BACKGROUND: The cause of Crohn's disease has not been mechanistically proven. We tested the hypothesis that the disease is a form of immunodeficiency caused by impaired innate immunity. METHODS: We investigated inflammatory responses in patients and controls by quantifying neutrophil recruitment and cytokine production after acute trauma, interleukin 8 secretion by cultured monocyte-derived macrophages after exposure to inflammatory mediators, and local inflammatory and vascular changes in response to subcutaneous injection of heat-killed Escherichia coli. FINDINGS: In patients with Crohn's disease, trauma to rectum, ileum, or skin led to abnormally low neutrophil accumulation (differences from healthy individuals of 79%, n=8, p=0.0003; 57%, n=3, p=0.05; 50%, n=13, p<0.0001, respectively) and lower production of proinflammatory interleukin 8 (63%, n=7, p=0.003; 63%, n=3, p=0.05; 45%, n=8, p<0.0001) and interleukin 1beta (50%, n=8, p=0.0005). Interleukin 8 secretion by cultured macrophages was reduced after exposure to acute wound fluid (38%, n=50, p<0.0001), C5a (48%, n=41, p=0.0005), or tumour necrosis factor alpha (52%, n=27, p<0.0001). Local inflammatory reaction to inoculation with E coli was attenuated, as quantified by changes in bloodflow (ileal disease 50%, n=6, p=0.01; colonic disease 77%, n=6, p=0.0003). This response was mediated by nitric oxide in controls, was increased by sildenafil in patients, and was not related to CARD15 genotype. INTERPRETATION: In Crohn's disease, a constitutionally weak immune response predisposes to accumulation of intestinal contents that breach the mucosal barrier of the bowel wall, resulting in granuloma formation and chronic inflammation. Polymorphisms in CARD15 do not underlie this phenotype, but incapacitate the NOD2 pathway that can compensate for impairment of innate inflammation. Current treatment of secondary chronic inflammation might exaggerate the underlying lesion and promote chronic disease.
BACKGROUND: The cause of Crohn's disease has not been mechanistically proven. We tested the hypothesis that the disease is a form of immunodeficiency caused by impaired innate immunity. METHODS: We investigated inflammatory responses in patients and controls by quantifying neutrophil recruitment and cytokine production after acute trauma, interleukin 8 secretion by cultured monocyte-derived macrophages after exposure to inflammatory mediators, and local inflammatory and vascular changes in response to subcutaneous injection of heat-killed Escherichia coli. FINDINGS: In patients with Crohn's disease, trauma to rectum, ileum, or skin led to abnormally low neutrophil accumulation (differences from healthy individuals of 79%, n=8, p=0.0003; 57%, n=3, p=0.05; 50%, n=13, p<0.0001, respectively) and lower production of proinflammatory interleukin 8 (63%, n=7, p=0.003; 63%, n=3, p=0.05; 45%, n=8, p<0.0001) and interleukin 1beta (50%, n=8, p=0.0005). Interleukin 8 secretion by cultured macrophages was reduced after exposure to acute wound fluid (38%, n=50, p<0.0001), C5a (48%, n=41, p=0.0005), or tumour necrosis factor alpha (52%, n=27, p<0.0001). Local inflammatory reaction to inoculation with E coli was attenuated, as quantified by changes in bloodflow (ileal disease 50%, n=6, p=0.01; colonic disease 77%, n=6, p=0.0003). This response was mediated by nitric oxide in controls, was increased by sildenafil in patients, and was not related to CARD15 genotype. INTERPRETATION: In Crohn's disease, a constitutionally weak immune response predisposes to accumulation of intestinal contents that breach the mucosal barrier of the bowel wall, resulting in granuloma formation and chronic inflammation. Polymorphisms in CARD15 do not underlie this phenotype, but incapacitate the NOD2 pathway that can compensate for impairment of innate inflammation. Current treatment of secondary chronic inflammation might exaggerate the underlying lesion and promote chronic disease.
Authors: Kaoru Geddes; Stephen Rubino; Catherine Streutker; Joon Ho Cho; Joao G Magalhaes; Lionel Le Bourhis; Thirumahal Selvanantham; Stephen E Girardin; Dana J Philpott Journal: Infect Immun Date: 2010-10-04 Impact factor: 3.441
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Authors: Simon A Hirota; Jeffrey Ng; Alan Lueng; Maitham Khajah; Ken Parhar; Yan Li; Victor Lam; Mireille S Potentier; Kelvin Ng; Misha Bawa; Donna-Marie McCafferty; Kevin P Rioux; Subrata Ghosh; Ramnik J Xavier; Sean P Colgan; Jurg Tschopp; Daniel Muruve; Justin A MacDonald; Paul L Beck Journal: Inflamm Bowel Dis Date: 2010-09-24 Impact factor: 5.325
Authors: Marjorie De la Fuente; Luigi Franchi; Daniela Araya; David Díaz-Jiménez; Mauricio Olivares; Manuel Álvarez-Lobos; Douglas Golenbock; María-Julieta González; Francisco López-Kostner; Rodrigo Quera; Gabriel Núñez; Roberto Vidal; Marcela A Hermoso Journal: Int J Med Microbiol Date: 2014-02-06 Impact factor: 3.473
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