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

Interview with eLife on being a scientist parent

eLife in their Scientist and Parent series

At what career stage did you become a parent?

My partner and I did PhDs in Canberra, Australia, before post-doc’ing in Seattle, USA. After our post-docs my partner decided to move to industry while I wanted to take a shot on being an academic. At this point we relocated to Belgium and started a family. We were 30 years old at the time, in a new country and both starting out on new career pathways. Now our son is six years old, and all three of us have hit our stride, with happy lives at home and successful careers at work (well, for my wife and I, our son is not yet an astronaut).

What support have you received as a parent from your country (including parental leave), institution, and friends and family?

We moved to Belgium just before having a child, which means we were not able to draw upon our network of friends and family. My host institution did not provide any support, but Belgium in general has a lot of governmental support systems, including cheap available all-day care for infants from 3 months of age, in-home care by a nurse if your child is too sick to go to school but you need to work, subsidised cleaning services, and so forth. While parental leave is very limited (4 months for the mother, 10 days for the father, with zero flexibility), the system is set-up to allow parents to go back to work in a full-time basis.

What are the most difficult aspects of balancing parenthood and science?

Major challenges of parenthood:

• The love of my life became my logistics co-manager for the first year. It often felt like every conversation was transmitting critical baby-related information as we did a baby-transfer so the other person could get to work or sleep
• Travel was a major issue. Both my partner and I travel for work once a month, but when a baby is around this turns the other person into a single parent for the week. We both felt guilty about doing this to each other, and I turned down conference and talks that I would normally take – which looked bad on my tenure review
• Illness. Babies are disgusting vectors of disease, and I had non-stop respiratory infections for several years. Normally when you get sick you can just rest and recover, but that is not an option when a baby is around – I had to keep pushing myself beyond the point of collapse. When my son finally started in kindergarten (2.5 years, at which point my partner could take over half the logistics of drop-off and pick-up), I slept for a week to recover.
• Your flexibility becomes very limited – for the first 2.5 years, if I had a faculty dinner or invited speaker event after hours (which happened most weeks), I had to bring my baby along with me. Fancy faculty club dining rooms are rather unused to have a baby around or warming up baby food – and the reception from other faculty was mixed – some were charmed by my son, others strongly disapproved
• The last major challenge was the perception of others, especially the assumption that you cannot be successful at work and raise a child. This was not so much a challenge for me as people tend to (rightly) assume that most fathers don’t actually help that much, but was a major challenge for my partner. Even if it comes from a source of compassion, these assumptions lead to parents not given the opportunity to work on major projects that can lead to promotions

What more could be done to improve the lives of scientist parents? And what single change would have the biggest impact on you? 

Belgium is a good place to start a family, and my partner and I both entered parenthood with a strong agreement on equal parenting. It was much harder than we expected, but in general the support networks were there through government services and our work colleagues. The one thing that really hits hard on scientist parents (although it applies to non-parents) is just the sheer pressure that is placed on us to constantly perform. The career is an immense pressure-cooker, and you are only as good as your last recent success. With so much anxiety and real fear about dropping into a negative spiral (no grant = no paper = no more grants), it is just really difficult to fully disconnect from work to spend the time at home. So I guess if I could change one thing it would be to remove the culture of pressure from science.

What advice would you give to other scientist parents (or scientists who are thinking of having children)?

My advice for new and prospective parents: 

• If you are relocating and you expect to be a parent in the new location, factor baby needs into the decision of where to move to. Will you need IVF, and is this covered by the health care system? Is infant daycare affordable and available, or will one person essentially have to put their career on hold for five years? Is there good financial support for new parents? How about schools? It doesn’t make sense to take a job that pays more if you then have to hand it all back to pay for private schools and health insurance.
• Reduce future commitments in advance. A baby is not a surprise, you have months of notice. You are going to have a major restriction on your time, so start saying “no” in advance. Don’t teach that course, don’t agree to write that minor review, rotate off that committee and say no to reviewing. It is always easy to say yes when the deadline is 6 months away, but the problem is your time is limited and you need to save it for the stuff that actually matters to your career – mainly, big grants and major papers.
• You have to start equal parenting on day one. A long maternity leave can be a self-fulfilling trap – the mother learns how to look after the baby, and as the baby is constantly changing needs, confidence builds. At the same time, the father often doesn’t learn, and never becomes self-reliant. I would really very strongly recommend that new fathers are given substantial amounts of time alone with their child from day one – they need to figure out the same tricks and develop the same confidence that the mother does. Breast-feeding should not be used as an excuse for fathers not to solo parent an infant – babies are able to switch between breast and bottle on a daily basis. The other proviso of equal parenting is that you need to let the other parent find their own method, and not to try to force them to parent the way that you do.
• If you are coordinating baby information between two parents, use an app like BabyConnect, where you can enter all the details so they are available to the other parent (like, when they last took medication), rather than spending your valuable minutes together synchronising care
• Be prepared to delegate at home and at work. You need to reserve time for the important parts, both at home and at work, so delegate away the rest. Hire a cleaner to come in once a week and tidy up the house, so you can spend valuable hours relaxing. Train your post-docs (in advance) to take over your teaching duties – it will be good for their CV and frees up your time at work. Reduce the intake of new students who will need a lot of training, and make sure that your experienced people know when they can make decisions without you.
• Do things for you. It is easy to become focused around the baby and to forget doing the things that made you happy. But a happy parent makes for a happy child, and you will find that you can do anything with a baby that you used to do without one. At the start it can be difficult, but you will soon find your stride and you end up with a family routine that makes everyone happy.

How do you think the challenges of being a scientist and a parent compare with the challenges faced by other professionals who are also parents? 

My partner always says that academics have the freedom to work whichever 60 hours a week they want to. There is a lot of truth to this. The advantage is in the flexibility – I could change my work around the baby logistics at any time. The disadvantage is that I never truly leave my work behind – I am always on call, and always thinking and working.