Faulty Termination of Immune Responses in the Pathogenesis of T1D

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In the pathogenesis of autoimmune diseases, emphasis is usually placed on inductive steps and on the breaking of mechanisms that control tolerance to self antigens. Although these are certainly important, emerging evidence suggests that a key feature of T1D, and possibly of other autoimmune diseases, is the failure of mechanisms that normally terminate immune responses.

The main pathways for the termination of immune responses appear to be defective in the NOD mouse (Table 3). Intriguingly, the autoimmune diabetes susceptibility locus idd3 has been mapped to a 0.35-cM interval containing the IL-2 gene (124). The NOD IL-2 gene appears to be an allelic variant resulting in a serine-to-proline substitution at position 6 of the mature IL-2 protein, which is, nevertheless, functional (124). IL-2 or IL-2 receptor-deficient mice develop severe autoimmune diseases, probably due to the non-redundant function of IL-2 in tolerance to self via two major pathways: homeostasis of CD4+CD25+ regulatory T cells (125), and priming for apoptosis of proliferating T cells (126).

Idd5 has been mapped to the CTLA-4-CD28 region and shown to control resistance to apoptosis of NOD peripheral T cells (127). Another autoimmune diabetes-associated locus maps to the region containing the anti-apoptotic gene Bcl-2; Idd7 maps to the region containing the TGF01 locus that controls progression of insulitis to overt disease (128) and could also be implicated in faulty termination of immune responses in the NOD mouse.

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