In the 1980s, not many people were interested in the intestinal immune system… Forty years later, the terms “gluten sensitivity” or “microbiota” have become established in common usage. A spotlight to which the work of Nadine Cerf-Bensussan has contributed significantly and which is recognized with the Grand Prix Insert.
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Giving intestinal immunity its effect
Nadine Cerf-Bensussan, Inserm Research Director, has been at the helm of the laboratory for more than four decades Gut immunity at the Imagine Institute in Paris is interested in the intestinal immune system, which protects us from pathogens and is tolerant at the same time nutrient and the millions of bacteria in the microbiota. An ambivalent role that she studies to understand intestinal pathologies, including gluten-induced celiac disease, as well as the connections between the intestinal microbiota and its host. His approach, which was awarded the Inserm Grand Prix, has enabled him to improve the diagnosis of often serious diseases and to identify treatment options.
Although gut immunity is now the focus of much work and is becoming better understood, it received little attention when Nadine Cerf-Bensussan became interested in it. His entry into the field “is interrupted by chance, a little luck and access to extraordinary places”, she emphasizes. So chance led her to her first hospital internship in Claude Griscelli’s Department of Immunology and Hematology at Necker-Enfants Malades Hospital. “An extraordinary place! There was a desire to understand very serious immune diseases in young children in order to better care for them. At her side, we had the impression that we were asking ourselves real questions, She adds. Later, the guards at the François Vachon Infectious Diseases Intensive Care Unit at the former Claude Bernard Hospital, another extraordinary place, sparked my interest in immunology and infectious diseases. Finally, it all started in 1978 when Claude Griscelli, after training in immunology and pediatrics, agreed for me to become an intern in his department. »
A deep passion for research that emerged across the Atlantic
Another happy coincidence: in 1980, her husband received a contract at the Massachusetts Institute of Technology in Boston, USA. This is the opportunity for Nadine Cerf-Bensussan to anticipate her research training. She is completing a DEA, the equivalent of Master 2, with Delphine Guy-Grand, an anatomopathologist who, along with Claude Griscelli, developed groundbreaking work on intestinal immunity in mice. “By offering to work with Delphine and use my American stay for further development antibody ” She suggests. With her DEA and a scholarship in hand, she landed an internship with Atul K. Bhan’s team at Massachusetts General Hospital in Boston She developed her first antibody against rat intestinal lymphocytes.
When she returned to Paris in 1983, she resumed her internship at the Necker Hospital with Alain Fischer as clinic manager and then considered a clinic in that department. But, ” At the end of a complicated pregnancy, the dean refused me the proposed position and even praised the benefits of prolonged breastfeeding … she tells. It was shocking, but I dedicated myself to research, an activity that fascinated me and which would have been difficult for me to reconcile with the work of caring for seriously ill children and their families. »
Bilateral lymphocytes
Nadine Cerf-Bensussan received a receptionist position at Inserm, then passed the competition as research manager in 1987 and then continued her work in the team of Claude Griscelli – who was general director of Inserm from 1996 to 2001. She developed the first one Antibodies against human intraepithelial lymphocytes and sees celiac disease as a model for studying the role of these lymphocytes and, more generally, intestinal immunity. In fact, it provides the first evidence that this is the case probably to protect the epitheliumbut that’s what they are at the origin of Lymphomas which represent the most serious complication of celiac disease. Intraepithelial lymphocytes appeared to be the “Doctor Jekyll and Mister Hyde” of the intestine, which was confirmed by the work of the team the researcher founded in 1998 at Necker Medical School.
In collaboration with gastroenterologists Christophe Cellier and Georgia Malamut, she shows that intraepithelial lymphocytes in patients come under the influence of inflammatory molecules, particularly interleukin 15, which leads to inflammation attack the intestines or, if they have acquired certain mutations can cause lymphoma. “Our work opens up therapeutic possibilities, the benefit-risk ratio of which we are investigating. In fact, certain treatments could promote the emergence of resistant malignant cells or blunt antitumor responses. We must therefore remain cautious,” emphasizes the researcher.
A key bacteria for our internal immunity
The creation of the team also marks the opening to new topics, including the study of interactions between the host and its microbiota. “We became interested in this thanks to François Taddei, an evolutionary microbiologist and neighbor of our laboratoryemphasizes Nadine Cerf-Bensussan. He tried to understand why a strain of bacteriaEscherichia coli The lab acquired adaptive mutations when he implanted them into the intestines of a sterile mouse. » A question that coincided with the arrival in the team of Valérie Gaboriau-Routhiau, who specializes in the controlled colonization of sterile mouse models. “ However, contrary to our hypothesis, these mutations were not selected by the mouse’s immune response, but rather by the bacteria’s need to resist bile acids in the intestinal lumen. explains Nadine Cerf-Bensussan. Another surprise is the immune response this triggers E. coli was modest and challenged the general assumption that all gut bacteria could induce postnatal maturation of gut immunity. » In fact, the team demonstrated the key role of segmented filamentous bacteria. This work contributed to the creation of this bacterium, “A star of gut immunity! However, a comparable role in the maturation of the intestinal immune system has not been demonstrated in humans. annoys the researcher whose team continues to study the bacteria in question. In particular, she tries to decipher the mechanisms of action and the way in which the host controls its spread in the intestine. These studies are also continued by Pamela Schnupf, who now leads her own team, having developed a cultivation method that consists of it the epithelial cells that the segmented filamentous bacteria absolutely need to live.
In the early 2000s, research into the microbiota was just beginning. “We were among the pioneers. For this reason, Yves Lévy, then President and CEO of Inserm, tasked me with coordinating the interdisciplinary microbiote program in 2016. brings Nadine Cerf-Bensussan forward. In fact, the relationships between the microbiota and its host are now the subject of extensive work, and the Food Microbiome Priority Research Program and Equipment (PEPR) launched by the state should further accelerate research and promote its national coordination. »
The genetic origins of intestinal diseases
Against this background, the team was integrated into the Imagine Institute in 2014 “A very great opportunity and chance to develop a new topic around genetic intestinal diseases, which are still little researched in France,” explains Nadine Cerf-Bensussan. The team then sets two goals: to better understand the development and functioning of human gut immunity and to establish a diagnostic platform to improve patient care. This ambitious project is financially supported by the European Research Council ERC Advanced Grant funding.
In collaboration with Frank Rümmele, gastroenterologist, pediatrician and co-head of the reference center for rare digestive diseases in Necker, the team developed a cohort of patients with suspected monogenic intestinal disease. Today there are more than 700 children and a growing number of adults. Already, About 30% of them had a genetic diagnosis. This work enabled Fabienne Charbit-Henrion to develop a diagnostic tool based on high-throughput sequencing as a team during her thesis work. The latter now uses it “routinely” in the Molecular Genetics Department at Necker Hospital, “testing” a panel of 150 genes that are updated as new identifications are made. These diagnoses have a significant impact on patient care as they influence the choice of the most appropriate treatment. Finally, starting from the identification of these genes, the team aims to create a catalog of those that are essential for the balance of the intestinal barrier and, if they are little or poorly known, to define their precise role.
Gut immunity has not yet revealed all its secrets. Nevertheless, Nadine Cerf-Bensussan is already happy about the imitation, especially among the researchers who were trained in her team. In the same sense, “I am very pleased to receive this top prize, which I see as a recognition of the importance of this interface, which is constantly exposed to a significant amount of microbes and the diverse components of our food and our environment. she emphasizes. It’s as if we gave the prize to the intestines! »
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