Do pancreatic beta cells facilitate their own destruction?
13. August 2018
Type 1 diabetes: do pancreatic beta cells facilitate their own destruction?
A study led by R. Mallone 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). These discoveries change our understanding of T1D mechanisms and suggest novel ways to develop vaccines to fight against T1D.
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. They 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, they improve 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 exposure 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. R. 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.
Figure - The immune image of the pancreatic beta cell
In type 1 diabetes, the pancreatic beta cell is targeted by auto-immune cytotoxic T lymphocytes. These lymphocytes can dock on beta cells through the recognition of peptides of unknown origin, which are associated with HLA molecules on the surface of beta cells. Gonzalez-Duque et al. have identified and characterized 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 image shows the Queen Beta Cell in from of her mirror, wearing her cell membrane crown 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. Art image by Diego Andidero & Claudia Schembari.
Sergio Gonzalez-Duque, Marie Eliane Azoury, Maikel L. Colli, Georgia Afonso, Jean-Valery Turatsinze, Laura Nigi, Ana Ines Lalanne, Guido Sebastiani, 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 targeted by circulating naïve CD8+ T cells in type 1 diabetic and healthy donors. Cell Metabolism, 2018.