(Yet another) reason to vaccinate your child

Vaccination may be one of the greatest scientific breakthroughs of all time. Smallpox eradication alone probably saves 3 million lives a year, and the routine childhood vaccines save another 3 million lives a year. Vaccines are so effective and successful, in fact, that they are no longer seen with the awe they deserve. The virulent fear of infectious disease has faded so completely forgotten that clueless celebrities are happy to campaign against vaccines based on the incorrect claims of a discredited  fraud.

Take measles, for example. While often dismissed as a harmless childhood disease, measles can be a killer. It is extremely infectious virus, putting most other viruses to shame for just how incredibly infectious it is. For children or adults in poor health (immunocompromised or malnourished), measles has a mortality rate of 30%. Even under the best scenario, measles can cause blindness and brain damage and kill 0.2% of those infected. 0.2% doesn't sound that much, but consider that in the USA without vaccination we would have 3-4 million cases a year - that is 8000 infant deaths being prevented every year.

Well, it turns out that measles is probably even worse than this. A new study demonstrates that measles infection increases the risk of dying of other diseases (scientific paper here, lay verion here). When measles vaccines are introduced, it is not only deaths from measles that are eliminated - deaths from a wide set of childhood infections dramatically drop. In fact, rather than "what doesn't kill you makes you stronger", surviving measles seems to suppress the immune system for several years, making children more likely to die from alternative diseases. Vaccination gives protection against measles without the risks of infection and without the immunosuppression of infection - a great "win-win" situation.

New cause for early-onset lupus discovered

In a new study out by the Autoimmune Genetics Laboratory, we have discovered a new genetic cause for early-onset systemic lupus erythematosus - mutation in the gene IFIH1. In 2014, mutations of this gene were independently found to cause the neurodegenerative disease Aicardi-Goutières syndrome (AGS). Despite lupus and AGS manifesting as clinically different symptoms, this study shows that mutation in the same gene causes both diseases. The mutation in IFIH1 works via driving excessive production of the cytokine IFN alpha, so this discovery opens up the possibility for treatment once anti-IFN alpha antibodies (currently in development) are approved for use. 

Read more: Van Eyck, De Somer, Pombal, Bornschein, Frans, Humblet-Baron, Moens, de Zegher, Bossuyt, Wouters* & Liston*. IFIH1 mutation causes systemic lupus erythematosus with selective IgA-deficiency. Arthritis Rheumatol. 2015, in press.

If you would like to support our clinical research, and allow us to take on more cases like this one, 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".

New fund to support translational research into paediatric inflammatory diseases

A new fund has been set up to drive bench-to-bedside research for children with inflammatory immune diseases. The Ped IMID fund (Fonds Pediatrische Immuun-inflammatoire Aandoeningen) was set up by Prof Carine Wouters (Pediatric Rheumatology), Prof Patrick Matthys (Immunobiology) and Prof Adrian Liston (Autoimmune Genetics) to build on our strong research cooperation. More than merely "translational research", where basic science is pushed into the clinic, our group performs "dialog research", where we meet regularly to discuss the clinic and the science of the most difficult-to-treat patients. We use the clinic to inform the research and the research to inform the clinic, and have already had multiple break-throughs in understanding and treating children with rare inflammatory diseases. 

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

A new look at immune ageing

The thymus is the organ in which all T cells, a key white blood cell in our immune system, develop. The thymus shrinks with age, degenerating from a plump milky organ (just above the heart) to a ratty-looking fat-riddled vestige which barely produces any new T cells. This degeneration means that older persons are producing fewer and fewer T cells, contributing to the poor responses to vaccines and infections with age. Despite the importance of this process, there is a great debate in immunology over why the thymus gets worse with age, with some scientists pointing out the structural degeneration of the thymus itself, while others suggest that it is instead due to poorer function of the bone-marrow that sends stem cells to the thymus to be turned into T cells.

