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Genetic lesions in thymic T cell clonal deletion and thresholds for autoimmunity.

The cause of common polygenic autoimmune diseases is poorly understood because of genetic and cellular complexity in humans and animals. We have investigated the mechanisms of two genetic causes of organ-specific autoimmunity by tracking the fate of high avidity organ-specific CD4 T cells using a transgenic mouse model. Firstly, we have found that an Idd-associated duster of loci from the NOD strain causes a T cell intrinsic failure to delete during in vivo encounter with high-avidity autoantigen, a trait distinguished by the failure to induce the pro-apoptotic gene Bim. Secondly, we have found that inactivation of the autoimmune regulator (Aire) gene reduces the level of thymic expression of organ-specific genes, in a gene-dose dependent manner. In this paper we describe a model relating efficiency of thymic deletion and susceptibility to autoimmunity. Using this model, subtle quantitative trait loci can have an additive effect on each of the parameters of thymic deletion, and the result of interaction between subtle modifications in the multiple parameters can result in large changes in the susceptibility to autoimmunity.