Congratulations Dr Aleksandra Brajic!

 Congratulations to Dr Brajic, who was successful in the prestigious (and highly competitive) FWO Post-doctoral Fellowship awards. Aleksandra will work on developing new tools to study the function of regulatory T cells in kidney disease.

A new era for the Golden Pipette

Another lab retreat, and the Golden Pipette has found a new home. Dr Emanuela Pasciuto passed the batton on to Dr Carlos Roca, for the development of a revolutionary new software package for automated analysis of flow cytometry data. A first for the Golden Pipette, won for bioinformatics, and a first for Dr Roca, having never held a pipette before.

Translational Immunology: A Great Team!

Congratulations to Dr Aleksandra Brajic!

Dr Aleksandra Brajic just won the best poster award at the Center for Brain and Disease Research. Winning against such strong competition, and on a project that does not involve the brain, is a real achievement! Dr Brajic's work on the lncRNA Flatr and regulatory T cells will be published soon.

 

Translational Immunology lab in the news

Our research was featured tonight on VRT News:

Speaking roles by Carine Wouters, Erika Van Nieuwenhove and Adrian Liston. Cameos from Stephanie Humblet-Baron, John Barber and Pier-Andree Penttila

 

 

Original research: Van Nieuwenhove et al. 2018 Journal of Allergy and Clinical Immunology. "A kindred with mutant IKAROS and autoimmunity"

If you would like to support our clinical research, and allow us to take on more cases like these, you can make a tax-deductable donation the Ped IMID fund, by transferring to IBAN-number BE45 7340 1941 7789, BIC-code: KREDBEBB with the label "voor EBD-FOPIIA-O2010".

Scientists uncover new genetic cause of lupus on World Lupus Day

A team of scientists and clinicians has identified a novel mutation causing an unusual form of the autoimmune disease lupus. The genetic analysis of a Belgian family sheds new light on the disease mechanisms underlying lupus, which could possibly yield new therapeutic approaches for patients. The findings are published in the Journal of Allergy and Clinical Immunology in the week leading up to World Lupus Day.

Lupus is an autoimmune disorder, meaning that the body’s immune system mistakenly attacks its own tissues. Lupus can affect multiple organs but its cause is often not clear. Usually a combination of genetic and environmental factors is at play.

Researchers in Leuven have now discovered a novel genetic mutation in a patient that presented at the age of 12 with both lupus and problems in the ability of the immune system to fight common infections. This unusual combination of symptoms was quite puzzling.

By analyzing the patient’s DNA and that of the parents, the scientists could trace the problem down to a specific mutation in the so-called Ikaros gene. This gene encodes the Ikaros protein that in turn binds DNA to affect the expression of other proteins.

Erika Van Nieuwenhove, clinician and scientist at VIB-KU Leuven, explains how the mutation caused the patient’s immune system to be hyperactive: “Because of the mutation, Ikaros can no longer bind its target DNA properly. We also observed that certain immune cells of the patients were hyperactive, even in the absence of stimulation. The link between both observations turned out to be CD22, a protein that normally dampens the immune response. In normal conditions, Ikaros stimulates the expression of this inhibitor, but this was not the case in this patient.”

About 5 million people worldwide have lupus, but a causative mutation in Ikaros is very rare. “Small changes in Ikaros are associated with susceptibility to adult-onset lupus, but because the effects are weak it is hard to work out what Ikaros is doing to the immune system,” explains prof. Adrian Liston (VIB-KU Leuven), who heads the lab for translational immunology and is lead author of the study. “In this particular family, however, a mutation created a large change in Ikaros, causing early-onset lupus. The mutation was strong enough to allow us to work out how changes in Ikaros cause lupus and immune deficiency.”

Although the patient in this study has a very rare form of lupus, the discovery nevertheless helps to map the overall disease mechanisms, underscores prof. Carine Wouters, pediatric rheumatologist at University Hospitals Leuven and co-lead of the study: “The mechanism we uncovered in this patient could also be meaningful in a different context with other patients. Now that we understand what goes wrong in this particular case, it could help us think of better targeted treatments for others as well.”

Original research: Van Nieuwenhove et al. 2018 Journal of Allergy and Clinical Immunology. "A kindred with mutant IKAROS and autoimmunity"

If you would like to support our clinical research, and allow us to take on more cases like these, you can make a tax-deductable donation the Ped IMID fund, by transferring to IBAN-number BE45 7340 1941 7789, BIC-code: KREDBEBB with the label "voor EBD-FOPIIA-O2010".

Nieuwe genetische oorzaak van lupus ontdekt

Leuvense artsen en onderzoekers ontdekken een DNA-fout die een ongewone vorm van de auto-immuunziekte lupus kan veroorzaken. Door het DNA van een jonge patiënt en diens ouders na te gaan slaagden ze erin het ziektemechanisme beter te belichten, wat op termijn tot betere behandelingsmogelijkheden zou kunnen leiden, ook voor andere patiënten. De resultaten werden vlak voor Wereld Lupusdag gepubliceerd in het vakblad ‘Journal of Allergy and Clinical Immunology’.

