European “ImmunAID” project for the diagnosis of rare autoinflammatory systemic diseases launched in Belgium

The project wishes to diagnose rare autoinflammatory systemic diseases through the identification of biomarkers

In December 2020 a new project has been launched in the University Hospitals Leuven. The ImmunAID project aims to identify new tools for the diagnosis of systemic auto-inflammatory diseases (SAID). SAID are a complex and evolving group of rare diseases characterised by extensive clinical and biological inflammation. These conditions are caused by a dysregulation of the innate immune system leading to a release of immune cells and mediators provoking fevers, tissue and organ inflammation and damage.

Sometimes it is difficult for the physicians to make a correct diagnosis, since the main symptoms of these diseases (such as fever, rash, joint pain, etc.) are also present in many other conditions. Thus, a patient may have received on average up to 5 inappropriate or ineffective treatments before being properly diagnosed, having a great impact on their health and quality of life. The aim of ImmunAid is to understand the mechanisms that drive the pathology in order to provide better diagnosis and care for patients with these rare but potentially devastating diseases.

An unprecedented body of clinical and biological data in the field of SAID

This new project aims to find new and more effective ways to diagnose SAID. While it is already known that some SAID are due to specific genetic mutations, a large number of SAID can only be detected by a set of clinical signs and symptoms and after other diagnostic possibilities have been excluded. Since SAID are rare conditions, a large group of patients suffering from various SAID is being recruited throughout Europe. As such, the ImmunAID cohort represents a very important tool for researchers defining biological fingerprints, or biomarkers, specific to distinct SAID.

The team expects to find a set of biological features common to all SAID, which will allow to quickly confirm or refute the diagnosis of suspected autoinflammatory syndrome. In addition, for each SAID, a list of characteristic biomarkers and an algorithm will be generated to allow the physician to make an appropriate diagnostic assessment.

In order to achieve the project's objectives, biological samples collected from the patients will be analysed in a European-wide research network by set of state-of-the-art technologies and will generate an unprecedented amount of data (genomics, transcriptomics, proteomics and microbiome). Simultaneously, other analyses will focus on immune cells, molecular mechanisms and specific agents of the immune system (cytokines, etc.). All data generated will be subjected to artificial intelligence and modelling analysis.

Prof. Carine Wouters, paediatric rheumatologist at the University Hospitals Leuven, is highly committed to the success of the project "We are delighted and proud to be able to work with ImmunAID partners as it represents a unique opportunity for the European scientific community to advance research in an important field of rare diseases that can only be tackled at large scale. We will do our best to come up with meaningful results that will improve patients’ diagnosis and medical care.”

Leuven teams are the forefront of the project

The teams of the Leuven University Projects are at the forefront of the project. The activities carried out in the Belgian centre will be two-fold. First, the team from professor Carine Wouters and professor Steven Vanderschueren will be in charge of recruiting patients suffering from monogenic SAID (FMF, CAPS, TRAPS, MKD) or genetically-undiagnosed SAID (Still disease, neutrophilic dermatosis, Schnitzler syndrome, Takayasu arteritis, Kawasaki disease, Behçet disease, chronic osteitis, recurrent pericarditis and chronic systemic inflammation of unknown origin).

Second, professor Wouters, professor Patrick Matthys and professor Paul Proost from the Rega Institute and KU Leuven department for Microbiology, Immunology and Transplantation will be involved in the biochemical and biological analysis of the samples. The team of Carine Wouters and Patrick Matthys will apply their extensive knowledge on Natural Killer cells to identify and characterize their possible altered activity in SAID patients. On the other hand, the team of Paul Proost will study whether modifications of messengers of the immune system (cytokines and chemokines) in patients play a role in regulation of the inflammation processes. The team of professor Stephanie Humblet-Baron and professor Adrian Liston will analyse in-depth the immune cellular compartment of the blood of affected patients in addition to genetic investigation in order to identify new genes responsible for SAID.

These activities are intended to gain insight into the mechanisms triggering the aberrant behaviour of the autoinflammation process. The results will be pooled with other analyses from other European research laboratories to help identify biomarkers of the diseases and possible therapeutic interventions.   