In a new study from the Autoimmune Genetics Laboratory, published in the European Journal of Immunology, we use a range of imaging and genetic techniques to address this key question. We undoubtly find the structural degeneration in the organ with age, but by comparing two mouse strains that have a thymus ageing at different rates, we find that the structural abnormalities do not actually limit production of T cells. Instead, it is the reduced function of the bone-marrow that leads to a reduction in new T cells. These results suggest that researchers looking into immune ageing direct their attention towards the bone-marrow, where rescuing stem cell production may allow even older persons to produce fresh T cells for a healthy life.

Data from Franckaert et al, European Journal of Immunology. The C57BL/6 mouse (top) has a thymus that ages slowly, while the FVB/N mouse (bottom) has a thymus that ages rapidly.

Jeffrey Modell Foundation supports Belgian research on primary immunodeficiency

For the first time the Jeffrey Modell Foundation is giving a research grant to a Belgian laboratory. The team of Adrian Liston from VIB-KU Leuven will use the grant to develop a gene therapy to cure children that suffer from IPEX syndrome, a rare and fatal autoimmune disorder in which the immune system attacks the body’s own tissues and organs. At the moment, the only successful therapy to treat the syndrome is a bone marrow transplantation, which is not available for all children.

 “This is a real chance for a cure”, said lead-researcher Adrian Liston. “The gene responsible for this disease was identified 13 years ago, but for the first time we may have learned enough about the basic biology to solve it. We should know within a year whether the gene therapy works in mice, after which we can move to patients at top speed.”

The Jeffrey Modell Foundation (JMF)

JMF is a global non-profit organization for patients who suffer from Primary Immunodeficiency (PI) and their relatives. The organization is devoted to early and precise diagnosis, meaningful treatments and, ultimately, cures. Through clinical and basic research, physician education, patient support, advocacy, public awareness and new-born screening they want to make a difference in the lives of patients with PI.

Vicki and Fred Modell established the Foundation in 1987, in memory of their son Jeffrey, who died at the age of fifteen from complications of PI. During the years, the foundation has created a network of the world’s leading expert immunologists. Two years ago the Child Immune Deficiencies Department of UZ Leuven was given the first certification as a "Jeffrey Modell Foundation Diagnostic and Research Center for Primary Immunodeficiencies” in Belgium.

IPEX and primary immunodeficiency (PI)

IPEX is an acronym for immune dysregulation, polyendocrinopathy (diseases affecting multiple endocrine glands), enteropathy (disorder of the intestines), and X-linked (pattern of inheritance).

IPEX Syndrome is classified as a primary immunodeficiency disorder. Primary immunodeficiencies are disorders in which part of the body's immune system is missing or does not function normally. IPEX is caused by mutations in the FOXP3 gene which lead to the dysfunction of regulatory T cells (a type of white blood cells).

IPEX syndrome is an autoimmune disorder, meaning that the immune system mistakenly attacks the body’s own tissues and organs. The syndrome is characterized by severe diarrhoea, dermatitis (inflammation of the skin), diabetes and severe, life-threatening infections. The disease only affects boys.

Current therapies still remain of partial efficacy. Immunosuppressive drugs are most commonly used, but they only delay the disease. Stem cell transplantation, when performed before severe autoimmunity develops, is currently the only effective cure. However transplantation is only a solution for those children with a compatible donor, unless a gene therapy option is available to correct the mutation in the patient’s own stem cells. 

Update on Wednesday, September 10, 2014 at 3:55PM by Adrian Liston

METRO.be

Amerikaanse beurs voor Vlaams onderzoek naar auto-immunziekte IPEX

Bio-Medicine

Jeffrey Modell Foundation supports Belgian research on primary immunodeficiency

News-medical.net

Belg ontvangt onderzoeksbeurs van Jeffrey Modell om behandelingsIPEX syndroom te helpen

MSN nieuws

Amerikaanse beurs voor Vlaams onderzoek naar auto-immunziekte IPEX

BRF.be

Belgische Genforscher erhalten Geld einer US-Stiftung

sNEWSi.com

Jeffrey Modell Foundations supports Belgian research on primary immunodeficiency

LokaalNieuws.be

Amerikaanse beurs voor Vlaams onderzoek naar auto-immunziekte IPEX

New VIB group leader position available

The VIB is starting up a new group leader position in Hasselt University focused on autoimmunity research. The position will come with a €1.4 million start-up grant. Interested? Apply here.

