NOD2
Mutations
implicated in
CrohnÕs Disease
What
is CrohnÕs Disease?
CrohnÕs Disease is a chronic inflammatory disease of the intestine. The
picture below shows a general overview of common locations of inflammation. The
inflammation is caused by an irregular immune system response. It is thought
that microbes found normally within the gut are perceived as invading pathogens
that produce the normal immune response. This normal immune response causes
chronic inflammation at the sight of mis-recognition.
There are about 400,000-600,000 people affected by CrohnÕs
Disease in
Official CrohnÕs Disease web site. http://www.ccfa.org/
Another Source of CrohnÕs Disease
information. NIH site
on Crohn's
Image of where in the body CrohnÕs disease mostly occurs:
|
Common NOD2 Mutations |
Arg-702-Trp |
Gly-908-Arg |
Leu1007-frameshift-Cys |
90% of All Mutations are found in the LRR (Leucine Rich Repeat) domain( the
sight of ligand binding)
How
are these mutations affecting the signaling from NOD2 that result in a increased risk of CrohnÕs
disease?
There
has been much research into this question and so far there are a few hypotheses
but this page will only focus on the most widely accepted theory.
Hypothesis: The mutations in NOD2 are unable to bind
MDP efficiently leading to a loss of function in the pathway. NOD2 signaling
leads to many pro inflammatory cytokines being produced but also some
anti-inflammatory cytokines such as IL-10.
NOD2 signaling in paneth cells are responsible
for release of a-defensins5/6. Defensins are
small peptides that are natural antibiotics. Because of mutations in the LRR
domain of NOD2 , these very important peptides are significantly lowered in
production and release. The combination of lowered IL-10(anti-inflammatory)
production and lowed defensins release leads to a
bacteria population that looks foreign to the body. As a response large amounts
of TNF-a are produced and secreted inflicting a pro-inflammatory
condition.
Scheme
of Hypothesis:
What
treatments is there that take this mutated pathway into account?
Treatments:
Many
treatments for CrohnÕs Disease tend to go after the
global immune system, such as Sulfasazine. On the
other hand there is a drug that goes after a specific protein
, TNF-a,
that has been shown to be elevated because of NOD2 mutations. This is Infliximab: it is an antibody that binds TNF-a.
Once bound by the antibody, TNF-a can no longer produce an
inflammatory response helping CrohnÕs Disease to go into
recession. The antibody is made from 75% Human antibody (Fc
constant region) and 25% Mouse antibody(Fab region) and binds TNF-a very specifically.
see image§
It
is given every 6-8 weeks, cost about $1000 for 100mg dose. Requires
close to 5mg/kg.