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Role of
Mycobacterium avium subsp. paratuberculosis in the
pathogenesis of Crohn’s disease
Since the
first clinical description of Crohn’s disease (CD), a chronic
inflammatory disease of the small intestine, attention has been
drawn to the possibility that Mycobacterium avium subsp.
paratuberculosis (Map) may be the causative agent. This
supposition has been primarily based on the similarity of the
clinical features of CD with Johne’s disease (JD), a disease that
occurs in cattle and other ruminants that is caused by Map.
Like CD, chronic inflammatory lesions develop in the small intestine
(ileum) during the clinical phases of the disease. Studies of JD
have clearly shown inflammation is associated with the presence of
Map in the lesions. Demonstrating a similar association in
tissues taken from patients with CD has, until recently, been
difficult. However, advances in the methods of detection and
isolation of Map have now revealed Map can be isolated
from patients with CD, lending support to the supposition of the
potential role of Map in CD pathogenesis. Multiple
genetically distinct isolates, obtained from patients with CD, have
also been isolated from cattle, goats, and sheep, showing cross
species transmission does occur and that these species may be the
source of Map found in patients with CD.
Although the
findings point to the potential role of Map in CD
pathogenesis, the etiological basis of CD remains unclear. There
are three primary hypotheses that have been put forth to explain the
etiology of CD:
- CD is caused by an infectious agent such as
Map,
- CD is associated with mutations in one or more genes
involved in regulation of the immune response, and
- CD is
associated with development of an autoimmune response to unknown
self antigens.
A unifying concept has yet to be developed that can
prove or disprove any of these hypotheses. The objective of our
studies is to test the first hypothesis. Studies are designed to
determine if the mechanisms of pathogenesis of CD and JD are similar
and whether Map plays a central role in pathogenesis for both
diseases. As shown in the figure, we have developed a cannulated
ileum model in calves that permits direct access to the target
tissue for continuous monitoring of lesion development and study of
the factors modulating the response to Map. The first
studies will establish that isolates of Map from humans remain
infectious in calves. Subsequent studies will show whether chronic
inflammation is mediated by dysregulation of the immune response to Map and whether the mechanisms accounting for dysregulation
are the same or different than those found in patients with CD.
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Food and Waterborne Diseases Integrated Research Network
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