Rare genetic immune disease XLP2 examined

Researchers have taken an important step in understanding a rare genetic immune disorder which affects male children. Using biochemical analyses, the team was able to map how the XIAP protein activates a vital component of the immune defense system, specifically the component that fights bacterial infections in the gastro-intestinal system. The study, conducted by researchers at The Novo Nordisk Foundation Center for Protein Research at the University of Copenhagen, is published in Molecular Cell. Mads Gyrd-Hansen, Associate Professor from The Novo Nordisk Foundation Center for Protein Research, explains: "Our results are an important step on the way to understanding the very serious - but fortunately rare - genetic immune disorder called X-linked lymphoproliferative syndrome type 2 (XLP2), which affects male children. The gastro-intestinal system can be viewed as a long tube running through the body, absorbing nutrients and water. The contact surface between the intestinal system and the rest of the body is protected by an efficient immune barrier that confines the bacteria to the intestine. This barrier is not intact in XLP2 patients, who thus lack the necessary bulwark, so to say, between bacteria and body." The researchers found that individuals with XLP2 have genetic variations that destroy XIAP's ability to bind the signaling protein ubiquitin to other proteins. This process is crucial for activating the immune system and survival. The team highlights that these results can also help cancer researchers. Gyrd-Hansen said: "Several pharmaceutical companies have developed drugs to act on IAP proteins, including XIAP, as part of cancer treatment. Several of the drugs are currently being tested in clinical trials for their efficacy in treatment of leukemia and other forms of cancer. It is therefore essential to know precisely which biological processes in the organism the treatment can potentially affect." Gyrd-Hansen and his team, who have been collaborating with researchers in the UK, Germany and Australia for around 18 months, explained: "International collaboration has made it possible - in a short time - to describe detailed molecular processes, to use the descriptions to create mouse models for further tests and thereafter to link the results of these tests to genetic mutations identified in patients."