Genetic and molecular mechanisms dysregulating CD4 T cell tolerance in organ-specific autoimmunity

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This project will analyse mechanisms that regulate CD4 T cells and normally prevent the immune system from attacking parts of our own body. Unknown errors in the control of T cells result in autoimmune diseases such as Type 1 diabetes, multiple sclerosis, Addison s disease and thyroid disease, where T cells damage or destroy vital organs. In order to develop rational, specific methods for treating and preventing these diseases, it is necessary to identify and understand the genetic and biochemical mechanisms that normally control T cell responses to self components, and how inherited defects lead these mechanisms to break down. The project focuses on defining how CD4 T cell regulation breaks down in a well established but poorly understood example of polygenic inherited susceptibility to autoimmune disease. Polygenic diseases are those where susceptibility is inherited in a complex way involving many different genes either acting together or in opposition, and the molecular basis for this kind of inheritance is particularly poorly understood. The project will analyse the basis for this kind of inheritance pattern by analysing the direct action of diabetes susceptibility genes at the level of the specific T cells responsible for autoimmune attack and in terms of the biochemical pathways within the T cells that are dysregulated. By identifying the mechanisms and biochemical pathways that are dysregulated in autoimmune disorders, the results of this project will concepts and targets for understanding and diagnosing autoimmune diseases and for developing new drugs or vaccines to prevent T cells damaging vital organs and cure these diseases.