Regarding the ImmunAID project: ImmunAID is a research project (www.immunaid.eu), which aims to identify a set of disease-specific biomarkers to confirm the diagnosis of SAID. ImmunAID is implemented by a large consortium (25 partners in 12 European countries) and has been funded with € 15.8 million by the European Commission. The ImmunAID project has received funding from the European Union's Horizon 2020 research and innovation programme under Grant Agreement No. 779295.

IL-2 cytokine networks

If anyone is interested in our lab's work on IL-2 cytokine networks, I just gave a seminar on the topic, which I am putting up here:

It is a new talk for me, and was an interesting one to write. I started to work on IL-2 right at the start of my PhD. I was very keen to return to the topic when I opened my own lab in Belgium (2009), with one of my first PhD students (Dr Wim Pierson) working on the niche-sensing and niche-filling negative feedback loop that provides a stable number of Tregs in the system. (An excellent collaboration with one of my favourite immunologists, Prof Daniel Gray from WEHI, Australia).

Then Prof Stephanie Humblet-Baron joined my lab for a post-doc, wanting to work on a disease known as Familial hemophagocytic lymphohistiocytosis (FHL). At the time, this was thought to be a disease of CD8 hyper-activation and IFN-gamma. Thanks to great work by Stephanie, in mouse and human, we now know that FHL is only partly driven by IFN-gamma, and instead a key part of pathogenesis comes from flipping the negative feedback loop between IL-2 and Tregs into a postivie feedback loop between IL-2 and CD8 T cells.

Right back in 2009 we started to work on a new genetic switch that would let us turn IL-2 on in different cell types. At first I just wanted to see what would happen if Tregs could make their own IL-2. By breaking that dependency on exogenous IL-2 do you get a run-away Treg reaction? (answer: yes, yes you do). Once we finally made the mice, however, it just opened so many different doors. What happens if CD8 T cells make their own IL-2? How about NK cells, dendritic cells, B cells? What if we turn it on in different organs? It has really been a phenomenal mouse that just kept on delivering interesting results. Dr James Dooley led a team working on the mouse, and more recently Dr Carly Whyte drove the project to publication. Or, at least, pre-publication - you can see the paper here on BioRxiv. So many interesting aspects of IL-2 biology were illuminated by this work - easiest to show in a circuit diagram:

I hope you enjoy the seminar. Keep an ear out for the muffled bang at the 29 minute mark. It doesn't sound like much on the audio feed, but across Cambridge we all jumped up as the windows rattled and the building shuddered. I fumbled the graph on this slide, calling Tregs Tconv by mistake, wondering if an explosion had gone off downstairs. Fortunately it was just a sonic boom as fighter jets scrambled overhead.

Top 10 health innovations of 2020

Great to see our recent Cell paper on brain T cells licensing microglia listed as one of the top 10 health innovations of 2020!

Dissecting the immune characteristics of severe COVID-19 responses

• Researchers have analysed immune cell types and numbers from the blood of healthy volunteers, COVID-19 patients experiencing mild-to-moderate effects and patients classified as severe to understand whether particular characteristics of their immune system response can identify treatment targets or indicate disease severity.
• After comparing the T cell immune response, the researchers noted the surprising absence of a strong anti-viral response in the blood of COVID-19 patients.
• The study identified an elevated presence of anti-inflammatory-producing regulatory T cells in the severely affected patients. If confirmed by larger studies, this could be used as a marker for identifying worsening cases and could provide an insight into the mechanism of disease pathology.

A team of immunology experts from Belgium and the UK research organisations have come together to apply their pioneering research methods to put individuals’ COVID-19 response under the microscope. Published today in the journal Clinical and Translational Immunology, their research adds to the developing picture of the immune system response and our understanding of the immunological features associated with the development of severe and life-threatening disease following COVID-19. This understanding is crucial to guide the development of effective healthcare and ‘early-warning’ systems to identify and treat those at risk of a severe response.  

One of the most puzzling questions about the global COVID-19 pandemic is why individuals show such a diverse response. Some people don’t show any symptoms, termed ‘silent spreaders’, whereas some COVID-19 patients require intensive care support as their immune response becomes extreme. Age and underlying health conditions are known to increase the risk of a severe response but the underlying reasons for the hyperactive immune response seen in some individuals is unexplained, although likely to be due to many factors contributing together.

