IBD geassocieerde genotypes en hun immunologische fenotype in perifere bloed leukocyten

Inflammatory bowel disease (IBD) is comprised of two major disorders:
ulcerative colitis (UC) and
Crohn's disease (CD). UC affects the colon, whereas CD can involve any
component of the
gastrointestinal tract from the oral cavity to the anus. It is commonly
recognized that the disease that we
currently mark as IBD is rather a group of diseases with 5 or more marked
pathogenetic pathways, each
requiring different therapeutic approaches.
In normal healthy individuals the immune response to commensals in the
intestine is kept under strict
regulation. When these regulatory mechanisms fail, an inflammatory response in
the intestines can
result in IBD. What has become clear from research in the last years is that it
is a complex genetic as
well as immunological disease. Antigens in the lumen of the gut initiate an
inadequate immune response
in a genetic susceptible host. In the last few years enormous progress has been
made on the genetic
field by identifying new susceptibility loci in genome wide association studies.
The current grant proposal is based on the recently identified Crohn*s
associated genes NOD2, IL23R
and ATG16L1 and their function within several yet unidentified cellular
pathways. As there is still little
known about these pathways questions regarding these functions rise and will be
addressed in this
project. As such, the objectives of this project are (1) to link CD
immunological phenotypes to cellular
pathways and thereby create insight in the pathogenesis of CD and (2) to
associate the immunological
phenotype to the clinical phenotype and associated genotypes known from our
data stored in our
extensive IBD database consisting of 1400 IBD patients and 1500 healthy
controls.
In this translational study we will use an immunological approach to determine
the different pathways. By
means of inventarisation of immunological phenotype and correlation of this
phenotype to the genotype,
patients and healthy controls will be included. All subjects included will be
subjected to various ex vivo
assays that assess: (1)genotyping of newly identified associated genes,(2)
production of cytokines and
chemokines,(3) phagocytosis and oxidative burst,(4)sensitivity to apoptosis and
(5) killing of microbes.
The proposed studies may provide more knowledge on the variety of functional
pathways in the different
IBD phenotypes and thereby maybe create a new insight in the pathogenesis of
IBD.

The aim of this project is to assess differential responses in immune cells
derived from peripheral blood
of IBD patients concerning:
Immunological phenotype in CD patients:
1. defining the genotype in CD patient cohort
2. production of interleukin-8 after c5a stimulation
3. production of key cytokines after CD3/CD28 stimulation
4. phagocytosis and oxidative burst by granulocytes
Correlation of genotype to immunological phenotype:
5. sensitivity to apoptosis of monocytes and DC's
6. killing of microbes by monocytes and macrophages
Next, the differential responses, that we call the immunological phenotype will
be correlated with the
known CD associated genotypes. We expect that we can group several associated
genotypes in distinct
pathways that give rise to the specific immunological phenotype. In addition
the immunological
phenotype can be correlated with the clinical phenotype by means of the data
gathered during clinical
care in our IBD database.

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