  2. Meinzer U, Hugot JP. Nod2 and Crohn's disease: many connected highways. Lancet . 2005; 365: 1752- 1754. Google Scholar CrossRef Search ADS PubMed  3. Maeda S, Hsu LC, Liu H. et al. Nod2 mutation in Crohn's disease potentiates NF-kappaB activity and IL-1beta processing. Science . 2005; 307: 734- 738. CrossRef Search ADS PubMed  4. Olson TS, Reuter BK, Scott KG, et al. The primary defect in Crohn's-like ileitis originates from a non-hematopoietic source. J Exp Med . In press. 5. Cominelli F. Cytokine-based therapies for Crohn's disease-new paradigms. N Engl J Med . 2004; 351: 2045- 2048. CrossRef Search ADS PubMed  Copyright © 2006 by Lippincott Williams & Wilkins.
TI - Directions for Basic Science
JO - Inflammatory Bowel Diseases
DO - 10.1097/0054725-200604002-00031
DA - 2006-04-01
UR - https://www.deepdyve.com/lp/oxford-university-press/directions-for-basic-science-3C6lFqDPH3
SP - S16
EP - S16
VL - 12
IS - suppl_2
DP - DeepDyve
ER -