To investigate the immune system variations that might explain the spectrum of responses, teams of researchers from the VIB Centre for Brain and Disease Research and KU Leuven in Belgium and the Babraham Institute in the UK worked with members of the CONTAGIOUS consortium to compare the immune system response to COVID-19 in patients showing mild-moderate or severe effects, using healthy individuals as a control group.

Professor Adrian Liston, senior group leader at the Babraham Institute in the UK, explained: “One of our main motivations for undertaking this research was to understand the complexities of the immune system response occurring in COVID-19 and identify what the hallmarks of severe illness are. We believe that the open sharing of data is key to beating this challenge and so established this data set to allow others to probe and analyse the data independently.”

The researchers specifically looked at the presence of T cells – immune cells with a diverse set of functions depending on their sub-type, with ‘cytotoxic’ T cells able to kill virus-infected cells directly, while other ‘helper’ T cell types modulate the action of other immune cells. The researchers used flow cytometry to separate out the cells of interest from the participants’ blood, based on T cell identification markers, cell activation markers and cytokine cell signalling molecules.

Surprisingly, the T cell response in the blood of COVID-19 patients classified as severe showed few differences from the healthy volunteers. This is in contrast to what would usually be seen after a viral infection, such as the ‘flu. However, the researchers identified an increase in T cells producing a suppressor of cell inflammation called interleukin 10 (IL-10). IL-10 production is a hallmark of activated regulatory T cells present in tissues such as the lungs. While rare in healthy individuals, the researchers were able to detect a large increase in the number of these cells in severe COVID-19 patients.

Potentially, monitoring the level of IL-10 could provide a warning light of disease progression, but the researchers state that larger-scale studies are required to confirm these findings.

“We’ve made progress in identifying the differences between a helpful and a harmful immune response in COVID-19 patients. The way forward requires an expanded study, looking at much larger numbers of patients, and also a longitudinal study, following up patients after illness. This work is already underway, and the data will be available within months,” says Professor Stephanie Humblet-Baron, at the KU Leuven in Belgium.

“This is part of an unprecedented push to understand the immunology of COVID-19”, concludes Professor Liston. “Our understanding of the immunology of this infection has progressed faster than for any other virus in human history – and it is making a real difference in treatment. Clinical strategies, such as switching to dexamethasone, have arisen from a better understanding of the immune pathology of the virus, and survival rates are increasing because of it”.  

Professor Liston and Professor Humblet-Baron both emphasized the importance of the scientific team that led the study. "This work happened during a period of incredible stress. When much of our laboratory was shut down due to the pandemic, Dr Teresa Prezzemolo and Silke Janssens were in the hospital day-after-day, preparing blood samples that were critical not just for this study but for a whole host of clinical trials on COVID-19 based in Leuven. Julika Neumann and Dr Mathijs Willemsen put their PhD research on hold to run samples, and Dr Carlos Roca and Dr Oliver Burton provided the computational support to turn the data into biological understanding. We are both incredibly proud of the entire team."

Neumann, J., Prezzemolo, T., Vanderbeke, L. & Roca, C.P. et al. Increased IL-10-producing regulatory T cells are characteristic of severe cases of COVID-19. Clinical and Translational Immunology

The 2020 Golden Pipette

Congratulations to Julika Neumann for winning the 8th Golden Pipette at the 2020 virtual lab retreat.  

Brutally tough competition this year - the quality of science is just constantly rising year after year. I was really tempted by Orian's UMAP analysis (it looks like an elephant!):

But for that single piece of data that just speaks for itself, it is hard to go past this crystal structure of a point mutation found in a novel primary immunodeficiency gene:

Well done Julika!

Julika receiving the Golden Pipette from past winner Lidia, in our virtual happy hour

Lab retreat 2020 edition

Our lab retreat is a real highlight of the lab, with the Leuven and Cambridge teams getting together to share ideas and progress, brainstorm and socialise. We usually have a couple of retreats a year. Unfortunately our first was cancelled in 2020 by the lockdown, and we decided to make the second one virtual.

Having spent many, many hours on zoom calls over the past six months, I was quite worried about three solid days of a virtual zoom meeting. Fortunately it was a great success! Excellent science (of course) and the level of interaction was as good as an in-person retreat. I don't think it can ever replace in-person meetings, since the success builds on the already-existing personal connections, but perhaps a virtual retreat will substitute for every second retreat going forward?

