Grant: Operating Grant

Type 1 diabetes (T1D) is an autoimmune disease that happens when the T-cells of the immune system, whose normal job is to attack microbial invaders, mistakenly attack the insulin-producing beta cells in the pancreas. The cause of this loss of self-tolerance is not known and, although genetic predisposition is important, it accounts for about half the causation. Non-inherited DNA mutations that happen after fertilisation could explain some of what is left unexplained. Each of our millions of T-cells recognises one specific substance (antigen). When one T-cell meets its antigen it proliferates to create millions of descendants to fight the enemy. Thus, autoimmune disease is caused by the descendants of a handful of T-cells that mistakenly recognised self-antigen. This rapid proliferation is reminiscent of leukemia, a disease caused by the progeny of a single cell that undergoes vast expansion. During the many cell divisions involved, DNA mutations happen in leukemia that inactivate proliferation controls accelerating the process. We propose that something similar happens when autoreactive T-cells expand. These mutations inactivate tolerance mechanisms rather than proliferation controls. To test this, we examined T-cells from the pancreas of diabetic mice and found non-inherited DNA alterations. We propose to confirm the phenomenon, characterise its chronology and consequences, and identify driver genes whose mutations are causal rather than incidental. We will do similar studies in insulin-reactive T-cells from the blood of diabetic children. Knowledge of the inherited T1D-risk variants has still not uncovered therapeutic targets or lead to personalised medicine because the variants involved are many and the effect of each is small. Somatic mutations, on the other hand, have not been selected against by evolution and their effects would be much larger and, potentially, patient-specific thus creating the ideal conditions for personalised medicine.