<http://www.sciencedaily.com/releases/2008/03/080312141253.htm>

New Defense Mechanism Against Intestinal Inflammation Found

ScienceDaily (Mar. 15, 2008) — The body's first line of defence against
pathogenic bacteria that we ingest may not be the immune system but rather
the cells that line the intestine. This surprising conclusion is just one
facet of a study by Dr. Maya Saleh, a researcher at the Research institute
of the McGill University Health Centre that will be published in the
journal Cell Host & Microbe on March 12.

This, and the various mechanisms revealed by this discovery, could lead to
important therapeutic innovations, particularly in the treatment of
diarrheal diseases and inflammatory bowel diseases such as Crohn's disease.

When pathogenic E. coli bacteria infect the body, they bind to epithelial
cells on the interior wall of the intestine before injecting infectious
material into the cells with a syringe-like mechanism. This contact
triggers a defence reaction within the epithelial cell called the Nod
pathway, which results in alerting the immune system as well as in the
release of antimicrobial peptides called defensins.

Defensins act as antibiotics: they kill bacteria directly by puncturing
holes in their walls. These peptides also play a role in activating the
immune system itself and tuning the inflammatory reaction.

"This mechanism expands our idea of immunity: it hinges upon epithelial
cells, not immune cells, early on during infection," says Dr. Saleh.
"Furthermore, our study demonstrates that this mechanism is regulated
negatively by the Caspase-12 protein, meaning that this protein limits
defensin production. This hampers the elimination of bacteria, which then
trigger an intense inflammatory reaction manifested by various symptoms
including severe diahrrea."

These fundamental discoveries change our understanding of the immune
defence. They also open new avenues for a deeper understanding and more
targeted treatments of diseases related to intestinal inflammation, such
as diarrheal diseases caused by pathogenic E. coli or Crohn's disease.

In the case of diarrhea, intestinal inflammation is caused by a process
similar to the one described above by Dr. Saleh. Treatments that target
Caspase-12 would decrease inflammation by acting on the source rather than
on the symptoms.

Crohn's disease is the chronic inflammation of the digestive tract, and
its specific causes are unknown. What is known, however, is that this
pathology is linked to a genetic mutation in the Nod pathway. "This study
allows us to consider three possible explanations for Crohn's disease: the
Nod pathway mutation could induce either a lack of bacterial "sensing" or
a hyperactivation of the immune system resulting in both cases in
excessive inflammation against bacteria naturally present in the digestive
system; it is also possible that the pathology is caused by an excessive
and recurring reaction against a pathogenic microorganism," says Dr.
Saleh. The debate is now open.

In each of these cases, medication targeting Caspase-12 would decrease
inflammation symptoms by directly attacking the underlying cause.

Dr. Maya Saleh is a researcher with the Critical Care Division and the
Centre for the Study of Host Resistance at the Research Institute of the
McGill University Health Centre (MUHC) as well as an assistant professor
with McGill University's Faculty of Medicine.

This study was funded by the Canadian Institutes for Health Research
(CIHR) and the Canada Foundation for Innovation (CFI).

Adapted from materials provided by McGill University Health Centre.