Lupus is een auto-immuunziekte die verschillende organen kan aantasten. Het afweersysteem maakt hierbij antistoffen aan tegen het eigen lichaam. De oorzaak is in veel gevallen onduidelijk, vaak speelt er een combinatie van zowel erfelijke als omgevingsfactoren.

Leuvense onderzoekers ontdekten nu een nieuwe genetische mutatie bij een patiënt die al op 12-jarige leeftijd lupus kreeg, maar tegelijkertijd ook heel weinig antistoffen aanmaakte om zich te beschermen tegen infecties. Deze ongewone combinatie van symptomen vormde een raadsel voor de artsen.

Dankzij een speurtocht in het DNA van de patiënt en van beide ouders, kon het team van wetenschappers de oorzaak herleiden naar een specifieke fout in het gen voor Ikaros. Dit gen is de blauwdruk voor een eiwit dat op zijn beurt aan DNA kan binden om de productie van andere eiwitten te stimuleren.

Erika Van Nieuwenhove, arts-onderzoeker aan VIB-KU Leuven, verduidelijkt waarom de drempel voor activatie van het afweersysteem daardoor zo laag is bij deze patiënt: “Door de fout in het gen kan Ikaros niet meer goed aan het DNA binden. We zagen ook dat bepaalde immuuncellen van de patiënt hyperactief waren, zelfs zonder stimulatie. De link tussen beide was het CD22 eiwit, dat normaalgezien de immuunreactie tempert. Ikaros stimuleert normaal de productie van deze demper, maar dus niet bij deze patiënt.”

Lupus bij kinderen komt relatief vaak voor, maar dat de oorzaak bij het Ikaros eiwit ligt is heel zeldzaam. “Kleine wijzigingen in Ikaros verhogen de kans op lupus bij volwassenen, maar omdat de effecten zo klein zijn was het aanvankelijk moeilijk om uit te vissen hoe Ikaros het immuunsysteem beïnvloedt,” vertelt professor Adrian Liston (VIB-KU Leuven), die aan het hoofd van het labo voor translationele immunologie staat. “Bij deze familie gaat het om een genetische wijziging met grotere gevolgen, die dan ook al op jonge leeftijd lupus veroorzaakt. Maar net door het grotere effect konden we nu uitklaren op welke manier het defecte Ikaros de immuunreactie verstoort.”

Hoewel het gaat om een zeldzame vorm van lupus helpt deze doorbraak om het hele plaatje beter in kaart te brengen, bevestigt Prof. Carine Wouters, kinderreumatoloog aan UZ Leuven, die samen met prof. Liston de studie leidde: “Het mechanisme dat we bij deze patiënt ontdekten kan ook een rol van betekenis spelen bij andere patiënten. Nu we bij deze persoon begrijpen wat er fout loopt kan dat ook helpen om voor anderen meer gerichtere therapieën te ontwikkelen.”

World Primary Immunodeficiency Week

This week is World Primary Immunodeficiency week. Primary immunodeficiencies (PID) are a cluster of rare immunological diseases, caused by genetic defects in any one of dozens of immunological diseases. The diseases are highly diverse at both a genetic and clinical level, ranging from immunodeficiency to multiple autoimmune manifestations to autoinflammatory manifestations. Typically, the diseases are caused by Mendelian mutations creating a specific defect in a single immunological checkpoint. Key problems in the field have been identifying the gene of interest (as many of the disorders show clinical heterogeneity and overlap) and identifying the immunological checkpoint that is disturbed.  

While gene discovery had been previously limited by the need for large affected families or distinct clinical presentations across multiple families (for classical genetic mapping), the advent of next generation sequencing gave rise to the possibility that even single families could be investigated. In 2010 we set up a large-scale immunogenetics study on PID patients from the clinic in Leuven.

The PID research program that we run has led to the mechanistic understanding of multiple new gene- disease associations. Results include the identification of Olmsted syndrome as an immunological as well as a dermatological disorder (Danso-Abeam et al, Orphanet Journal of Rare Diseases, 2013), STAT2 deficiency as a cause of severe viral childhood disease (Moens et al, Journal of Allergy and Clinical Immunology, 2017), IKAROS and IFIH1 mutations as a cause of juvenile systemic lupus erythematosus (Van Eyck et al, Arthritis and Rheumatology, 2015; Van Nieuwenhove et al, Journal of Allergy and Clinical Immunology, in press), and Roifman Syndrome as a disease of defective B cell development (Heremans et al, Journal of Allergy and Clinical Immunology, 2018). We have also identified novel treatments through this approach, such as in deficiency in adenosine deaminase 2 (DADA2, frequency unknown), which we independently identified and found to be cured by hematopoetic stem cell transplantation (Van Eyck et al, Journal of Allergy and Clinical Immunology, 2015). Several examples of this work deserve extra attention:

