Identification of the driver of autoimmunity and early intervention before established disease is urgently needed. As in many autoimmune diseases, viral infections have been associated with T1D, recently confirmed by large and highly sensitive screenings using well–characterized material from autopsy and biopsy. We looked closer into the pancreases from organ donors with early T1D–associated autoimmunity before T1D diagnosis and with established T1D and found the factor YAP, co–transcriptional activator of the Hippo cell and organ developmental pathway highly increased. Absent in mature functional beta–cells, YAP was especially found in areas of enterovirus–infected cells which remain deposited in the pancreas long after acute viral infection and drive inflammation and immune cell infiltration. Such changes in the exocrine pancreas have been completely overlooked. To our surprise, in a scenario of T1D, YAP did not balance the immune response but acted oppositely of what has previously been known; it potentiated the deleterious effect of the enterovirus and constituted a vicious cycle; YAP increased virus load, inflammation and cell death in both exocrine and endocrine cells. Eventually, even YAP+–cells migrated into islets. Our project shifts two paradigms: we hypothesize that (1) autoimmune diabetes starts in the exocrine pancreas with areas of inflammation and immune infiltration and (2) YAP acts as early driver of autoimmunity and T1D by potentiating inflammatory signals towards immune cell attack and damage to beta–cells. Our analyses will explain the early pathology seen very early even in first degree relatives (FDR) of patients with T1D, who have already reduced pancreas mass. The objective of this exploratory project is to unravel how YAP expression in viral+ cells in the pancreas fosters T1D initiation and progression and how this cycle of inflammation can be interrupted to establish an early pharmaceutical intervention against autoimmunity andT1D.