Faculty position opening up in Leuven

See the details on NatureJobs

Women in Molecular Immunology

It is easy to discuss equality in science through anecodote. Just by spending most of my waking adult life on university campuses across three continents I am fairly confident in saying that sexual equality is better in biology and medicine than in chemistry or physics, is great at undergraduate level and lagging at professorial level, and is better in Australia than in Belgium. Much better than anecodote, though, is quantitative analysis, which is why I love this website. If you don't publish your research it is a hobby, not science, and a good publication record is the A to Z of career success for a scientist. This website collates data on authorship across time and across disciplines, at a global level, and assesses the participation of women. There are a few caveats: papers are only assessed if they are listed in the JSTOR database, and a gender is only assigned by first name analysis (using the US Social Security database as a reference, so it probably fails for first names not commonly used in the US). Still, it is an absolutely beautiful reference point.

There is an wealth of knowledge in this database, but my interest is in molecular immunology, so how are we performing? Well, the question kind of depends on "compared to what?" In 1991-2010, 29.7% of authors on molecular immunology papers were women. This is an improvement from 1971-1990 (23.9%), and a huge improvement from pre-history (being everything from 1970 and before, at 13.7%). It is also outstanding compared to fields such as mathematics, where women still only account for 10% authors (maths clearly has a problem with women; anyone who says the reverse is kidding themselves). But 29.7% is still a long way from 50%. Even among first authors (typically PhD students or post-docs), only 33.2% of molecular immunology authors were women, and among last authors (typically professors) only a dismal 15.4% were women. 

I've said before what I think the problem is (hint, it is men), but this database gives us a resource to see who is fixing the problem, and how fast, and who is content to live in the stone-age and try to do science with a 50% lobotomy. So many questions arise. Why has virology been more equal than immunology throughout the time period? I would love to see a break-down by country to know if this is a discipline-thing, or is a statistical quirk due to regional differences in sexism correlating by chance with regional differences in research focus.

Oh, and for the trivia-minded, within molecular biology the most equal area of research is heat shock proteins, while the most sexist is prostaglandins. In the entire database, the most female-dominated area of research is gender studies (57.8% female authors), while the most male-dominated area of research is a discipline of mathematics called Riemannian manifolds (99.3% male authors). Check it out.

Aire creates immune tolerance via an unconventional transcriptional mechanism

by Dina Danso-Abeam

The white blood cells of our immune system defend us from infection, a function which is coordinated by T cells. Immature T cells are formed with an ability to attack random targets (an adaptation to the rapid evolution of microbes), which means that by chance some targets are "self-targets" (normal proteins part of a healthy body). As a consequence, these "self-reactive" T cells can atatck the body, so it is critical to prevent them from causing autoimmune disease. To prevent autoimmunity, the immature T cells are screened in an organ called the thymus (located just above the heart), in order to ensure that all self-reactive T cells are eliminated.

The Aire gene plays an important part in eliminating self-raective T cells, by expressing genes that are normally restricted to specific organs (eg, insulin in the pancreas) in the thymus, providing full coverage for screening against self-reactivity. In patients that have mutations in the gene Aire, the thymus cannot provide full coverage of self-targets and fatal autoimmune disease develops. One of the mysteries of how Aire functions is its ability to express thousands of genes like insulin in the thymus. 

It has previously been shown that Aire is a transcription factor (meaning, it can bind DNA to activate genes and cause the expression of proteins) which can activate the expression of other transcription factors. We hypothesized that these secondary transcription factors might mediate the expression of the thousands of Aire-dependent genes like insulin; in effect, we predicted that Aire creates a cascade of transcription factors that results in the expression of thousands of genes.

In order to test this hypothesis, we investigated whether such a cascade regulates the transcription and tolerance of pancreas-specific antigens (e.g. insulin and glucagon) in the thymus. In the pancreas, Pdx1 is the key transcription factor which drives the expression of insulin. Interestingly both Pdx1 and insulin have been shown to be Aire-dependent in the thymus, so it was possible that Pdx1 was acting as a secondary transcription factor in the cascade by which Aire expresses insulin. Therefore we generated mice that specifically lack Pdx1 in the thymus.

