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

Nature Immunology volume 5, pages 1028–1035 (2004)Cite this article

A Corrigendum to this article was published on 01 November 2004

Abstract

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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Figure 1: Characterization of PPIns2 transgenic mice.
Figure 2: Metabolic characterization of PPIns2 transgenic mice.
Figure 3: Insulitis and diabetes in PPIns2 transgenic versus control mice.
Figure 4: Insulin-specific T cell response.
Figure 5: Spontaneous anti-insulin immune response and response to unrelated autoantigen.
Figure 6: Dominant versus recessive tolerance.

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Acknowledgements

We thank M. Anderson (Joslin Diabetes Center, Boston, Massachusetts) for helping to determine the insulin autoantibody titers; R.N. Smith (Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts) for the evaluation of histological slides; H. van Santen for providing the modified invariant chain promoter; and Xiaoyan Li for technical support. Culture filtrate protein was provided by the College of Veterinary Medicine and Biomedical Sciences of the University of Colorado, produced with funds from the National Institutes of Health, National Institute of Allergy and Infectious Diseases (contract NO1-AI-75320; Tuberculosis Research and Vaccine Testing). Supported in part by the Koerber Foundation (Hamburg, Germany), Juvenile Diabetes Research Foundation (9-1998-1005 to H.v.B.), Juvenile Diabetes Research Foundation Center for Islet Cell Transplantation at Harvard (281541 to H.v.B., E.J. and M.A.L.) and German Research Foundation (JA977/1-1 to E.J.).

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Authors and Affiliations

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

    Elmar Jaeckel & Harald von Boehmer

  2. Department of Medicine, Joslin Diabetes Center, Brigham and Women's Hospital, Harvard Medical School, 1 Joslin Place, Boston, 02215, Massachusetts, USA

    Myra A Lipes

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  1. Elmar Jaeckel
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Correspondence to Harald von Boehmer.

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Supplementary information

Supplementary Fig. 1

Expression of transgenic fusion protein. (PDF 164 kb)

Supplementary Fig. 2

Islet architecture. (PDF 141 kb)

Supplementary Fig. 3

Non diabetic PPIns2 transgenic mice still contain insulin producing β-cells. (PDF 82 kb)

Supplementary Fig. 4

Intracellular cytokine staining of insulin-reactive T cells. (PDF 281 kb)

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Jaeckel, E., Lipes, M. & von Boehmer, H. Recessive tolerance to preproinsulin 2 reduces but does not abolish type 1 diabetes. Nat Immunol 5, 1028–1035 (2004). https://doi.org/10.1038/ni1120

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