Crohn's disease appears to be caused by a weak immune response, not the exaggerated response of a hyperreactive immune system that has long been suspected as the cause, according to Dr. Daniel J. B. Marks, of University College London, and his associates.

The researchers conducted a series of experiments on a small number of patients and control subjects to examine the immunologic underpinnings of Crohn's disease. They concluded that the disease stems from an impaired immune response that allows bacteria in the intestinal contents to accumulate in areas of the bowel. There, some bacteria breach the mucosal barrier of the bowel wall. Their persistence within the tissue results in granuloma formation and a secondary chronic inflammation.

If their theory proves to be correct, it means that current immunosuppressive therapies for the disorder are actually exacerbating the underlying immunodeficiency even as they dampen the secondary intestinal inflammation, Dr. Marks and his associates said (Lancet 2006;367:668–78).

The investigators began by obtaining serial biopsies of the posterior rectal wall in six patients with quiescent Crohn's disease, three with ulcerative colitis, and nine control subjects with noninflammatory bowel disorders. Biopsies also were taken from other locations in the bowel in three more Crohn's patients who had undergone colectomy and in two patients with familial adenomatous polyposis. The procedures confirmed that there was no endoscopic or microscopic evidence of Crohn's lesions.

The biopsies served a second purpose, which was to induce a tiny area of trauma to the bowel wall so that local immune responses could be monitored. The control subjects showed a vigorous inflammatory response at the biopsy sites, with large increases in neutrophils and cells positive for interleukin-8. In contrast, the Crohn's patients showed 79% fewer neutrophils and 63% fewer interleukin-8-positive cells.

To determine whether this abnormal response was localized to the bowel, the researchers then induced a small area of skin trauma by abrading a 3-cm patch on the volar surface of the forearm. Crohn's patients and control subjects showed similar degrees of trauma in these skin lesions and had equivalent levels of C3a, histamine, prostaglandin E₂, and leukotriene B in response to the wounds.

However, neutrophil efflux to the cutaneous wounds was impaired in the Crohn's patients after 5 hours, and was still reduced by half at 24 hours, compared with controls. This indicates that people with Crohn's disease have a generalized constitutional abnormality in their immune response, the investigators said.

Crohn's lesions typically develop at sites within the bowel where bacterial concentrations are highest. “Our present findings suggest that reduced or delayed recruitment of neutrophils to sites at which bacteria penetrate the mucosa might lead to persistence of bacteria and other organic debris in the tissues, possibly within macrophages. Secondary secretion of proinflammatory cytokines, after the failure of initial clearance, could drive the development of chronic inflammation,” they noted.

To assess whether the response to bacteria within bodily tissues was abnormal in patients with Crohn's disease, the researchers then examined the response to subcutaneous injections of heat-killed Escherichia. coli.

The injections yielded vigorous inflammatory responses in all subjects, including pain, erythema, and swelling. Control subjects showed a fivefold increase in blood flow around the lesions at 8 hours and a ninefold increase at 24 hours, which returned to baseline levels within 48 hours. But Crohn's patients showed abnormally low increases in blood flow even though the superficial appearance of the lesions was identical. In particular, Crohn's patients with colonic disease showed a 77% reduction in blood flow, compared with controls; those with ileal disease showed a 50% reduction.

“In 2 patients with ulcerative colitis, blood flow response was greater than that in patients with Crohn's disease and did not show the normal resolution after 48 hours, clearly distinguishing it from the hyporesponsiveness characteristic of Crohn's disease. The inflammatory response was so florid in one patient with ulcerative colitis that we terminated these studies in patients with this condition,” they said.

The investigators then studied whether treatment with the vasodilator sildenafil might correct the deficient blood flow in Crohn's patients. “Oral administration of 50-mg sildenafil to 5 healthy individuals and 10 patients with Crohn's disease at 24 or 48 hours after bacterial injection resulted in marked increases in blood flow,” they noted.

“We propose that the underlying impairment of acute inflammation that predisposes to Crohn's disease can be boosted by a second tier of immune enhancers,” the investigators said. “It might be feasible to introduce interleukin-8 or other proinflammatory stimuli directly into acute lesions, either by direct enteral administration or through synthesis by genetically modified gut organisms, since this cytokine would penetrate the bowel wall only through damaged mucosa.”

In addition, agents such as sildenafil that increase blood flow and proinflammatory drugs also might be useful in healing or preventing lesions.

Crohn's Caused by Weak, Not Exaggerated Immune Response?