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Entries in immunology (56)

Thursday
May102018

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"

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Thursday
May102018

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.”

Saturday
Apr072018

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

Tuesday
Feb062018

The 2018 Golden Pipette Award

Lab retreat 2018: the baton is being passed on, as Dr Oliver Burton, 2017 winner of the Golden Pipette, presents the trophy to Dr Emanuela Pasciuto. Our prestigious prize for the best experiment was awarded for the generation of a transgenic mouse to study brain Tregs.

Tuesday
Jan232018

Having Kids Radically Reshapes Parents’ Immune Systems

  

Imagine this: The love of your life is 10 inches shorter than you. This being a non-issue, the two of you get on with moving in together and starting a small brood of young humans of your own. Over time, something a little strange starts to occur. You seem to be shrinking just as your partner spurts up. When the dust settles, you maintain the height advantage but the distance between you is cut in half, down to just five inches.

This is analogous to what happens to your immune system when you co-parent. “You are completely changing the cells that constitute your immune system in a way as radical as changing your height,” says Adrian Liston, a researcher at the Translational Immunology Laboratory at VIB in Belgium.  In 2016, Liston was part of the team that documented the physical composition of co-parents’ immune cells shifting to resemble their partners’ cells. Eventually, he says, co-parents end up with more in common immunologically than identical twins.

Are these changes for better or for worse? It’s a tough question to answer, because parenting brings both benefits and deficits. More critically, though, there is no such thing as an ideal immune system — their strength is in their diversity, and between healthy individuals it’s hard to say if one setup is better than another setup. Basically, it depends entirely on the context of what you need your immune system for, and what you need it to do.

It’s clear, however, that becoming a parent changes you fundamentally. Now we know that those changes take effect at the cellular level and define the structure of your inner defense systems. There’s still more we don’t know than we do about how this works, but here are five factors that likely affect it.

 

 Read the full article in Fatherly.

Saturday
Dec232017

An interview with Stephanie Humblet-Baron

An interview between Dr Liesbeth Aerts and Dr Stephanie Humblet-Baron on her recent paper in JACI:

 

Can you summarize the significance of your findings in a few sentences for people outside your field?

Working in the field of primary immunodeficiency disorders, we described a new mouse model for severe combined immunodeficiency (SCID), recapitulating the key clinical features of SCID patients suffering of both immunodeficiency and autoimmunity (leaky SCID). Importantly our model proposed a novel efficient therapeutic approach for this disease.

What made the paper particularly outstanding?

Due to the pre-clinical evidence of a drug efficiency to treat a rare disease, patient clinical trials can be directly proposed. This treatment is already approved for human use in arthritis, so it could be rapidly be repurposed for leaky SCID patients. In addition, our model is available for further pre-clinical assay, including gene therapy.

When did you realize you were on to something interesting?

When I started to work with this model I already knew which gene was mutated (Artemis). However when I saw the mice for the first time I could tell that they were developing the exact same symptoms that we see in the clinic. I knew that other mouse models working on this gene had never seen leaky SCID symptoms, so I knew we needed to explore in depth the model. The other key moment was after treating our mice with the drug (CTLA4-Ig) – it completely blocked disease, making this a very valuable project with new therapeutic opportunities for patients.

Did the technology available at the department make a difference?

The FACS core was the major technique used for investigation this project.

A huge amount of work and energy must have gone into the paper. How did you cope with stress and doubts?

Liesbeth this is a joker question!

The project went actually quite smoothly, the hard time I got during this project was rather adjusting myself with motherhood and life in science at the same time.

What are you personally most proud of?

This work can be seen as translational medicine, with direct therapeutic benefit for the patients. The ability for better understanding the mechanism of the disease was also valuable to me.

Can you share some advice for others?

Always envision your project as a story to write and tell. When you find a new result ask what would be the next question and continue to explore it further.

Friday
Dec082017

Commercial staining kits

Foxp3 staining is notoriously difficult. The original protocols did not work, and it was a major breakthrough when BD and eBio released fix/perm kits that allowed good Foxp3 staining. The companies keep the formula secret, so that you have to buy from them, but it turns out 0.1% dishwashing liquid works just as well...

Saturday
Dec022017

Belgian Immunology Society meeting 2017

This year the Belgian Immunology Society meeting was hosted by the Translational Immunology laboratory in Leuven, with the theme "immune regulation". We had record attendence, with dedicated sessions on fundamental immunology, clinical immunology, neuroimmunology and tumour immunology. Great morning talks by Belgian scientists, an interactive poster session, and an afternoon keynote session with outstanding presentations from Anne Puel (INSERM, France), Denise Fitzegerald (QUB, UK), Gabriele Bergers (VIB), Anne Dejean (Toulouse, France) and Gitta Stockinger (Crick Institute, UK). I certainly learned a lot of immunology on the day!

Many thanks to our scientific coordinators and session chairs: Susan Schlenner (KUL), Niels Hellings (Hasselt), Erika Van Nieuwenhove (UZ Leuven) and Abhishek Garg (KUL). The meeting would not have been such a success without Wim Cockx, Caroline Lenaerts and all the volunteers from the lab who helped out on the day.

Great support from our sponsors made it all happen:

Platinum sponsor: BD Bioscience

Silver sponsors: ThermoFisher, Stem Cell Technologies, Sanbio, BioLegend, Bioconnect, Analis, Miltenyi Biotech

Bronze sponsors: VWR, biotechne

Presentation of the EFIS-IL lecture award to Prof Gitta Stockinger (Crick Institute, UK) by BIS President Oberdan Leo. 

Sunday
Nov262017

Jobs, jobs, jobs!

Two post-doc positions now open in immunology, plus a technician position in the FACS Core, and very soon we will be opening up a new position in endocrinology!

 

Sunday
Aug272017

Immunology Group of Victoria

The 2017 IgV meeting in the Yarra was a beautiful reminder of what a vibrant and friendly community Australian immunology is. Top level science in one of the most  internationally creative hubs for medical research, coupled with a whole lot of fun. Perfect.