IL-10 Receptor alpha Single Nucleotide Polymorphisms

Recently, we identified single nucleotide polymorphisms (SNPs) in the coding region on the Interleukin-10 receptor alpha (IL-10RA). One of these point mutations is located in the middle of a region, which when deleted in mice, results in a superactivating receptor. The other mutation is located at the extracellular domain and has the potential to interfere with IL-10 binding. Previous studies indicated that Crohn`s disease patients who carry at least a single SNP allele showed a favorable response to IL-10 therapy. This research project investigates on possible mechanisms how naturally occurring IL-10RA variants may alter IL-10 signaling. This would open new insights into alternative IL-10 pathways and could help to target IL-10 immunotherapy in patients with various diseases such as inflammatory bowel disease, rheumatoid arthritis, psoriasis, pancreatitis or chronic hepatitis. This research project also aims to investigate on a possible genetic linkage between IL-10RA cSNPs and various disease phenotypes.

In this project we tested the importance of certain variants of the human genome concerning their effect on body function as well as on the origin of diseases. Approximately every 1000 base pairs, the human DNA carries a variation at a single base pair. Most of these variants are irrelevant; however, some change the function of proteins: for example, variants in the melanocortin-1 receptor determine the red color of hair. In this project we intended to examine the functional effects of variants within the interleukin-10 receptor 1 (IL-10R1). This receptor is a key molecule in mammalian immune defense. We had identified two such variants on the IL-10R1, which are likely to alter receptor function. In this project we learned more about the frequency of these variants in different world populations (they are most frequent in Caucasians with about 15% [SNP3] and 30% [SNP4]), as well as in some diseases. We found that IL-10R1 variants are associated with liver cirrhosis, inflammatory bowel diseases, and psychiatric disorders. We found immunological alterations in carriers of these variants. However, we did not succeed to discover the molecular basis of these immune changes, because we were unable to express IL-10R1 in cell culture. Finally we discovered the reason behind this phenomenon, which turned out to be a previously unknown IL-10R1 function namely the ability to induce cell death. From our findings we expect a better understanding of the physiological role of IL-10R1 biology with regard to immune response. This is relevant not only in view of the related diseases but also concerning viral infections, since certain viruses (e.g., EBV or CMV) take advantage of the IL-10R1 during infection.