Altered immune regulation in type 1 diabetes

Abstract

Research in genetics and immunology was going on separate strands for a long time. Type 1 diabetes mellitus might not be characterized with a single pathogenetic factor. It develops when a susceptible individual is exposed to potential triggers in a given sequence and timeframe that eventually disarranges the fine-tuned immune mechanisms that keep autoimmunity under control in health. Genomewide association studies have helped to understand the congenital susceptibility, and hand-in-hand with the immunological research novel paths of immune dysregulation were described in central tolerance, apoptotic pathways, or peripheral tolerance mediated by regulatory T-cells. Epigenetic factors are contributing to the immune dysregulation. The interplay between genetic susceptibility and potential triggers is likely to play a role at a very early age and gradually results in the loss of balanced autotolerance and subsequently in the development of the clinical disease. Genetic susceptibility, the impaired elimination of apoptotic β -cell remnants, altered immune regulatory functions, and environmental factors such as viral infections determine the outcome. Autoreactivity might exist under physiologic conditions and when the integrity of the complex regulatory process is damaged the disease might develop. We summarized the immune regulatory mechanisms that might have a crucial role in disease pathology and development.

Figure 1

In addition to proinflammatory cytokines such as IL-1 and IFN-γ, the signaling via IFIH1 and various other pathogen recognition receptors mediate β-cell apoptotic death: upregulate certain BH3 proteins and also promote the secretion of numerous chemokines. Certain BH3 “sensitizer” proteins, for example, DP5, bind to BCL2 and BCL-XL which inhibit BAX and BAK activation and at the same time liberate the “activator” proteins (such as BIM and PUMA). PTPN2 is a negative regulator of the pancreatic β-cell apoptosis that reduces the BH3 protein-related apoptotic activation cascade in the β-cell.