Identification, characterization and application of autoantigens in type 1 diabetes mellitus

Type 1 diabetes mellitus or insulin dependent diabetes mellitus is a disease characterized by the selective destruction of insulin producing B-cells in the islets of Langerhans. The exact cause of this destruction is unknown, but is mediated by cells of the immune system. The immune system has a remarkable ability to recognize self from non-self, thereby providing a constant surveillance-mechanism that protects us for foreign invaders. This mechanism has failed in type 1 diabetes and attacks and destroys B-cells. The autoimmune basis of type 1 diabetes is described in chapter 1. The central problem in autoimmunity is why and how the immune system sometimes fails to distinguish between self and non-self. Re-instructing the immune system or blocking faulty immune reactions could result in primaryor secondary prevention of type 1 Diabetes Mellitus. This requires however, the molecular dissection of the process, including the identification of B-cell proteins involved in the autoimmune reactions. This thesis aims to contribute to this by the identification and characterization of two humoral autoantigens in type 1 Diabetes Mellitus, a 64kD and a 38kD protein. These aims are specified as follows: 1. Identification of the 64kD autoantigen in type 1 Diabetes Mellitus. 2. Biochemical and Cell biological characterization of the 64kD protein. 3. Identification of the 38kD autoantigen in type 1 Diabetes Mellitus. 4. Biochemical and Cell biological characterization of the 38kD protein. 5. Analysis of the frequencies of autoantibodies to the 64kD and the 38kD autoantigen at clinical diagnosis and in the prediabetic period. 6. Assessment of the predictive value of these autoantibodies, in particular in relation to other markers of autoimmune B-cell destruction.