Diabetologia

, Volume 41, Issue 1, pp 40–46

Molecular mimicry in diabetes mellitus: the homologous domain in coxsackie B virus protein 2C and islet autoantigen GAD65 is highly conserved in the coxsackie B-like enteroviruses and binds to the diabetes associated HLA-DR3 molecule

Authors

  • G. R. Vreugdenhil
    • University of Nijmegen, Department of Medical Microbiology, Nijmegen, The Netherlands
  • A. Geluk
    • University of Leiden, Department of Immunohematology and Blood Bank, Leiden, The Netherlands
  • T. H. M. Ottenhoff
    • University of Leiden, Department of Immunohematology and Blood Bank, Leiden, The Netherlands
  • W. J. G. Melchers
    • University of Nijmegen, Department of Medical Microbiology, Nijmegen, The Netherlands
  • B. O. Roep
    • University of Leiden, Department of Immunohematology and Blood Bank, Leiden, The Netherlands
  • J. M. D. Galama
    • University of Nijmegen, Department of Medical Microbiology, Nijmegen, The Netherlands
Original articles

DOI: 10.1007/s001250050864

Cite this article as:
Vreugdenhil, G., Geluk, A., Ottenhoff, T. et al. Diabetologia (1998) 41: 40. doi:10.1007/s001250050864

Summary

It has been proposed that molecular mimicry between protein 2C (p2C) of coxsackie virus B4 and the autoantigen glutamic acid decarboxylase (GAD65) plays a role in the pathogenesis of insulin-dependent diabetes mellitus (IDDM). In this study we show that the amino acid sequence of p2C which shares homology with a sequence in GAD65 (PEVKEK), is highly conserved in coxsackie virus B4 isolates as well as in different viruses of the subgroup of coxsackie B-like enteroviruses. These are the most prevalent enteroviruses and therefore exposure to the mimicry motif will be a frequent event throughout life. Presentation of the homologous peptides by HLA molecules is essential for T-cell reactivity. Therefore, we tested whether the PEVKEK motif can bind to the IDDM-associated HLA-DR1, -DR3 and -DR4 molecules. Synthetic peptides with sequences derived from p2C and GAD65 did bind to HLA-DR3 but not to HLA-DR1 or -DR4. Replacement of amino acids within the motif showed that the PEVKEK motif binds specifically to HLA-DR3. Moreover, both p2C and GAD65 peptides bind in the same position within the peptide binding groove of the DR3 molecule which is an essential requirement for T-cell cross-reactivity. The results support molecular mimicry between p2C of coxsackie B-like enteroviruses and GAD65. However, this molecular mimicry may be limited to the HLA-DR3 positive subpopulation of IDDM patients. [Diabetologia (1998) 41: 40–46]

Keywords Coxsackie B viruspeptide bindingHLA-DRmolecular mimicryIDDM.
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Copyright information

© Springer-Verlag Berlin Heidelberg 1998