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Lesson 1
Autoimmunity: predominant effector mechanism of T1D
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This course is an overview of the discoveries, hypotheses and concepts that shaped the type 1 diabetes (T1D) field over the last 3 decades. T1D is a chronic autoimmune disease which is characterized by a selective destruction of the insulin producing β cells. The NOD mouse is currently the best model for understanding the genetic and immunological basis, and treatment, of T1D. It shows striking similarities with human diabetes. In the early phase of the disease the infiltration of immune cells strongly suggests that is a marker of autoimmunity and the β cells are the main target. A brief description of the mechanisms of physiological immune tolerance to self-antigen (central and peripheral tolerance), raises two questions aiming to explain the onset of autoimmune reactions in the context of genetic and environmental predisposition to T1D. Is autoimmunity triggered by a defective central tolerance which then generates β-cell reactive cells and/or a defective peripheral regulation (defects in suppressive functions of Treg)? These two issues are addressed in detail and it is pointed out that the immune tolerance mechanisms are regulated by a genetic background (immune genes and β -cell gene) which contributes to disease risk. It is widely accepted that the MHC class II variants confer the strongest predisposition to T1D and the insulin VNTR polymorphisms seem to be the most relevant antigen in triggering β-cell autoimmunity. With respect to the role of the environment, epidemiological observations failed to clearly identify factor(s) that trigger T1D. Immune therapy for T1D has been proposed and two approaches have been reported: immune suppression (inhibitors of T cell activation) and tolerance restoration (antigen-specific immune therapies).

In conclusion: It is crucial to identify the autoantigen (s) that drives initiation and perpetuation of the disease. Multifaceted solution will be required for prevention, treatment and a durable cure.

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