Proctocolitis and Crohn’s Disease
Ulcerative colitis and Crohn’s disease are two types of inflammatory disease in adults with different etiologies. Their common denominator is a genetic predisposition for exaggerated responses by the intestinal immune system.
A deficiency in or reduced activity of suppressive cytokines, particularly TGF-b, may play an important role in the pathogenesis of these inflammatory diseases (Kanazawa et al., 2001). Under physiological conditions, TGF-b prevents the destruction of the intestinal mucous membrane. The absence of TGF-b receptors results in an increased expression of antigens in an MHC II context with auto-antibodies causing major lesions in the intestinal mucous membrane (Barnard et al., 1995).
Crohn’s Disease
Crohn’s disease is a chronic inflammatory disease that can affect any part of the digestive tract. Intestinal inflammation is associated with joint inflammation in at least 60% of patients (De Vos, 2002).
A genetic predisposition to Crohn’s disease due to a mutation of the NOD2 gene has been identified. Joint inflammation, especially spondylarthropathy associated with Crohn’s disease, is related to the HLA B27 phenotype. The specific nature of events that trigger the disease is unknown. The exaggerated response of the intestinal immune system may be related to an increase in intestinal permeability with a loss of tolerance for commensal intestinal flora.
Regarding the articular manifestations, macrophages probably play a role in transporting bacterial antigens from the intestine to synovial membranes, while lymphocytes activated through contact with the bacterial antigens in the intestinal mucous membrane would be attracted by the adhesion molecules of articular tissue (De Vos, 2002).
An increase in intestinal permeability precedes the development of Crohn’s disease, which is present not only in patients with the disease but also in more than 10% of relatives who are first-degree asymptomatic (Secondulfo et al., 2001). The factor that triggers this change in intestinal permeability could be bacteria or bacterial products. Peripheral blood macrophages resembling monocytes are probably recruited to the active inflammatory foci of Crohn’s disease; these are markedly more responsive than resident macrophages and show an important expression of the CD14 receptor for lipopolysaccharides (Grimm et al., 1995). They may be spontaneously activated either by commensal bacteria, enteropathogens or bacterial antigens such as lipopolysaccharides and may provoke major changes in the epithelial transport of ions and the intestinal barrier (Zareie et al., 2001). The lack of CD14 in resident macrophages limits their response and avoids an inflammatory response given the daily exposure of intestinal epithelium to the lipopolysaccharides of physiological bacterial flora. In the event of an inflammatory response, the influx of blood monocytes provides a major population of CD14+ macrophages that are sensitive to lipopolysaccharides. This sensitivity becomes particularly important if it is associated with an increased permeability of the mucous membrane making it possible for large quantities of lipopolysaccharides to reach the sub-mucous membrane. These CD14+ macrophages release cytokines, including TNFa, IL-6 and IL-1b (Reinecker et al., 1993). TNFa interferes with epithelial ion transport and increases the permeability of the intestinal barrier by increasing the TH1 function of the intestinal immune system with IFNg production (Targan et al., 2000). The key role of TNFa in Crohn’s disease was confirmed by several therapeutic studies that showed that one treatment with an anti-TNFa monoclonal antibody (infliximab) neutralizes TNFa activity and restores the intestinal barrier (Van Assche and Rutgeerts, 2000).This results in rapid, spectacular and long-term improvement of intestinal and joint inflammation (Targan et al., 2000). IFNg production due to the TH1 immune response is reduced in the intestinal mucous membrane to a level observed for the normal non-inflammatory state. Although the anti-TNFa antibody is tolerated in the short term, this therapy could present potential side effects in the long term, such as the generation of human antibodies against chimeric antibodies and lymphoproliferative diseases.
