In 2013, we discovered a gene with properties that were very likely to make it an important regulator of the immune system. The gene, OTULIN, encodes and enzyme, a small molecular machine, that can remove small molecular “flags” raised in immune cells in response to detecting an invading microorganism. The immune cells raise these “flags”, which rewires the programming of the cells and instructs them to activate and start fighting an infection and to send out chemical signals to instruct other cells to do the same.
The properties of OTULIN led us to think that it might be important for limiting the immune response and protecting against over-activation and immune-mediated disease by removing the “flags” that signal immune activation.
To explore this idea, we generated genetically modified mice that lacked the OTULIN gene in their immune cells.These OTULIN-deficient mice developed a series of symptoms indicative of an over-active immune system: they lost weight, had very high numbers of immune cells and immune hormones in the blood, had swollen lymphatic glands (lymph nodes), and they showed signs of damage to various organs, including the liver and the spleen; all this in the absence of any infection by microorganisms. Indeed, we could confirm that the immune cells in these mice lacking the OTULIN gene could not control the level of the activation “flags”. Hence, the immune cells spontaneously activated and started their defence programs to combat an infection, even though there was none. The immune cells produced anti-microbial chemicals and sent out immune hormones to activate more cells to fight the infection. But in the absence of an infection, these defence programs started to target the mice’s healthy organs and eventually the mice became autoimmune. This showed us that indeed OTULIN is an important gene that restricts the activity of the immune system to possibly prevent immune-mediated disease.
To investigate the relevance to human disease, we sought after patients with unexplained and undiagnosed immune symptoms. We were able to find 3 patients that had severe and diffuse immune symptoms similar to what we observed in the OTULIN-deficient mice. From a few weeks after birth, the patients were very ill and had to be constantly hospitalised, often in intensive care units, with life-threatening symptoms. They had very high numbers of immune cells, immune hormones, and antimicrobial proteins in their blood, without signs of infection, and they had recurrent fevers, diarrhoea, rash and deep skin inflammation, as well as arthritis. These patients all had genetic defects (mutations) in their OTULIN genes, and we could show that these mutations destroyed the function of the gene, meaning that we had discovered a new immune-mediated disease caused by genetic defects in the OTULIN gene. We named this disease OTULIN-Related Autoinflammatory Syndrome (ORAS).
Remarkably, we were able to find a treatment for the patients. We discovered that if we treated the patients with a medicine that neutralised the effect of the highly potent immune hormone TNF, which is over-produced in the patients and instructs immune cells to seek out and destroy microorganisms (which are not there in this case), the immune system deactivated. The treatment ameliorated all the symptoms, and patients are no longer in need of hospitalisation, and they can go to school and live normal lives.
This research has been published as a research article in the scientific journal Cell, it has been presented at multiple international scientific conferences, and featured in news media, on science blogs, and on social media.
