Crohn's Disease: Immunodeficiency.

Revisiting Crohn's disease as a primary immunodeficiency of macrophages
Published in 2009.

[QUOTE]Although CD is immune mediated, it is not an autoimmune disease, as the immunological process appears to be triggered by the content of the gut lumen rather than a self-antigen.

[QUOTE]To date, CD is widely accepted as a genetically determined immunological disease that manifests principally in the gut and is triggered by bowel contents. But this is as far as scientific consensus and certainty go.

[QUOTE]The first breakthrough toward an understanding of the pathogenesis of CD came in 1976 when Anthony Segal demonstrated impaired influx of granulocytes into skin windows in CD patients (Segal and Loewi, 1976), a finding that was confirmed and extended to the gut in 2006 (Marks et al., 2006). As CD is an inflammatory disease, it was hard to imagine a more paradoxical and provocative finding than impaired inflammation (Korzenik, 2007). Moreover, although CD is principally localized to the gut, these studies claimed that the inflammatory defect was systemic and affected various tissues, such as the skin, that were not affected clinically. However, as the Hungarian physiologist Albert Szent-Györgyi pointed out, “a discovery is a discovery because it is at variance with accepted knowledge.”

In a clinical investigation reported by Smith et al. (2009) in this issue, Segal's group studied inflammation in response to skin wounded with heat-killed bacteria. Consistent with their past studies, patients with CD had impaired inflammation at the wound site, as demonstrated by tracking intravenously injected, radio-labeled granulocytes. Clearance of Escherichia coli at the sites of injection was also impaired in patients with CD, but not in those with another inflammatory disease, ulcerative colitis, or in healthy subjects. Notably, impaired bacterial clearance was evident for high, but not low, bacterial doses. Overall, these experiments suggest a causal link between impaired inflammation and impaired bacterial clearance. The intestine was not wounded with bacteria, but the skin defect was proposed to be systemic and to involve the gut in particular. In fact, E. coli was chosen for these studies because of its abundance in the intestinal flora. It is important to reiterate that the defect was seen only with high bacterial loads, given that the highest bacterial load in the human body is found in the intestinal tract, which is the primary target of CD. Impaired bacterial clearance presumably results in chronic inflammatory responses, accompanied by accumulation of granulomas consisting of macrophages and T lymphocytes. Therefore, in this model, excessive inflammation is the consequence of an underlying immunodeficiency rather than the primary cause of CD pathogenesis

[QUOTE]Macrophages from the patients are intrinsically defective, with impaired secretion of cytokines that are normally translated but internally degraded. Because of insufficient production of cytokines and chemokines, there is impaired attraction of granulocytes to mucosal breaches. Impaired acute, granulocytic inflammation results in impaired clearance of bacteria and debris from the gut wall, itself resulting in chronic, granulomatous inflammation.

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