Why does the immune system destroy pancreatic β-cells but not α-cells in type 1 diabetes?

In type 1 diabetes, the immune system destroys pancreatic beta-cells but not neighbouring alpha-cells. Here, the authors describe the key differences between beta-cells and alpha-cells that could account for their differential autoimmune vulnerability, and how these differences could result in the preferential endurance and survival of alpha-cells over beta-cells. A perplexing feature of type 1 diabetes (T1D) is that the immune system destroys pancreatic beta-cells but not neighbouring alpha-cells, even though both beta-cells and alpha-cells are dysfunctional. Dysfunction, however, progresses to death only for beta-cells. Recent findings indicate important differences between these two cell types. First, expression of BCL2L1, a key antiapoptotic gene, is higher in alpha-cells than in beta-cells. Second, endoplasmic reticulum (ER) stress-related genes are differentially expressed, with higher expression levels of pro-apoptotic CHOP in beta-cells than in alpha-cells and higher expression levels of HSPA5 (which encodes the protective chaperone BiP) in alpha-cells than in beta-cells. Third, expression of viral recognition and innate immune response genes is higher in alpha-cells than in beta-cells, contributing to the enhanced resistance of alpha-cells to coxsackievirus infection. Fourth, expression of the immune-inhibitory HLA-E molecule is higher in alpha-cells than in beta-cells. Of note, alpha-cells are less immunogenic than beta-cells, and the CD8(+) T cells invading the islets in T1D are reactive to pre-proinsulin but not to glucagon. We suggest that this finding is a result of the enhanced capacity of the alpha-cell to endure viral infections and ER stress, which enables them to better survive early stressors that can cause cell death and consequently amplify antigen presentation to the immune system. Moreover, the processing of the pre-proglucagon precursor in enteroendocrine cells might favour immune tolerance towards this potential self-antigen compared to pre-proinsulin.