Figure 4.

ER stress in T1D and T2D pathogenesis. In patients with T1D or T2D, ER stress, tissue barrier dysfunction, or a breakdown in the integrity of the intestines or other organs may be responsible for generating “new” surface proteins, or neo-proteins, leading to antigen activation of innate and adaptive proinflammatory (PI) immune cells and cytokines. These antigen-activated PI immune cells and cytokines may then circulate in the periphery, setting up systemic inflammation. The resulting systemic inflammation creates insulin resistance and allows for the PI cells and cytokines to target other tissues and organs. The arrival of antigen-activated immune cells and circulating PI cytokines may create ER stress in susceptible β-cells of the pancreas and other organs and tissues (e.g., adipose). The development of ER stress in islet β-cells and other tissues may produce altered self-proteins, contributing to the initiation of an autoimmune response. The PI immune cells in the pancreas may recognize the “novel” islet proteins or the proteins resulting from β-cell apoptosis or ER stress. These ER proteins may be the same proteins that are released during ER stress in the intestines or other tissues (adipose tissue), adding to the potential cross-reactivity between various tissues. Alternatively, the ER stress in the β-cell may develop novel proteins that stimulate autoreactive immune cells that are specific to the ER proteins of the pancreas. Differences in genetics, the robustness of the immune responses, antigen presentation, environmental antigens, or microbial antigens may underlie the differences in autoimmune reactivity between T1D and T2D. Immune responses in older individuals may need to be magnified as a result of a less robust immune system by adding inflammation in other tissues/organs in order to shift the immune balance toward autoimmunity. Autoreactive cells and PI cytokines may also migrate to other organs, establishing autoimmunity or cancer.