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.

Abstract

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.

• Authors: G R Vreugdenhil, A Geluk, T H Ottenhoff, W J Melchers, B O Roep, J M Galama
• Journal: Diabetologia (Diabetologia) Vol. 41 Issue 1 Pg. 40-6 (Jan 1998) ISSN: 0012-186X [Print] Germany
• PMID: 9498628 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Autoantigens
• Carrier Proteins
• DNA Primers
• HLA-DR1 Antigen
• HLA-DR3 Antigen
• HLA-DR4 Antigen
• Viral Nonstructural Proteins
• 2C protein, viral
• Glutamate Decarboxylase

Topics

• Amino Acid Sequence
• Autoantigens (chemistry)
• Base Sequence
• Binding Sites
• Carrier Proteins (chemistry)
• Conserved Sequence
• DNA Primers
• Diabetes Mellitus, Type 1 (enzymology, genetics, immunology)
• Enterovirus B, Human (genetics)
• Glutamate Decarboxylase (chemistry)
• HLA-DR1 Antigen (chemistry, immunology)
• HLA-DR3 Antigen (chemistry, immunology)
• HLA-DR4 Antigen (chemistry, immunology)
• Humans
• Islets of Langerhans (enzymology, immunology)
• Molecular Sequence Data
• Polymerase Chain Reaction
• Sequence Alignment
• Sequence Homology, Amino Acid
• Viral Nonstructural Proteins (chemistry)