Secret tips for a zoom retreat:

• Planning in advance. We sent out a spreadsheet with all the links, talk times and titles, discussion blocks, social activities, etc. There was a lot to plan, so I delegated tasks to lots of people, but that still means a lot of follow-up to make sure people have actually done their bit and communicated it. The investment in advance is worth it though! We were lucky to have Dr Loriana Mascali to coordinate much of the retreat, and there was great investment by many lab members on different sections.
• Have a dynamic schedule. Lots of small talks with breaks is easier to handle. For several people we broke up their talk into several subtalks to make sure that all talks were between 10 and 30 minutes. We also arranged to be zoom-bombed by Daisy the goat, to break up the rhythm. Enough discussion time needs to be added, otherwise you'll end up consuming the break time.

• Stick to the schedule as much as possible. Talks that start to really drag on are often those where there are big problems - there is only so long it is helpful to hammer home those points. Build some flexibility into the schedule (so you can keep positive discussions going even if they go over time), but don't let it derail the entire program. Having breakslides is also useful, so that people can always see when the talks resume by looking at the screen, rather than needing to check the program and try to remember if they were five minutes behind or not.
• Actively try to stimulate discussion and interaction. It does not happen organically on zoom, so you need to promote it. I used secret "cheerleaders and shade-throwers". A cheerleader needs to make a positive comment on a talk, while a shade-thrower needs to make a critical comment. They then pass the duty off (in secret) to another person. The net effect is that people get used to making comments, and you have a 2:1 ratio of positive:critical comments. It makes for a lot of conversation and use of the zoom chat. Eventually everyone catches on, but the habit is already established by then! We also used polls, with pre-defined multiple choice questions on each talk. If you see someone not participating, a private chat message can encourage them to engage once, after which they are more likely to engage again.

• Social activities. We had lab bingo running each day (with custom words), which people really got into. Zoom werewolf was a huge success. Virtual escape room was fantastic, which for us was custom made "escape from the lab cold room", but there are plenty of paid options available. Break-out rooms for social interaction are good, but should be broken into smaller groups to get conversation going (6-8 people are good).

• External guests. We invited several potential post-docs / students and long-term collaborators to join. I made it clear up front that they weren't expected for the full three days, and they had the program so that they could jump in for the sessions that interested them the most. A nice way to get expert feedback from people who are not the same old good. 

Congratulations to Julika Neumann!

CCongratulations to the very talented Julika Neumann, who successfully defended her application for a competitive FWO PhD fellowship!

Just starting her PhD, Julika already has several major successes under her belt, including identifying a new primary immunodeficiency (stay tuned!) and spear-heading an open science study on COVID pathology.

We anticipate more great successes from Julika during her FWO fellowship!

Dieet met veel suiker verhoogt risico op pancreaskanker

Knack

Suikerrijke voeding veroorzaakt de ontwikkeling van alvleesklierkanker en verhoogt de kans op een dodelijke afloop. Tot die bevinding zijn onderzoekers van het Vlaams Instituut voor Biotechnologie (VIB) en de KU Leuven gekomen.

Een suikerrijk dieet verhoogt niet alleen de kans op het ontwikkelen van pancreaskanker. Het stimuleert ook de agressieve groei van tumoren. Tot die conclusie komen onderzoekers van VIB-KU Leuven en collega's van het Babraham Institute van de Britse universiteit Cambridge.

De resultaten zijn gepubliceerd in het tijdschrift Cell Reports.

Alvleesklierkanker is een zeldzame maar dodelijke vorm van kanker door late detectie en een slecht begrip van risicofactoren. Bekende risicofactoren zijn obesitas, voeding en diabetes type 2, maar door de lage incidentie en de onderlinge samenhang is hun individuele bijdrage moeilijk in te schatten.

De onderzoekers voltooiden een uitgebreid project met experimenteel werk bij muizen en menselijke gegevens. Bij de dieren werd de progressie van pancreaskanker beïnvloed door voedingssuiker, met een snellere tumorgroei en verhoogde dodelijkheid.

