Inflammatory bowel diseases: from genetics to immunology

PhD ceremony: Ms. L. Zhou, 11.00 uur, Academiegebouw, Broerstraat 5, Groningen

Title: Inflammatory bowel diseases: from genetics to immunology

Promotor(s): prof. K.N. Faber, prof. M.P. Peppelenbosch

Faculty: Medical Sciences

 

Crohn’s disease (CD) and Ulcerative colitis (UC) are two clinically distinct forms of inflammatory bowel diseases (IBD). IBDs are complex diseases resulting from a combination of genetic, environmental and immunological factors. Their incidence strongly differs between ethnic and geographically-separated populations. Immunomodulatory drugs, like Azathioprine, are used to suppress inflammation, but no effective cure for IBD exists.

In the first part of this thesis, we identified genetic UC risk factors in 2 different ethnic populations. Following a candidate-gene approach, we found that Runt-related transcription factor 3 is a UC risk locus for Dutch patients. This is in line with its immunomodulatory function and the development of sponteneous colitis when absent in mice. Next, we determined whether 6 UC risk loci for Europeans/Americans also predispose for UC in Han Chinese, among which the incidence of UC is much lower. Only the IL2/IL21 gene region was significantly associated with Chinese UC. The different genetic linkage between IL2 and IL21 allowed us to identify both genes as independent UC risk loci in Han Chinese.

Recent data indicate that IBD is primarily caused by compromised innate immunity, rather than the originally-proposed uncontrolled adaptive immune response. Azathioprine is known to suppress adaptive immunity. In the second part of this thesis, we show that Azathioprine actually strongly enhances monocyte bacterial phagocytosis and IL8 production, both important innate immune functions.

Collectively, this thesis reveals genetic overlap in UC-associated risk loci between Europeans and Chinese and Azathioprine acting both as an adaptive immunity-suppressant and an innate immunity-stimulator.