Autoimmune Genetics Laboratory on the front cover of Cellular and Molecular Life Sciences

Our recent analysis of the function of microRNA-29 in the adaptive immune system was features on the front cover of the latest issue of Cellular and Molecular Life Sciences.

Adrian Liston, Aikaterini S Papadopoulou, Dina Danso-Abeam and James Dooley. ‘MicroRNA-29 in the adaptive immune system: setting the threshold’. 2012. Cellular and Molecular Life Sciences. 69(21) p3533. Pubmed | Direct access 

We also did some science

Lab retreat 2012 photos

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*

AIG laboratory members successful at the FWO

This week we received exciting news that the Autoimmune Genetics laboratory had three successful candidates at the FWO, the premier fellowship program in Belgium. 

Dr Stephanie Humblet-Baron won an FWO Post-doctoral Fellowship award to research a new genetic disease caused by a loss of dendritic cells:

In the immune system, dendritic cells (DCs) are a subset of white blood cells that are specialized to activate lymphocytes when a pathogen is present In the absence of DCs, activation of lymphocytes and clearance of infections is impaired.  A new genetic disease has recently been identified where patients have no DCs, and surprisingly not only do they have poor clearance of infections, but they also have a large expansion of myeloid cells in their blood. For this project we have created a mouse model of this disease, which we will use to try to understand the biology of the myeloid expansion and to test potential therapeutics. 

Dr Susan Schlenner won a Pegasus Post-doctoral Fellowship award to move to the laboratory from Harvard. Here she will use novel genetic approaches to understand the biology of regulatory T cells.

Regulatory T cells are an important subset of white blood cells that have the ability to prevent the immune system from attacking components of the body (“autoimmunity”) and from attacking harmless environmental components (“allergy”). In order to exert this function the regulatory T cells need to be educated as to which components are safe and should be protected from immune attack. The location where this occurs is highly controversial as previously there have not been the correct tools to do functional tests. This project aims to generate a sophisticated set of genetically-altered mouse strains to allow measurement of where regulatory T cells are educated, and then to use these mice in models of autoimmunity and allergy. Having more knowledge about the education process of regulatory T cells may allow the future development of therapeutic interventions in those patients where regulatory T cells fail to prevent autoimmunity or allergy.

Dr Lien Van Eyck won an FWO PhD Fellowship, to move from the clinic to the laboratory to study auto-inflammatory diseases.

Blau Syndrome (BS) and Early Onset Sarcoidosis (EOS) are rare monogenic auto-inflammatory diseases characterized by a clinical triad of granulomatous arthritis, uveitis and rash. Extended manifestations with potentially high morbidity have been reported recently. The pathologic hallmark of BS/EOS is the presence of multinucleated giant cell and epithelioid cell granulomas in affected tissues. Both diseases are associated with gain-of-function mutations in the NOD2 gene. NOD2 is a specialised intracellular protein that plays a critical role in the regulation of the host innate immune response through recognising conserved microbial molecular signatures, thus leading to the induction of pro-inflammatory and anti-microbial responses as well as apoptosis. While the genetic basis of BS/EOS has been characterized, the molecular mechanisms by which NOD2 mutations drive granuloma formation and the development of sarcoidosis remain unclear. A better understanding of these mechanisms is of direct relevance for the development of targeted immunotherapies. The present project aims to determine the mechanisms by which NOD2 gain-of-function mutations lead to immunopathology in BS/EOS by developing a murine model with a gain-of-function mutation in NOD2. This model will allow for a full characterization of the immunopathology of NOD2 associated inflammation, and for the unravelling of molecular and cellular mechanisms involved in disease pathogenesis.

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

Autoimmune Genetics Laboratory in the news

In De Staandard, 26th July

KUL en VIB boeken doorbraak in strijd tegen immuunziekten

De K.U.Leuven en het VIB (Vlaams Instituut voor Biotechnologie) hebben een stap voorwaarts gezet in de strijd tegen immuunziekten.

De onderzoekers ontdekten een nieuw type cellen dat kan helpen om het evenwicht te bewaren tussen een overactief en een onvoldoende actief immuunsysteem. Dat laten beide instellingen dinsdag weten in een mededeling.

Talloze mensen lijden aan een ziekte van het afweer- of het immuunsysteem. Als het systeem overactief is, kan dat leiden tot allergieën en auto-immuunziekten zoals Systemische lupus erythematosus (afgekort SLE), een aandoening waarbij het afweersysteem zich op overdreven wijze tegen het eigen lichaam richt. Maar is het afweersysteem onvoldoende actief, dan treden infecties of tumoren op. Het juiste evenwicht vinden, is dus essentieel.