One of the major successes of this program was the identification of a new PID, Pyrin-associated neutrophilic dermatosis (PAAND). The study started with a single large family in Flanders who manifested a severe inflammatory skin condition. Through using our genetic screening approach we identified a mutation in MEFV, the gene encoding Pyrin. MEFV mutations had previously been associated with a different PID, Familial Mediterranean Fever (FMF, affects 1 in 1000 individuals in Mediterranean groups). Different mutations in the same gene were driving PAAND and FMF, with clinically distinct outcomes. We found that the PAAND mutation had destroyed a key immunological safety switch on the inflammasome (the multi-protein complex that initiates inflammation). In the absence of this safety switch, small triggers could drive the production of the inflammatory cytokine IL-1 (Liston and Masters, Nature Reviews Immunology, 2017). Returning to the clinical setting, we identified additional families with the disease and found that we could successfully treat the inflammation with recombinant IL-1 antagonist (Masters et al, Science Translational Medicine, 2016). We are now leading further multi-centred clinical trials on this disease.

Another PID we have worked on is Familial hemophagocytic lymphohistiocytosis (FHL). The genetic origin of FHL is largely known, with defects in the perforin pathway by which cytotoxic CD8 T cells kill viruses. Before our work, the general model for FHL disease mechanism was that certain viruses were difficult to control without perforin, leading to excessive viral titres. The compensatory increase in the cytokine interferon gamma would then drive the inflammatory and haematological symptoms of the disease. Using mouse models that mimic the disease, we demonstrated that while interferon gamma certainly increases to very high levels, this cytokine was only driving the haematological symptoms and was not responsible for the fatal inflammatory symptoms. Instead, the disease mechanism is driven by the hyper-activation of CD8 T cells leading to the “theft” of a cytokine called IL-2, which normally feeds an anti-inflammatory T cell population known as regulatory T cells. In both mice and humans with FHL, this theft leads to a dramatic loss of regulatory T cells and drives the inflammatory aspects of the disease (Humblet-Baron et al, Journal of Allergy and Clinical Immunology, 2017 and in press, Liston and Gray, Nature Reviews Immunology 2015). This work has opened up a new target for therapeutic intervention for this disease.

A seemingly paradoxical PID is leaky severe combined immunodeficiency (leaky SCID) which combines both immunodeficiency and excessive immune activation. Having developed a model to account for this paradoxical combination (Siggs et al, Immunity 2007; Liston et al, Nature Reviews Immunology 2008), we sought to direct test the model in mice. We developed a new mouse model for leaky SCID and found that, as predicted, the immune activation features were caused by a deficiency in regulatory T cell functions. Further, we found that these symptoms could be abrogated through the treatment of abatacept, an approved treatment for rheumatic arthritis (Humblet-Baron et al, Journal of Allergy and Clinical Immunology 2017). As abatecept is already approved for clinical use, this approach could immediately move into clinical trials.

We are now working on many more cases of suspected PID in the clinic, and hope to make more major breakthroughs in the near future!

If you are worried that your child may have a primary immunodeficiency, take a look at the Jeffrey Modell Foundation site, which outlines the warning signs and will help you find an expert.

If you would like to support our clinical research, and allow us to take on more cases like these, you can make a tax-deductable donation the Ped IMID fund, by transferring to IBAN-number BE45 7340 1941 7789, BIC-code: KREDBEBB with the label "voor EBD-FOPIIA-O2010".

Treg plasticity

This is a great video by PhD candidate Steffie Junius, sharing what her PhD is on:

How do microbial biofilms evade the immune system?

Microbial biofilms are a major medical problem. While the immune system is excellent at picking off individual yeast or bacteria, when these pathgoens band together into a multicellular biofilm they gain the ability to evade the immune system. In a study just out in Frontiers of Immunology, we come up with a theoretical framework to understand how this immune evasion occurs. There are three basic models by which the biofilm could evade the immune system: 1) it could be immunologically silent, using the biofilm as a barrier to make sure that no microbial products leak out to alert the immune system; 2) it could trick the immune system, creating new products that get the immune system to attack in the wrong way; or 3) it could resist the immune system, using the biofilm to block the attack by host cells. By using a mouse model of Candida biofilm infection we were able to demonstrate that the third model is correct - the biofilm is neither silent or diverting, permitting the generation of an effective anti-Candida immune response. Instead, the biofilm acts to somehow block the immune attack on any cells that stay within the biofilm. These findings will allow researchers to focus on understanding the molecular mechanism of biofilm immune resistance, hopefully one day contributing to new treatments for biofilm infections.

Original study: A Framework for Understanding the Evasion of Host Immunity by Candida Biofilms. Garcia-Perez et al. 2018. Front. Immunol., https://doi.org/10.3389/fimmu.2018.00538