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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

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.

References

  1. 1

    Wegmann, D. R., Norbury-Glaser, M. & Daniel, D. Insulin-specific T cells are a predominant component of islet infiltrates in pre-diabetic NOD mice. Eur. J. Immunol. 24, 1853–1857 (1994)

    CAS  Article  PubMed  Google Scholar 

  2. 2

    Lieberman, S. M. et al. Identification of the β cell antigen targeted by a prevalent population of pathogenic CD8+ T cells in autoimmune diabetes. Proc. Natl Acad. Sci. USA 100, 8384–8388 (2003)

    ADS  CAS  Article  PubMed  Google Scholar 

  3. 3

    Abiru, N. et al. Dual overlapping peptides recognized by insulin peptide B:9–23 T cell receptor AV13S3 T cell clones of the NOD mouse. J. Autoimmun. 14, 231–237 (2000)

    CAS  Article  PubMed  Google Scholar 

  4. 4

    Thébault-Baumont, K. et al. Acceleration of type 1 diabetes mellitus in proinsulin 2-deficient NOD mice. J. Clin. Invest. 111, 851–857 (2003)

    Article  PubMed  PubMed Central  Google Scholar 

  5. 5

    Moriyama, H. et al. Evidence for a primary islet autoantigen (preproinsulin 1) for insulitis and diabetes in the nonobese diabetic mouse. Proc. Natl Acad. Sci. USA 100, 10376–10381 (2003)

    ADS  CAS  Article  PubMed  Google Scholar 

  6. 6

    Jaeckel, E., Lipes, M. A. & von Boehmer, H. Recessive tolerance to preproinsulin 2 reduces but does not abolish type 1 diabetes. Nature Immunol. 5, 1028–1035 (2004)

    CAS  Article  Google Scholar 

  7. 7

    Daniel, D., Gill, R. G., Schloot, N. & Wegmann, D. Epitope specificity, cytokine production profile and diabetogenic activity of insulin-specific T cell clones isolated from NOD mice. Eur. J. Immunol. 25, 1056–1062 (1995)

    CAS  Article  PubMed  Google Scholar 

  8. 8

    Wong, F. S., Moustakas, A. K., Wen, L., Papadopoulos, G. K. & Janeway, C. A. Jr. Analysis of structure and function relationships of an autoantigenic peptide of insulin bound to H-2Kd that stimulates CD8 T cells in insulin-dependent diabetes mellitus. Proc. Natl Acad. Sci. USA 99, 5551–5556 (2002)

    ADS  CAS  Article  PubMed  Google Scholar 

  9. 9

    Simone, E. et al. T cell receptor restriction of diabetogenic autoimmune NOD T cells. Proc. Natl Acad. Sci. USA 94, 2518–2521 (1997)

    ADS  CAS  Article  PubMed  Google Scholar 

  10. 10

    Mordes, J. P., Bortell, R., Blankenhorn, E. P., Rossini, A. A. & Greiner, D. L. Rat models of type 1 diabetes: genetics, environment, and autoimmunity. ILAR J. 45, 278–291 (2004)

    CAS  Article  PubMed  Google Scholar 

  11. 11

    Todd, J. A., Bell, J. I. & McDevitt, H. O. HLA-DQβ gene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus. Nature 329, 599–604 (1987)

    ADS  CAS  Article  PubMed  Google Scholar 

  12. 12

    Ellerman, K. E. & Like, A. A. Susceptibility to diabetes is widely distributed in normal class IIu haplotype rats. Diabetologia 43, 890–898 (2000)

    CAS  Article  PubMed  Google Scholar 

  13. 13

    Kubosaki, A. et al. Targeted disruption of the IA-2β gene causes glucose intolerance and impairs insulin secretion but does not prevent the development of diabetes in NOD mice. Diabetes 53, 1684–1691 (2004)

    CAS  Article  PubMed  Google Scholar 

  14. 14

    Jaeckel, E., Klein, L., Martin-Orozco, N. & von Boehmer, H. Normal incidence of diabetes in NOD mice tolerant to glutamic acid decarboxylase. J. Exp. Med. 197, 1635–1644 (2003)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. 15

