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Mucosal Immunology Lab

Friday 18 February 2011

The mammalian intestine contains a highly complex ecology of microorganisms whose composition is critical to, on the one hand, establishing tissue homeostasis and, on the other, contributing to immune-mediated pathologies. Almost all of these bacteria accumulate within the colon, whereas colonization of the small intestine is very limited suggesting that powerful host mechanisms exist to exclude and/or limit bacteria from this site. Although increasing knowledge is available on genetically predetermined host responses to intestinal microbes, there is less understanding about how bacterial commensalism is established in mammalians and what host factors specifically contribute to this process.

Bacteria that are destined to colonize the intestines interact with the host at a variety of levels. At the cellular level, the major cell types involved include intestinal epithelial cells (IEC) and hematopoietic cells which interact with and respond to the bacteria in an integrated fashion through a variety of pathways that are associated with innate and adaptive immune functions. Hematopoietic cells, and in particular B lymphocytes, respond with the production of commensal bacteria-specific immunoglobulins of the IgA class that serves to limit bacterial translocation across epithelial cells. IECs can regulate mucosal homeostasis by responding to ligands from the subcellular components of bacteria through the expression of Toll receptors (TLR).

Inflammatory bowel disease (IBD) is a chronic intestinal inflammatory disorder resulting from aberrant mucosal immune responses to intestinal (commensal) bacteria. In patients with Crohn’s disease (CD), a disturbed antimicrobial peptide (AMP) shield has been suggested to result in the mucosal invasion of intestinal bacteria, as well as in alterations of the luminal bacterial composition, leading to mucosal inflammation.

Our lab focusses on the role of bacteria-host interactions at the intestinal mucosa. We determine the effect of bacterial colonisation on the immune response to inflammation and on the other hand the effect of changes in the host on the bacterial community. As the mucosal immune system and the colonising microbiota are rather complex, we use modelsystems like zebrafish and in vitro epithelial organoid cultures to study our specific research questions.

Furthermore, we recently started collaboration with the lab of Hans Clevers from the Hubrecht Institute to translate the organoid epithelial cell culture technique into clinical application in order to treat severe malabsorption syndromes in pediatric patients.

Cell culture of T cells and different types of DC, FACS, Elisa, luminex, gel electrophoresis, confocal microscopy, immunohistochemistry, in vivo animal studies

6 or 9 months

Dr. Mark Klein, 088 75 555 55 (pager 4118), mklein01@umcutrecht.nl