Immunopathogenesis of Crohn's disease.
This review highlights the huge advances made in the understanding of Crohn's disease in the last 15 years. The pathogenic immune response in the gut wall is a highly polarised T helper cell type 1 response, probably directed against antigens of the commensal flora. There is marked over-expression of pro-inflammatory cytokines such as tumor necrosis factor (TNF)-alpha and increased production of matrix degrading enzymes by fibroblasts and macrophages, which are probably responsible for ulceration and fistula formation. Crohn's disease runs in families and the susceptibility genes identified so far are associated with innate recognition of microbial products (Nod2) or epithelial barrier function (OCTN cation transporter genes and DLG5). Endogenous healing pathways mediated by transforming growth factor (TGF)-beta1 are inhibited because mucosal inflammatory cells express Smad7, the endogenous intracellular inhibitor of TGF-beta signalling. This makes it unlikely that enteral feeds containing TFG-beta are therapeutic by means of direct anti-inflammatory effects, however TGF-beta may still be involved because it is a well known epithelial motogen and may promote mucosal healing, in synergy with changes in mucosal bacterial populations as a result of the change in the diet.
MacDonald
Thomas T
TT
Division of Infection, Inflammation and Repair, University of Southampton School of Medicine, Southampton, United Kingdom. t.t.macdonald@soton.ac.uk
Di Sabatino
Antonio
A
DiSabatino
Antonio
A
Gordon
John N
JN
D003424:Crohn Disease / Q000209:etiology / Q000276:immunology / Q000473:pathology / Q000628:therapy; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D004750:Enteral Nutrition; D020022:Genetic Predisposition to Disease; D006098:Granulocytes / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007413:Intestinal Mucosa / Q000276:immunology* / Q000382:microbiology* / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
D016207:Cytokines