Defective acute inflammation in Crohn's disease: a clinical investigation.
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.


RESULTS
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.


CONCLUSIONS
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.
Marks
Daniel J B
DJ
Department of Medicine, University College London, London WC1E 6JJ, UK.
Harbord
Marcus W N
MW
MacAllister
Raymond
R
Rahman
Farooq Z
FZ
Young
Jodi
J
Al-Lazikani
Bissan
B
Lees
William
W
Novelli
Marco
M
Bloom
Stuart
S
Segal
Anthony W
AW
D016022:Case-Control Studies; D003424:Crohn Disease / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism; D018836:Inflammation Mediators / Q000276:immunology*; D016209:Interleukin-8 / Q000096:biosynthesis*; D012007:Rectum / Q000473:pathology
D018836:Inflammation Mediators; D016209:Interleukin-8