Figure 3.
Suggested model for the role of citrullination in the induction of autoreactive responses in T1D. In this proposed model, different forms of cell death, i.e. beta-cell apoptosis and neutrophil death (NETosis), are both implicated in the generation of citrullinated proteins. Any form of environmental stress, such as viruses, inflammatory cytokines or high metabolic demand, can induce oxidative and ER stress in the beta-cells. Oxidative stress induces NETosis. Both beta-cell apoptosis and NETosis have been shown to be involved in T1D initiation and propagation. With expression and activation of PADs during stress conditions, this model suggests that both beta-cells and neutrophils, can induce citrullination. These citrullinated peptides/proteins may be processed by the immune system in different immunogenic ways, forming a source of citrullinated autoantigens. Processing of these modified proteins/peptides by antigen presenting cells, and subsequent presentation to T cells, can in turn trigger several immune responses, including activation of B cells (producing islet autoantibodies) and islet antigen-specific (effector/memory) T cells that can directly kill beta-cells presenting citrullinated islet peptides. The expression of PAD enzymes in beta-cells and neutrophils, and their activation during processes of cellular stress, underscores the relevance of this model. Dashed arrows indicate the potential interactions between B cells and CD8+ T cells and between B cells and DCs. BCR, B cell receptor; TCR, T-cell receptor.