Photo credit: Ine Eriksen, UiO
For those living with celiac disease, every meal comes with a question: Is this truly safe to eat? While the gluten-free diet is the only available treatment, researchers are working tirelessly to uncover the immune system’s hidden mechanisms that drive this disease—offering hope for future therapies. One of the biggest mysteries? Why the immune system mistakenly attacks the body’s own tissues after gluten exposure. Thanks to groundbreaking research by Dr. Fleur du Pré, the latest findings are helping to piece together this complex puzzle.
The Celiac Disease Foundation is proud to announce that Dr. Fleur du Pré, a researcher at the University of Oslo/Oslo University Hospital, has been awarded the ISSCD – Celiac Disease Foundation Research Fellowship Award, a $300,000 grant for her research dedicated to unraveling the complex immune mechanisms behind celiac disease. The International Society for the Study of Celiac Disease (ISSCD) is a global organization that brings together national celiac societies, researchers, and healthcare providers to advance scientific knowledge, collaboration, and understanding of celiac disease. By partnering with ISSCD to fund this award, the Celiac Disease Foundation aims to strengthen global collaboration and drive research advancements in celiac disease diagnosis and treatment.
For individuals and families affected by celiac disease, Dr. du Pré’s research represents hope for more effective therapies. Read our interview with Dr. du Pré below:
Please tell us about yourself and your background in celiac disease research. What drew you to the field of celiac disease research?
I’m an experimental immunologist with solid experience in the field of celiac disease. I developed my interest for celiac disease during my PhD research in the lab of Professor Janneke Samsom at the Erasmus University Medical Center in Rotterdam, the Netherlands where I was studying the induction of immunological tolerance to food proteins in the intestine.
The role of our immune system is to protect us against pathogens such as viruses and bacteria. But in the intestine the immune system faces an exceptional challenge. While it needs to be ready to always respond to threats in case of a viral or bacterial infection, it also needs to induce tolerance to all the harmless substance such as food proteins that enter the gut. The immune tolerance response is the ‘default’ outcome of an immune response in the intestine. But in patients with celiac disease, something goes wrong and the tolerance to gluten is lost. I became interested in how and why the immune system of individuals with celiac disease misinterprets gluten as something dangerous. After my PhD I joined the group of Professor Ludvig Sollid at the University of Oslo/Oslo University Hospital, Norway which is a world leading research environment on celiac disease immunology to continue my training and explore these questions.
Can you share an overview of your current research project? What question or challenge are you setting out to address?
Patients with celiac disease develop antibodies to a component of the body itself: the enzyme transglutaminase 2 (TG2). These so-called autoantibodies are only produced when the patients are consuming gluten. The goal of our research is to understand how these autoantibodies are formed when gluten is present. Two specific cell types of the immune system are important for the production of antibodies, the B cells and the T cells. B cells are the cells that become antibody producers. The B cells have molecules on their cell membrane called B cell receptors that can recognize (foreign) molecules or “antigens”. To start producing antibodies, the B cell needs to take up and present the antigen that bound to its receptor to a T cell. If the T cell recognizes the antigen, the B cell and T cell talk together so that the B cell starts to produce antibodies.
We believe that in celiac disease the crosstalk between B cells that recognize TG2 and T cells that recognize gluten drives disease development, and that disrupting this interaction offers a potential new treatment strategy. It is therefore important to understand how TG2-specific B cells and gluten-specific T cells talk to each other. It’s not a coincidence that patients with celiac disease make antibodies to TG2. The enzyme deamidates gluten, a modification that makes gluten more easily recognized by gluten-specific T cells. During the deamidation reaction, TG2 forms a short-lived complex with gluten: we think that these complexes explain why TG2-specific B cells and gluten-specific T cells can talk to each other. A big unsolved question is however where in the body TG2, gluten, B cells and T cells come together. This has not been possible to study because we have not had the proper animal models to do so.
What is so essential about your research?
Over the last 10 years, we have developed advanced humanized mouse models that will allow us to study celiac-disease relevant T cell-B cell crosstalk. The mice have got introduced to their genomes T cell and B cell receptors from TG2 specific B cells and gluten specific T cells isolated from celiac disease patients. Using these genetically engineered mice we have recently developed models that allow us to study where and how this B cell-T cell crosstalk happens in the small intestine.
Do you have an analogy to help people understand your work?
I think that doing research can be compared to putting together pieces of a puzzle without knowing how the picture will look like. We are figuring out the picture bit by bit as we go. For my current project, many pieces have already been put together and we can start to clearly see the scene the puzzle is depicting!
What is the potential impact of your research on celiac disease understanding, treatment, and patient quality of life?
We believe that therapies that would interfere with the crosstalk between gluten-specific T cells and TG2-specific B cells could be promising new treatment strategies for celiac disease patients. Inhibition of the enzymatic activity of TG2 has already been shown to be a very promising therapeutic approach for celiac disease. But it is unclear where the enzyme TG2 is active and thus also where the TG2 inhibitors are effective as drugs. Hopefully findings from our research can contribute to the development of improved TG2 inhibitors or B-cell directed therapies for the treatment of celiac disease.
What message would you like to convey to individuals and families affected by celiac disease?
From an immunological point of view, we have a pretty good understanding of what goes wrong when a patient with celiac disease consumes gluten. Many years of scientific research, often addressing fundamental immunological questions has already resulted in promising drug therapies being in development. Yet, there are a few important unknowns that we need to understand to be able to offer better treatment or potentially a cure. We have been able to develop such advanced models in celiac disease because patients willingly participate in research and donate blood and biopsies. I am confident that this investment will pay off and that alternatives to the gluten-free diet will be available for patients in the future and will reduce the burden of living with celiac disease. And of course, I would like to thank all the patients who have over the years participated in clinical and translational research studies!