IgG4 antibody level for fructose-specific transporter in Streptococcus pyogenes is significantly elevated in sera of patients with IgG4-related disease

Immunoglobulin G4-related disease (IgG4-RD) is a systemic condition characterized by elevated serum IgG4 and abundant IgG4-bearing plasma cell infiltration and is considered to have an autoimmune pathogenesis. Given the reported associations between autoimmune diseases and bacterial infections and the absence of clearly identifiable preceding infections in IgG4-RD, we hypothesized that commensal bacterial infection may contribute to its development. We sought to identify a commensal and opportunistic bacterial pathogen potentially associated with IgG4-RD using an enzyme-linked immunosorbent assay (ELISA) with two bacterial species and three cell components. We identified significant elevation of IgG4 antibody levels against the peptidoglycan-polysaccharide (PG-PS) 100p fraction (100,000 × g precipitated fraction by ultracentrifugation) from the Streptococcus pyogenes in patients with IgG4-RD, suggesting the presence of molecules reactive to IgG4 antibody. Western blot analysis of the PG-PS 100p fraction revealed a specific 70-kD band reactive with IgG4-RD sera, which was identified as the fructose-specific transporter of the phosphoenolpyruvate-dependent sugar phosphotransferase system (EII-Fru) by mass spectrometric analysis. Recombinant EII-Fru protein and its predicted a 21-amino acid epitope peptide that demonstrated specific IgG4 antibody elevation with IgG4-RD sera in ELISA. These findings suggest that EII-Fru from S. pyogenes may be a candidate target of the IgG4 antibody in IgG4-RD.