Het effect bij mensen blijkt hetzelfde. Bij 500 deelnemers aan de studie onderzochten de onderzoekers de interactie tussen genen en voeding en ontdekten dat hoge niveaus van voedingssuiker het risico op alvleesklierkanker verhoogden. 'We hebben jarenlang gekeken naar verschillende voedings- en genetische veranderingen en niets komt in de buurt van de nadelige gevolgen van een dieet met veel suiker', zegt James Dooley, senior wetenschapper bij het Babraham Institute.

Plantaardige voeding met een equivalent van een avocado per dag vermindert het risico op pancreaskanker met tien procent.

Today in Cell

Not a bad day for the VIB Brain and Disease department...

  

New role for white blood cells in the developing brain

Whether white blood cells can be found in the brain has been controversial, and what they might be doing used to be complete mystery. In a seminal study published in Cell, an international team of scientists led by Prof. Adrian Liston (VIB-KU Leuven, Belgium & Babraham Institute, UK) describe a population of specialized brain-resident immune cells discovered in the mouse and human brain, and show that the presence of white blood cells is essential for normal brain development in mice.

Like a highly fortified headquarters, our brain enjoys special protection from what is circulating in the rest of our body through the blood-brain barrier. This highly selective border makes sure that passage from the blood to the brain is tightly regulated.

The blood-brain barrier also separates the brain from our body’s immune system, which is why it has its own resident immune cells, called microglia, which trigger inflammation and tissue repair. Microglia arrive in the brain during embryonic development, and later on, the population becomes self-renewing.

Yet, white blood cells—which are part of our immune system—have been found to play a role in different brain diseases, including multiple sclerosis, Alzheimer’s and Parkinson’s disease or stroke. Whether or not white blood cells can be found in healthy brains as well, and what they might be doing there, has been subject of intense debate. An interdisciplinary team of scientists led by Prof. Adrian Liston (VIB-KU Leuven, Babraham Institute) set out to find the answers.

White blood cells in the brain

"A misconception about white blood cells comes from their name,” explains Dr. Oliver Burton (Babraham Institute). “These 'immune cells' are not just present in the blood. They are constantly circulating around our body and enter all of our organs, including—as it turns out—the brain. We are only just starting to discover what white blood cells do when they leave the blood. This research indicates that they act as a go-between, transferring information from the rest of the body to the brain environment"

The team quantified and characterized a small but distinct population of brain-resident T helper cells present in mouse and human brain tissue. T cells are a specific type of white blood cells specialized for scanning cell surfaces for evidence of infection and triggering an appropriate immune response. New technologies allowed the researchers to study the cells in great detail, including the processes by which circulating T cells entered the brain and began to develop the features of brain-resident T cells.

Dr. Carlos Roca (Babraham Institute): “Science is becoming increasingly multidisciplinary. Here, we didn't just bring in expertise from immunology, neuroscience and microbiology, but also from computer science and applied mathematics. New approaches for data analysis allow us to reach a much deeper level of understanding of the biology of the white blood cells we found in the brain.”

An evolutionary role

When T helper cells are absent from the brain, the scientists found that the resident immune cells – microglia – in the mouse brain remained suspended between a fetal and adult developmental state. Observationally, mice lacking brain T cells showed multiple changes in their behavior. The analysis points to an important role for brain-resident T cells in brain development. If T cells participate in normal brain development in mice, could the same be true in humans?

“In mice, the wave of entry of immune cells at birth triggers a switch in brain development,” says Liston. “Humans have a much longer gestation than mice though, and we don't know about the timing of immune cell entry into the brain. Does this occur before birth? Is it delayed until after birth? Did a change in timing of entry contribute to the evolution of enhanced cognitive capacity in humans?”

The findings open up a whole new range of questions about how the brain and our immune system interact. "It has been really exciting to work on this project. We are learning so much about how our immune system can alter our brain, and how our brain modifies our immune system. The two are far more interconnected than we previously thought," says Dr. Emanuela Pasciuto (VIB-KU Leuven).

The study also brings in a connection with the gut microbiome, says Liston: “There are now multiple links between the bacteria in our gut and different neurological conditions, but without any convincing explanations for what connects them. We show that white blood cells are modified by gut bacteria, and then take that information with them into the brain. This could be the route by which our gut microbiome influences the brain.” 

Taken together, the results contribute towards the increasing recognition of the role of immune cells in the brain and shed new light on its involvement in a range of neurological diseases.

Check out the full article here