By generating these mice, we found that expression of pancreatic-specific antigens such as insulin, needed Aire expression in the thymus, but did not need the transcription factor Pdx1. These results suggest that the broad tolerance that Aire creates in the thymus is not mediated by a conventional cascade of transcription factors, but rather relies on an unconventional transcriptional mechanism.  

This work will be published in a forthcoming issue of The European Journal of Immunology as:

Aire mediates thymic expression and tolerance of pancreatic antigens via an unconventional transcriptional mechanism

by Dina Danso-Abeam, Kim A Staats, Dean Franckaert, Ludo Van Den Bosch, Adrian Liston, Daniel H D Gray* and James Dooley*

Thymic involution: how a chance observation saved years of work

An interview with the VIB following the recent publication of our article:

The thymus is an organ crucial for the functioning of our immune system. During aging or infection the thymus can shrink severely, a process called involution. Although the mediators that trigger involution are known, the mechanisms regulating the sensitivity to their presence remained a mystery. Now, Smaragda Papadopoulou from the Bart De Strooper Lab and James Dooley from the Adrian Liston Lab describe in Nature Immunology a microRNA network that plays a key role. A chance observation kick-started the collaboration.

What did you discover about the regulation of thymic involution?

Adrian Liston: The main finding was the tight regulation by miR-29a over sensitivity to thymic involution. miR-29a serves to suppress the involution response, in effect "saving" involution for those situations where we really need it, such as during a major infection. Knowing what drives the reaction of the thymus is important, since it is the only place where T cells can develop. No thymus, no T cells, no infection prevention.

Is there an application side to those results?

For most of us, being born with a healthy thymus, we will generate enough T cells to last a life-time. Thymus involution during an infection is generally not a problem, nor the slow progressive involution that occurs from birth. The major problem is among the very elderly and with radiation/chemotherapy patients. If we could reverse thymic involution in those populations, we could rejuvenate their T cell population, providing them with a younger, more robust, immune system.

How did you go from studying regulatory T-cells to the regulation of thymic involution?

We have been interested in both the thymic epithelium and microRNA for years, so it was natural for us to look at what microRNA does in the thymic epithelium. As for thymic involution in particular, that was observation-driven. When we knocked out microRNA in the thymic epithelium using a Cre-Lox system, the main phenotype was chronic involution. But working out which microRNA is important was an enormous task. The big breakthrough for us was serendipitous. The Bart De Strooper Lab had generated a novel knockout mouse with a defect in one particular microRNA, miR-29a, to look at the neurophenotype. A conversation, a quick look and just by chance this microRNA turned out to be the one we needed for our lead. This enabled us to start a cross-disciplinary collaboration years before anyone else even knew there was a story there.

Did you use or design any new technologies for this research?

Far from it. The most important read-out in this work was the humble cell count. There are still enormous opportunities for high-level research using basic technologies. In this particular case the edge we had was a new mouse strain (the miR-29a knockout) and a new permutation of old mouse strains (Foxn1-Cre and Dicer-flox), but the rest was simply applying old techniques to a new problem. Immunology has so many fascinating questions that remain under-investigated that we spend our time working out which ones to tackle next, rather than designing new technology.

What’s the next step in your microRNA research?

MicroRNA are such interesting molecules. So tiny, they hold only a fraction of the information of a normal gene, yet they are incredibly versatile, affecting multiple completely unrelated targets in every cell type. We pretty much cracked the role of miR-29a in the thymic epithelium, but we are sure it is doing a lot more in other cell types of the immune system.

For the full research results see:

Aikaterini S. Papadopoulou#, James Dooley#*, Michelle A. Linterman, Wim Pierson, Olga Ucar, Bruno Kyewski, Saulius Zuklys, Georg A. Hollander, Patrick Matthys, Daniel H. Gray, Bart De Strooper and Adrian Liston. #Equal first authors. *Co-corresponding authors. 'The thymic epithelial microRNA network elevates the threshold for infection-associated thymic involution via miR-29a mediated suppression of the IFN-α receptor.' 2012. Nature Immunology. 13 p181.  Pubmed | Direct access