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Abstract: TH-PO838

A Staphylococcal Plasmid Encoded Peptide Induces Anti-Myeloperoxidase Nephritogenic Autoimmunity

Session Information

Category: Glomerular Diseases

  • 1202 Glomerular Diseases: Immunology and Inflammation

Authors

  • Kitching, A. Richard, Monash University, Clayton, Victoria, Australia
  • Ooi, Joshua D., Monash University, Clayton, Victoria, Australia
  • Jiang, Jhih-Hang, Monash University, Clayton, Victoria, Australia
  • Peleg, Anton Y., Monash University, Clayton, Victoria, Australia
  • Holdsworth, Stephen R., Monash University, Clayton, Victoria, Australia

Group or Team Name

  • Autoimmune Kidney Disease and Vasculitis Research Group
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.

Methods

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-γ 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, MPO-ANCA IIF/ELISA, neutrophil ROS production, MPO-ANCA transfer). Anti-6PGD antibodies (Ab) were measured in sera of healthy humans and patients.

Results

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 the 6PGD mimotope, also induced anti-MPO GN with anti-MPO cellular and humoral autoimmunity, showing that plasmids with this sequence induce nephritogenic anti-MPO autoimmunity.

Conclusion

A microbial plasmid encoded peptide induces anti-MPO autoimmunity via molecular mimicry implicating plasmids, as bacterial replicons capable of horizontal gene transfer, in autoimmune disease.

Funding

  • Government Support - Non-U.S.