Minimal Impact of a De Novo–Expressed β-Cell Autoantigen on Spontaneous Diabetes Development in NOD Mice

  1. Marianne M. Martinic1,
  2. Amy E. Juedes1,
  3. Damien Bresson1,
  4. Dirk Homann2,
  5. Kresten Skak3,
  6. Christoph Huber4,
  7. Eleanor Ling1,
  8. Mette Ejrnaes1,
  9. Tom Wolfe1,
  10. Lisa Togher1,
  11. Urs Christen5 and
  12. Matthias G. von Herrath1
  1. 1Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, California
  2. 2Barbara Davis Center for Childhood Diabetes, University of Colorado at Denver and Health Sciences Center, Aurora, Colorado
  3. 3Pharmacology Research, Novo Nordisk A/S, Måløv, Denmark
  4. 4Department of Immunology, The Scripps Research Institute, La Jolla, California
  5. 5Klinik der Johann Wolfgang Goethe Universität, Frankfurt, Germany
  1. Address correspondence and reprint requests to Marianne M. Martinic or Matthias G. von Herrath, Immune Regulation Lab DI-3, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037. E-mail: marmar{at}liai.org or matthias{at}liai.org

Abstract

During an autoimmune process, the autoaggressive response spreads from the initiating autoantigen to other antigens expressed in the target organ. Based on evidence from experimental models for multiple sclerosis, such “antigenic spreading” can play an important role in the exacerbation of clinical disease. We evaluated whether pathogenesis of spontaneous diabetes in NOD mice could be accelerated in a similar way when a novel autoantigen was expressed in pancreatic β-cells. Unexpectedly, we found that the expression of the lymphocytic choriomeningitis virus nucleoprotein only led to marginal enhancement of diabetes, although such NOD-nucleoprotein mice were not tolerant to nucleoprotein. Although the frequency of nucleoprotein-specific CD8 T-cells in the pancreatic draining lymph node was comparable with the frequency of islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)-specific T-cells, more IGRP-specific CD8 T-cells were found both systemically and in the islets where there was a fourfold increase. Interestingly, and in contrast to nucleoprotein-specific CD8 T-cells, IGRP-specific T-cells showed increased CXCR3 expression. Thus, autoreactivity toward de novo–expressed β-cell autoantigens will not accelerate autoimmunity unless large numbers of antigen-experienced autoreactive T-cells expressing the appropriate chemokine receptors are present.

Footnotes

  • M.M.M. and A.E.J. contributed equally to this work.

    The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Accepted November 22, 2006.
    • Received January 14, 2005.
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