Overview of Inflammatory Bowel Disease Pathogenesis

Inflammatory bowel disease (IBD) represents a difficult andchallenging condition for patients, clinicians and basic investigators alike. Itsetiology and pathogenesis are still unclear in spite of extensive investigationsthat have yielded a wealth of clinical. epidemiological, biochemical, bacteriologicaland immunological data on Crohn 's disease and ulcerative colitis.Although the precise mechanism(s) responsible for the intestinal inflammatoryprocess remain to be defined, enough information has been assembled tohypothesize which components are likely to be important for this probablymultifactorial disease. A consistent association between class I or II histocompatibilityantigens and either Crohn's disease or ulcerative colitis has yet to befound. Nevertheless, ample epidemiological studies leave no doubt about thehigh frequency of familial clustering, and it must be determined whether thisphenomenon translates a true genetic predisposition or a common environmentalexposure, or both. Immune events occurring in the gastrointestinal tractare unquestionably linked to the pathogenesis of IBD, but it is unknown whichare primary or secondary in nature. While most immune abnormalities detectedin patients with established disease are likely to represent secondary events, theseare no less important, as they probably contribute to the perpetuation of gutinflammation and tissue damage. This does not exclude that IBD is due to aprimary defect of intestinal immunity, but this may no longer be detectable atthe time of clinical manifestations. The answer to the question of wh1ch of thevarious intestinal immune abnormalities is central to pathogenesis must wait foradditional research. Whether immune responses to the luminal flora, antigenprocessing mechanisms, antibody production, immunoregulation, cytotoxic activity,cytokine and mediator release are defective or disregulated is under intenseinvestigation. It is likely that several of these events are involved, but they mayinteract in a complex and unpredictable fashion. lt is almost certain that thereare various initiating and secondary events, and different immune mechanismsshare relatively few common pathways for damaging the intestine, eg, cytokines,arachidonic acid metabolites, and oxidants. Perseverance in the study of thesesubstances is finally yielding promising new approaches to the manipulation ofimmune and inflammatory responses chat cause bowel destruction. Future drugsmay consist of combinations of highly specific inhibitors, antagonists or receptorblockers, that may selectively block one or several steps of the inflammatorycascade which is chronically active in the intestine of affected individuals.Therefore, we may soon face a situation not too dissimilar from what we haverecently witnessed for peptic ulcer disease. The specific cause of IBD may still bebeyond our comprehension, but a better understanding of its pathogenesis al lowsus to put highly effective therapies within reach