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

Nat Immunol. 2004 Oct;5(10):1028-35. doi: 10.1038/ni1120. Epub 2004 Sep 19.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Diabetes Mellitus, Type 1 / etiology
  • Diabetes Mellitus, Type 1 / genetics*
  • Diabetes Mellitus, Type 1 / immunology
  • Gene Expression Regulation*
  • Genetic Predisposition to Disease
  • Insulin
  • Islets of Langerhans / pathology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, Transgenic
  • Molecular Sequence Data
  • Proinsulin / genetics*
  • Protein Precursors / genetics*
  • Receptors, Interleukin-2 / analysis
  • T-Lymphocytes / immunology


  • Insulin
  • Protein Precursors
  • Receptors, Interleukin-2
  • preproinsulin
  • Proinsulin