The dyspeptic macrophage 30 years later: an update in the pathogenesis of Crohn's disease.
Alterations in autophagy leading to a defective intracellular response to low-level invasive bacteria are considered a major recent advance in the pathogenesis of Crohn's disease. A genome-wide association study has shown an association of Crohn's disease with the autophagy related 16-like 1 gene. A second autophagy gene, the immunity-related Guanosine triphosfatase, has also been found to be significantly associated with Crohn's disease. The enteric flora of Crohn's disease patients includes, more commonly than controls, strains of adherent/invasive E. coli. The high level of adherent/invasive E. coli colonizing the intestinal mucosa of patients with Crohn's disease strongly suggests that it may play an important role in the aetiopathogenesis of the disease. E. coli strains are able to cross the mucosal barrier, survive within macrophages and induce the secretion of TNFalpha and the formation of granuloma. Recently it has been clearly shown that Crohn's disease patients have a defective mucosal macrophage killing activity resulting in increased exposure to commensal bacteria and activation of T cells. However, the hypothesis of macrophages dysfunction in the pathogenesis of Crohn's disease was already suggested in 1977 by M. Ward, who introduced the concept of the "dyspeptic macrophage", consisting of an inability to degrade a variety of phagocytosed normal gut dietary and microbial luminal constituents. Defective autophagy and dyspeptic macrophages seems therefore indicate the same pathogenetic mechanism. What is really new is the demonstration that this impaired macrophage function is genetically determined.
Caprilli
R
R
University of Rome La Sapienza, Via di Novella, 11, 00199 Rome, Italy. caprilli@interfree.it
Frieri
G
G
D001343:Autophagy / Q000235:genetics / Q000276:immunology*; D003424:Crohn Disease / Q000235:genetics / Q000266:history / Q000276:immunology* / Q000382:microbiology; D004926:Escherichia coli; D049673:History, 20th Century; D006801:Humans; D007413:Intestinal Mucosa / Q000276:immunology / Q000382:microbiology; D008264:Macrophages / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology