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    Type 1 diabetes: do pancreatic beta cells facilitate their own destruction?

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    A study directed by Roberto Mallone

    INNODIA and nPOD has identified the molecules presented by pancreatic beta cells that mediate their abnormal recognition by the immune system and lead to their destruction in type 1 diabetes (T1D). This work stems from a collaboration with the Center for Diabetes Research led by D. Eizirik (Free University of Brussels), the Mass Spectrometry Laboratory at ESPCI in Paris (J. Vinh and Y. Verdier) and the Universities of Siena (F. Dotta) and Pisa (P. Marchetti). These discoveries change our understanding of T1D mechanisms and suggest novel ways to develop vaccines to fight against T1D.

    T1D is caused by the destruction of pancreatic beta cells that produce insulin, which is the hormone that controls blood glucose levels. This destruction is due to a so-called ‘auto-immune’ process, i.e. the abnormal recognition of cells of our own body by the immune system. A white blood cell subset called ‘cytotoxic CD8 T lymphocytes’ inappropriately attacks beta cells by recognizing some signals on their surface in the form of protein fragments (peptides) derived from the beta cells themselves. Despite its increasing frequency (+4% per year in the Western world), T1D treatment is today limited to replace the insulin that is not anymore produced by the pancreas through multiple daily injections. A better understanding of the molecular mechanisms underlying this auto-immune recognition would allow to develop vaccine tools to avoid beta-cell destruction.

    In T1D, lymphocytes mistakenly attack beta cells as they would do with infected cells. They do so by recognizing peptides presented on the surface of beta cells, thus docking on these cells before destroying them. Despite this notion, the origin of these peptides remained unknown till present.

    The group of R. Mallone has now identified these peptides in a study published in the journal Cell Metabolism. Using peptidomics and transcriptomics techniques that allow the analysis of large datasets, R. Mallone’s group has provided an exhaustive inventory of the peptides presented on the beta-cell surface. While some of them displayed an expected structure, some others were produced by aberrant processes within the beta cell. Moreover, these peptides were more abundantly exposed when beta cells were inflamed, as is the case in T1D. The analysis of circulating lymphocytes in the blood has shown that in all individuals, whether healthy or diabetic, these lymphocytes are able to recognize the identified peptides. On the contrary, it is only in T1D patients that this recognition takes place in the pancreas.

    These results are important for several reasons. First, the identification of the peptides targeted by T1D auto-immunity improves our understanding of T1D mechanisms, suggesting that the beta cell is not an innocent victim but may actively contribute to its own demise by making itself more visible via the exposition of the incriminated peptides and thus more vulnerable to lymphocytes. This may explain why these cytotoxic lymphocytes are more abundant than in healthy individuals in the pancreas of T1D patients (where they are exposed to more ‘visible’ beta cells), but not in the blood (where they have not entered in contact with beta cells).

    Second, these newly identified peptides can now be used to produce vaccines to prevent and treat T1D. Contrary to traditional vaccines, the aim will here be to neutralize rather than boost immune responses. Roberto Mallone’s group is actively working to develop vaccines of this kind, which can be administered through the oral route to minimize discomfort and risk. 

     

    Illustration

    The immune image of the Beta cell

    On the cover: the pancreatic beta cell is targeted by autoimmune T lymphocytes in type 1 diabetes. T lymphocytes can dock on beta cells through recognition of as yet unknown peptides presented in the frame of HLA Class I molecules. Gonzalez-Duque et al. identify these peptides and show that they are recognized by T lymphocytes that are enriched in the pancreas, but not in the blood, of type 1 diabetic patients. The illustration shows the Queen Beta Cell in front of her mirror, wearing her crown of phospholipid membrane decorated with peptide emeralds mounted on HLA molecules. This ‘immune image’ captures the attention of T lymphocytes in the pancreas, but not of those in the blood. Cover art by Diego Andidero & Claudia Schembari.

     

    Reference

    Sergio Gonzalez-Duque, Marie Eliane Azoury, Maikel L. Colli, Georgia Afonso, Jean-Valery Turatsinze, Laura Nigi, Ana Ines Lalanne, Guido Sebastiani6, Alexia Carré, Sheena Pinto, Slobodan Culina, Noémie Corcos, Marco Bugliani, Piero Marchetti, Mathieu Armanet, Marc Diedisheim, Bruno Kyewski, Lars M. Steinmetz, Søren Buus, Sylvaine You, Daniele Dubois-Laforgue, Etienne Larger, Jean-Paul Beressi, Graziella Bruno, Francesco Dotta, Raphael Scharfmann, Decio L. Eizirik, Yann Verdier, Joelle Vinh, Roberto Mallone. Conventional and neo-antigenic peptides presented by β cells are preferentially targeted in the pancreas, but not in blood, of type 1 diabetic patients. Cell Metabolism, august 2 2018.

     

    Contact

    Team Immunologie des diabètes