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.
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.
Vreugdenhil
G R
GR
University of Nijmegen, Department of Medical Microbiology, The Netherlands.
Geluk
A
A
Ottenhoff
T H
TH
Melchers
W J
WJ
Roep
B O
BO
Galama
J M
JM
D000595:Amino Acid Sequence; D001324:Autoantigens / Q000737:chemistry*; D001483:Base Sequence; D001665:Binding Sites; D002352:Carrier Proteins / Q000737:chemistry*; D017124:Conserved Sequence; D017931:DNA Primers; D003922:Diabetes Mellitus, Type 1 / Q000201:enzymology / Q000235:genetics* / Q000276:immunology; D029822:Enterovirus B, Human / Q000235:genetics*; D005968:Glutamate Decarboxylase / Q000737:chemistry*; D015798:HLA-DR1 Antigen / Q000737:chemistry / Q000276:immunology; D015803:HLA-DR3 Antigen / Q000737:chemistry / Q000276:immunology; D015804:HLA-DR4 Antigen / Q000737:chemistry / Q000276:immunology; D006801:Humans; D007515:Islets of Langerhans / Q000201:enzymology* / Q000276:immunology; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D017361:Viral Nonstructural Proteins / Q000737:chemistry*
D001324:Autoantigens; D002352:Carrier Proteins; D017931:DNA Primers; D015798:HLA-DR1 Antigen; D015803:HLA-DR3 Antigen; D015804:HLA-DR4 Antigen; D017361:Viral Nonstructural Proteins; C076023:2C protein, viral; D005968:Glutamate Decarboxylase