Antibodies to Glutamic Acid Decarboxylase and P2-C Peptides in Sera From Coxsackie Virus B4-Infected Mice and IDDM Patients

The possible role of amino acid sequence and epitope homologies between a protein P2-C of Coxsackie virus B4 and human GAD in the development of host-specific immune response in insulin-dependent diabetes mellitus (IDDM) (molecular mimicry) was investigated. Peptide antibodies to the P2-C protein, GAD₆₅, and GAD₆₇ were raised to analyze their immunoreactivity by enzyme-linked immunosorbent assay and immunoblotting with GAD purified from the brain and pancreas of mice that develop hyperglycemia after the infection. Additionally, antibody reactivity to these peptide antigens was assessed in sera from the virus-infected mice and IDDM patients. All three peptide antisera reacted very strongly with homologous peptides; P2-C antiserum cross-reacted with GAD₆₅ as efficiently as GAD₆₅ antiserum with P2-C, but no cross-reaction was detected between P2-C and GAD₆₇ although cross-reaction between the two GADs was quite pronounced. P2-C antiserum immunocomplexed with GAD₆₅ from mouse brain or pancreas, whereas GAD₆₅ and GAD₆₇ antisera both immunocomplexed with the two GADs from these sources. Most of the sera from virus-infected mice were reactive to brain and pancreas GAD₆₅ and also to P2-C peptide, whereas some reacted to GAD₆₅ and a few to GAD₆₇ peptides. A number of IDDM sera reacted with mouse GAD₆₅ and also with P2-C and GAD₆₅ peptides, whereas only a few reacted with GAD₆₇ peptide. The immunoreactivity of the mouse and IDDM sera to P2-C and GAD₆₅ peptides was blocked by pre-adsorption with mouse GAD. The results suggest that molecular mimicry may play a role in the pathogenesis of the disease.