Overview of Inflammatory Bowel Disease Pathogenesis

Abstract

Inflammatory bowel disease (IBD) represents a difficult and challenging condition for patients, clinicians and basic investigators alike. Its etiology and pathogenesis are still unclear in spite of extensive investigations that have yielded a wealth of clinical. epidemiological, biochemical, bacteriological and immunological data on Crohn 's disease and ulcerative colitis. Although the precise mechanism(s) responsible for the intestinal inflammatory process remain to be defined, enough information has been assembled to hypothesize which components are likely to be important for this probably multifactorial disease. A consistent association between class I or II histocompatibility antigens and either Crohn's disease or ulcerative colitis has yet to be found. Nevertheless, ample epidemiological studies leave no doubt about the high frequency of familial clustering, and it must be determined whether this phenomenon translates a true genetic predisposition or a common environmental exposure, or both. Immune events occurring in the gastrointestinal tract are unquestionably linked to the pathogenesis of IBD, but it is unknown which are primary or secondary in nature. While most immune abnormalities detected in patients with established disease are likely to represent secondary events, these are no less important, as they probably contribute to the perpetuation of gut inflammation and tissue damage. This does not exclude that IBD is due to a primary defect of intestinal immunity, but this may no longer be detectable at the time of clinical manifestations. The answer to the question of wh1ch of the various intestinal immune abnormalities is central to pathogenesis must wait for additional research. Whether immune responses to the luminal flora, antigen processing mechanisms, antibody production, immunoregulation, cytotoxic activity, cytokine and mediator release are defective or disregulated is under intense investigation. It is likely that several of these events are involved, but they may interact in a complex and unpredictable fashion. lt is almost certain that there are various initiating and secondary events, and different immune mechanisms share relatively few common pathways for damaging the intestine, eg, cytokines, arachidonic acid metabolites, and oxidants. Perseverance in the study of these substances is finally yielding promising new approaches to the manipulation of immune and inflammatory responses chat cause bowel destruction. Future drugs may consist of combinations of highly specific inhibitors, antagonists or receptor blockers, that may selectively block one or several steps of the inflammatory cascade which is chronically active in the intestine of affected individuals. Therefore, we may soon face a situation not too dissimilar from what we have recently witnessed for peptic ulcer disease. The specific cause of IBD may still be beyond our comprehension, but a better understanding of its pathogenesis al lows us to put highly effective therapies within reach.

Therapeutic effect of anti-OX40L and anti-TNF-α MAbs in a murine model of chronic colitis

“…Although its etiology remains unclear, it has been established that proinflammatory cytokine production by infiltrating T cells and macrophages plays a pivotal role in the pathogenesis of CD (9,36). Functional activation of T cells requires two distinct signals: one derived from T cell receptor (TCR)-mediated recognition of peptide-major histocompatibility complex on antigen-presenting cells (APC) and another, designated as the costimulatory signal, derived from the interaction of a costimulatory molecule (such as CD28) on T cells and its ligand (such as B7) on APC (4,6,16,30,39).…”

On the etiology of Crohn disease.

“…Intestinal vasculitis has also been implicated (3). Proposed infectious causes include persistent measles virus (4) and mycobacteria, particularly Mycobacterium paratuberculosis (5)(6)(7)(8)(9).…”

Molecular evidence for two forms of Crohn disease.

“…The etiology of CD remains unknown (6)(7)(8)(9). However, there is a consensus that cytokines play pivotal (10)(11)(12)(13), if on occasions apparently conflicting (12,(14)(15)(16), roles in the clinical manifestations of CD.…”