A staphylococcal plasmid encoded peptide induces anti-myeloperoxidase nephritogenic autoimmunity.

Background: Loss of tolerance to MPO in ANCA-associated glomerulonephritis (GN) is poorly understood. It is unknown whether molecular mimicry plays any role in this process. We tested whether microbial peptides homologous to a dominant pathogenic MPO CD4+ T cell epitope (MPO409-428), relevant to several MHCII and lying within an MPO epitope hot spot, would induce anti-MPO autoimmunity. Method(s): Immunity to MPO and MPO409-428 was studied in microbial peptide immunized C57BL/6 (B/6, I-Ab), BALB/c (I-Ad/Ed) and HLA-DR15 transgenic mice (proliferation, IFN-gamma and IL-17A ELISPOT). Anti-MPO GN and anti-MPO immunity in response to peptides, proteins (MPO/ovalbumin as positive/negative controls) and S.aureus strains with/without plasmids carrying the relevant 6-phosphogluconate dehydrogenase (6PGD) sequence were studied in B/6 mice (I-Ab/MPO415-428 tetramers, cytokines, MPOANCA IIF/ELISA, neutrophil ROS production, MPO-ANCA transfer). Anti-6PGD antibodies (Ab) were measured in sera of healthy humans and patients. Result(s): The 4 most homologous microbial peptides were immunogenic but did not induce anti-MPO autoreactivity. However, a plasmid-derived peptide from 6PGD (6PGDp) with similar critical binding residues for MPO409-428 in B/6, BALB/c and DR15+ mice, found in some S.aureus strains, induced expansion of MPO415-428 tetramer+CD4+ cells, anti-MPO T cell autoimmunity (to MPO408-428 and whole MPO) and bioactive MPO-ANCA in B/6 mice. 6PGDp induced anti-MPO autoreactivity in mice with different MHCII (I-Ad/Ed and DR15). Related 6PGD sequences from other S.aureus strains did not induce anti-MPO responses. Healthy human and vasculitis patient sera contained anti-6PGD Ab, demonstrating its immunogenicity in humans. 6PGDp-immunized mice developed GN when MPO was deposited in glomeruli by anti-basement membrane globulin. Immunization with S.aureus containing a plasmid with the mimic 6PGD sequence, or another S.aureus strain transformed with a different plasmid expressing t