Adrian Liston, van het VIB en de K.U.Leuven, is een nieuw type cellen op het spoor die helpen om dat evenwicht te bewaren. De ’folliculaire regulatorische T-cellen’ (Tfrs) zetten een rem op de groei van afweercellen die antistoffen aanmaken. Verder onderzoek zal het uiteindelijke belang van de Tfr-cellen moeten uitwijzen.

In Het Nieuwsblad, 26th July

KUL en VIB boeken doorbraak in strijd tegen immuunziekten

De K.U.Leuven en het VIB (Vlaams Instituut voor Biotechnologie) hebben een stap voorwaarts gezet in de strijd tegen immuunziekten.

De onderzoekers ontdekten een nieuw type cellen dat kan helpen om het evenwicht te bewaren tussen een overactief en een onvoldoende actief immuunsysteem. Dat laten beide instellingen dinsdag weten in een mededeling.

Talloze mensen lijden aan een ziekte van het afweer- of het immuunsysteem. Als het systeem overactief is, kan dat leiden tot allergieën en auto-immuunziekten zoals Systemische lupus erythematosus (afgekort SLE), een aandoening waarbij het afweersysteem zich op overdreven wijze tegen het eigen lichaam richt. Maar is het afweersysteem onvoldoende actief, dan treden infecties of tumoren op. Het juiste evenwicht vinden, is dus essentieel.

Adrian Liston, van het VIB en de K.U.Leuven, is een nieuw type cellen op het spoor die helpen om dat evenwicht te bewaren. De ’folliculaire regulatorische T-cellen’ (Tfrs) zetten een rem op de groei van afweercellen die antistoffen aanmaken. Verder onderzoek zal het uiteindelijke belang van de Tfr-cellen moeten uitwijzen.

Balance of the immune system determined by newly discovered T cells

From the VIB Press release: A newly discovered cell type helps to determine the balance of the immune system. The cells are derived from FoxP3(+) regulatory T cells, which recently have been demonstrated to suppress disease during transplantation. Nature Medicine and Blood, two high-ranking scientific journals, are publishing findings by the Autoimmune Genetics Laboratory about this discovery.

 

Innumerable people suffer from immune system disorders. If the immune system is overactive, it can result in allergies and autoimmune diseases such as Systemic lupus erythematosus (SLE). If the immune system is not active enough, infections or tumors occur. It is therefore essential to maintain the right balance.

 

The Autoimmune Genetics Laboratory is investigating a new type of cell that helps to maintain this balance. These ‘follicular regulatory T cells’ (Tfrs) suppress the process by which antibodies are produced during infections and SLE. The Tfrs themselves are daughter cells of FoxP3(+) T cells, key regulators of the immune system.

 

From lupus to cancer

In order to prevent disease the immune system needs to be in balance. If the system is too active, it produces antibodies against harmless substances, as is the case with allergies. An overactive immune system can even attack the body’s own tissues, causing autoimmune diseases such as lupus, rheumatism and diabetes. However, an insufficiently active immune system opens the way for rampant infections and tumors.

 

A complex network of regulatory cells is active to maintain this balance in our bodies. This must ensure that the immune system is sufficiently active and selective so that pathogenic intruders are recognized and eliminated in good time, but at the same time that it does not get out of control. This network of regulatory and activating cells is a long way from being fully unraveled. Dozens of researchers around the world are working to map this network.

 

This Tfr research is a joint collaboration between researchers from VIB-K.U.Leuven, the Australian National University (Aus) and the University of Cambridge (U.K.).

 

Publications

Linterman et al, Foxp3(+) follicular regulatory T cells control the germinal center response, Nat Med, 2011, doi:10.1038/nm.2425

 

Tian et al, Foxp3+ regulatory T cells exert asymmetric control over murine helper responses by inducing Th2 cell apoptosis, Blood, 2011, doi:10.1182/blood-2011-04-346056

FWO post-doctoral fellowship awarded to Bénédicte Cauwe

This week it was announced that Dr Bénédicte Cauwe won an FWO post-doctoral fellowship to perform research in the Autoimmune Genetics Laboratory. Dr Cauwe recently finished her PhD in the laboratory of Professor Ghislain Opdenakker at the Rega Institute and will continue her research on systemic lupus erythematosus at the Autoimmune Genetics Laboratory.

IRO fellowship won by Dina Danso-Abeam

Today it was announced that Ms Dina Danso-Abeam in the Autoimmune Genetics Laboratory was awarded an IRO fellowship to perform research towards her PhD. 

The Autoimmune Genetics Laboratory in 2010

All the members of the Autoimmune Genetics Laboratory, at our end of year dinner.