    Kash, S. F., Condie, B. G. & Baekkeskov, S. Glutamate decarboxylase and GABA in pancreatic islets: lessons from knock-out mice. Horm. Metab. Res. 31, 340–344 (1999)

    CAS  Article  PubMed  Google Scholar 

  16. 16

    Birk, O. S. et al. A role of Hsp60 in autoimmune diabetes: analysis in a transgenic model. Proc. Natl Acad. Sci. USA 93, 1032–1037 (1996)

    ADS  CAS  Article  PubMed  Google Scholar 

  17. 17

    Kubosaki, A., Miura, J. & Notkins, A. L. IA-2 is not required for the development of diabetes in NOD mice. Diabetologia 47, 149–150 (2004)

    CAS  Article  PubMed  Google Scholar 

  18. 18

    DiLorenzo, T. P. et al. During the early prediabetic period in NOD mice, the pathogenic CD8+ T-cell population comprises multiple antigenic specificities. Clin. Immunol. 105, 332–341 (2002)

    CAS  Article  PubMed  Google Scholar 

  19. 19

    Mathis, D. & Benoist, C. Back to central tolerance. Immunity 20, 509–516 (2004)

    CAS  Article  Google Scholar 

  20. 20

    Peterson, J. D. & Haskins, K. Transfer of diabetes in the NOD-scid mouse by CD4 T-cell clones. Differential requirement for CD8 T-cells. Diabetes 45, 328–336 (1996)

    CAS  Article  PubMed  Google Scholar 

  21. 21

    French, M. B. et al. Transgenic expression of mouse proinsulin II prevents diabetes in nonobese diabetic mice. Diabetes 46, 34–39 (1996)

    Article  Google Scholar 

  22. 22

    Mukherjee, R., Chaturvedi, P., Qin, H. Y. & Singh, B. CD4+CD25+ regulatory T cells generated in response to insulin B:9–23 peptide prevent adoptive transfer of diabetes by diabetogenic T cells. J. Autoimmun. 21, 221–237 (2003)

    CAS  Article  PubMed  Google Scholar 

  23. 23

    Chatenoud, L., Primo, J. & Bach, J. F. CD3 antibody-induced dominant self tolerance in overtly diabetic NOD mice. J. Immunol. 158, 2947–2954 (1997)

    CAS  PubMed  Google Scholar 

  24. 24

    Bluestone, J. A. & Tang, Q. Therapeutic vaccination using CD4+CD25+ antigen-specific regulatory T cells. Proc. Natl Acad. Sci. USA 101 (suppl. 2), 14622–14626 (2004)

    ADS  CAS  Article  PubMed  Google Scholar 

  25. 25

    Duvillié, B. et al. Phenotypic alterations in insulin-deficient mutant mice. Proc. Natl Acad. Sci. USA 94, 5137–5140 (1997)

    ADS  Article  PubMed  Google Scholar 

  26. 26

    Nakayama, M. et al. Establishment of native insulin-negative NOD mice and the methodology to distinguish specific insulin knockout genotypes and a B:16 alanine preproinsulin transgene. Ann. NY Acad. Sci. 1037, 193–198 (2004)

    ADS  CAS  Article  PubMed  Google Scholar 

  27. 27

    Yu, L. et al. Early expression of antiinsulin autoantibodies of humans and the NOD mouse: evidence for early determination of subsequent diabetes. Proc. Natl Acad. Sci. USA 97, 1701–1706 (2000)

    ADS  CAS  Article  PubMed  Google Scholar 

  28. 28

    Sreenan, S. et al. Increased β-cell proliferation and reduced mass before diabetes onset in the nonobese diabetic mouse. Diabetes 48, 989–996 (1999)

    CAS  Article  PubMed  Google Scholar 

Download references

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.

Author information

Affiliations

Authors

Corresponding author

Correspondence to George S. Eisenbarth.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.