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The role of OTULIN and Met1-linked ubiquitin in immune signaling and host defense in vivo

Periodic Reporting for period 1 - OTULINVIVO (The role of OTULIN and Met1-linked ubiquitin in immune signaling and host defense in vivo)

Reporting period: 2015-04-01 to 2017-03-31

Every day of our life, we are under attack. Billions of microorganisms (bacteria, viruses, fungi, and parasites) are trying to use our body to find shelter, feed themselves, and reproduce. To fight this never-ending battle, our bodies have developed an effective and complex army: the immune system.

The immune system consists of multiple different specialised defence cells collectively called immune cells (or white blood cells). Together, they perform the important defence functions our body needs to prevent the disastrous consequences of uncontrolled infection: detection and destruction of invading microorganisms.

The immune system is constantly poised for battle, but it remains at rest until a danger is sensed. It activates when it detects an intruder and immediately starts combatting this microorganism to destroy it. When the invading microorganism has been destroyed, the immune system deactivates and returns to its resting but poised state, ready to combat the next infection.

The immune response is a protective measure that is important to keep us healthy and free of infection. But when it goes wrong or is deregulated or uncontrolled it causes the development of a large range of severe and highly disabling diseases, e.g. inflammatory bowel disease, rheumatoid arthritis, diabetes, multiple sclerosis, autoimmune conditions like systemic lupus erythematosus, and skin disorders such as psoriasis, resulting in significant morbidity, reduced quality of life, and premature death for millions of affected individuals worldwide.

These immune-mediated diseases are all characterised by uncontrolled and unwarranted activation of the immune system, even in the absence of an infection, causing the cells of the immune system to attack our own body instead of an invading microorganism. This causes acute or chronic inflammation and damage to the affected organ(s). Unfortunately, researchers do not fully understand how these diseases develop, and hence what can be done to treat them. This is in large part because it remains poorly understood how the immune system is regulated and what determines its activation and deactivation in normal and healthy individuals. Therefore, our research aims to investigate the fundamental processes that control the activation and deactivation of the immune system to better understand what goes wrong when the immune system runs amok, activates uncontrollably, and starts to attack our own body. Our hope is that a better understanding of the fundamental biological mechanisms will increase our understanding of the immune-mediated diseases and prompt the development of new and better treatments.
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.
We have discovered a new gene, OTULIN, which is important for restraining the activity of the immune system and for avoiding development of a life-threatening immune disease, OTULIN-Related Autoinflammatory Syndrome (ORAS). Our research has identified a new fundamental mechanism by which the activity of the immune system is controlled by removal of activating signal “flags”. This principle may not only be relevant to patients with mutations in OTULIN; this process of removing the activating “flags” might be deregulated in other related diseases, e.g. inflammatory bowel disease, rash/psoriasis, and arthritis, as the ORAS symptoms indicate. Therefore, we might have discovered a universal principle in immune deregulation, a prospect we will continue to investigate in the coming years.

While the prevalence and incidence of ORAS remain unknown at this time, we can now diagnose these patients and treat them, which is tremendously important for the patients and their families’ quality of life. But it will most likely also safe hospitals and healthcare providers immense sums of money as Intensive Care Unit hospitalisation is incredibly expensive.
Diagram showing the characteristic symptoms of OTULIN-Related Autoinflammatory Syndrome (ORAS)
Schematic of a spontaneously activated ORAS immune cell sending out signals to activate other cells