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Prime role for an insulin epitope in the development of type 1 diabetes in NOD mice

Abstract

A fundamental question about the pathogenesis of spontaneous autoimmune diabetes is whether there are primary autoantigens. For type 1 diabetes it is clear that multiple islet molecules are the target of autoimmunity in man and animal models1,2. It is not clear whether any of the target molecules are essential for the destruction of islet beta cells. Here we show that the proinsulin/insulin molecules have a sequence that is a primary target of the autoimmunity that causes diabetes of the non-obese diabetic (NOD) mouse. We created insulin 1 and insulin 2 gene knockouts combined with a mutated proinsulin transgene (in which residue 16 on the B chain was changed to alanine) in NOD mice. This mutation abrogated the T-cell stimulation of a series of the major insulin autoreactive NOD T-cell clones3. Female mice with only the altered insulin did not develop insulin autoantibodies, insulitis or autoimmune diabetes, in contrast with mice containing at least one copy of the native insulin gene. We suggest that proinsulin is a primary autoantigen of the NOD mouse, and speculate that organ-restricted autoimmune disorders with marked major histocompatibility complex (MHC) restriction of disease are likely to have specific primary autoantigens.

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Figure 1: Serum anti-insulin autoantibody levels.
Figure 2: Histology of non-diabetic native insulin-negative mice (insulin 1-/-, insulin 2-/-, transgene+).
Figure 3: Histology of native insulin-positive mice.
Figure 4: Life tables of diabetes development.

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Acknowledgements

This work was supported by grants from the NIH, the Diabetes Endocrine Research Center, the Autoimmunity Prevention Center, the Immune Tolerance Network, the American Diabetes Association, the Juvenile Diabetes Foundation and the Children's Diabetes Foundation. M.N. was supported by a fellowship from the Juvenile Diabetes Foundation and the Naito Foundation.

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Correspondence to George S. Eisenbarth.

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Nakayama, M., Abiru, N., Moriyama, H. et al. Prime role for an insulin epitope in the development of type 1 diabetes in NOD mice. Nature 435, 220–223 (2005). https://doi.org/10.1038/nature03523

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