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Nat Immunol. 2004 Oct;5(10):1028-35. Epub 2004 Sep 19.

Recessive tolerance to preproinsulin 2 reduces but does not abolish type 1 diabetes.

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Harvard Medical School, Dana Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA.

Erratum in

  • Nat Immunol. 2004 Nov;5(11):1190.
  • Nat Immunol. 2005 Feb;6(2):219.


Although autoimmune diseases can be initiated by immunization with a single antigen, it is not clear whether a single self antigen is essential for the initiation and, perhaps, the perpetuation of spontaneous autoimmunity. Some studies have suggested that insulin may represent an essential autoantigen in type 1 diabetes. Here we show that unlike tolerance to glutamic acid decarboxylase, tolerance to transgenically overexpressed preproinsulin 2 substantially reduced the onset and severity of type 1 diabetes in nonobese diabetic mice. However, some mice still developed type 1 diabetes, suggesting that insulin is a key, but not absolutely essential, autoantigen. The results are consistent with the idea that the human IDDM2 locus controls susceptibility to type 1 diabetes by regulating intrathymic preproinsulin expression.

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