Recent update: chronic nature of beta cell autoimmunity
by Adam Burrack, PhD
Regular readers of this series will be aware that the network of pancreatic organ donation, operated through the University of Florida and collaborating institutions and funded by the JDRF, has been a boon to research of type 1 diabetes (T1D) pathogenesis. Today I will delve into a cutting-edge study that investigated the degree of “infiltration” of cells of the immune system into pancreas, and looked for correlations with degree of production of autoantibodies (our current best indicator of beta cell-specific immune responses), duration of disease, and age at T1D onset.
A very recent manuscript from the nPOD consortium and published in the journal Diabetes demonstrates an inverse correlation between degree of T cell and B cell infiltration in the pancreatic islets (where beta cells and alpha cells are located) and duration of type 1 diabetes. In essence, there are more immune cells in the T1D pancreas closer to disease onset, regardless of age at onset. The influence of genetics could be summed up as setting the stage for autoimmunity to develop. The environmental triggers that push the system over the “tipping point” are still poorly understood.
In a nutshell, these important results suggest that cells of the immune system not only specifically target insulin-producing beta cells for destruction, but that (1) this process is not complete at clinical diagnosis of diabetes (supporting and expanding on previous nPOD findings), and (2) once “all” of the beta cells are destroyed, cells of the immune system by-and-large leave the pancreas. Since there are no more insulin-producing beta cells to be destroyed, in the simplest model of the disease, the immune cells would no longer have any reason to remain within the islets. This study is more powerful than earlier publications because researchers had access to the entire pancreas in this protocol, so could literally analyze every single islet in these donated organs. These large groups of analysis facilitate much more clear conclusions than earlier studies in which only portions of diseased pancreata were analyzed.
Results in this study demonstrated greater levels of immune cell infiltration into the pancreas if there was remaining beta cell mass, suggesting the autoimmune attack leading to a type 1 diabetes diagnosis and insulin dependence occurs for many months – possibly years – following diagnosis. To quote the authors of this study, “… our findings support the existence of a potential long window of therapeutic opportunity.”
This is an exciting time to be working in this field. During this “therapeutic window” many interventions can be attempted. Some of these interventions will be T cell-specific, some will be beta cell-specific. Most likely, the most effective strategies will influence the behavior of both T cells and beta cells, as well as other cells of the immune system and perhaps glucagon-producing alpha cells as well. As we, as scientists, learn more about the regulation of T cell responses and the ability of beta cells to proliferate in the absence of continual waves of destruction by T cells, the field will hopefully develop more rational methods to perturb the autoimmune disease process and promote beta cell survival.