Innate immune dysfunction in inflammatory bowel disease.
The pathogenetic mechanisms that cause the two types of inflammatory bowel disease (IBD), Crohn's disease (CD) and ulcerative colitis (UC), are still under investigation. Nevertheless, there is broad agreement that luminal microbes are of particular relevance in the development of these conditions. In recent years, increasing evidence has shown that defects in the innate immunity are at the centre of both types of IBD. The innate intestinal barrier is provided by the epithelium which secretes antimicrobial peptides (so-called defensins) that are retained in the mucus layer. In ileal CD, the alpha-defensins are lacking owing to several Paneth cell defects. In colonic CD, the expression of beta-defensins is inadequate. This may be related to downregulation of the transcription factor peroxisome proliferator-activated receptor-gamma and in some cohorts is associated with a reduced HBD2 gene copy number. In UC, the mucus layer, which protects the host from the enormous amounts of luminal microbes, is defective. This is accompanied by an insufficient differentiation from intestinal stem cells towards goblet cells. All these disturbances in the gut barrier shift the balance from epithelial defence towards bacterial offence. The current treatment for CD and UC is based on suppression of this secondary inflammatory process. In future, patients may benefit from new therapeutic approaches stimulating the protective innate immune system.
Department of Internal Medicine I, Robert Bosch Hospital, Stuttgart Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart.
M
M
Gersemann
J
J
Wehkamp
E F
EF
Stange
D000276:Adjuvants, Immunologic / Q000627:therapeutic use; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D001419:Bacteria / Q000276:immunology / Q000378:metabolism; D003093:Colitis, Ulcerative / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D003424:Crohn Disease / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation; D020397:Goblet Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects*; D007249:Inflammation / Q000150:complications / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D047495:PPAR gamma / Q000378:metabolism; D019879:Paneth Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D023083:beta-Defensins / Q000378:metabolism*
D000276:Adjuvants, Immunologic; D000893:Anti-Inflammatory Agents; C106641:DEFB4A protein, human; D047495:PPAR gamma; D023083:beta-Defensins