Kidney Week

Abstract: TH-PO838

A Staphylococcal Plasmid Encoded Peptide Induces Anti-Myeloperoxidase Nephritogenic Autoimmunity

Session Information

• Glomerular Diseases: Immunology and Inflammation - I
  October 25, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1202 Glomerular Diseases: Immunology and Inflammation

Authors

• Kitching, A. Richard, Monash University, Clayton, Victoria, Australia

A. Richard Kitching,

• Ooi, Joshua D., Monash University, Clayton, Victoria, Australia

Joshua D. Ooi,

• Jiang, Jhih-Hang, Monash University, Clayton, Victoria, Australia

Jhih-Hang Jiang,

• Peleg, Anton Y., Monash University, Clayton, Victoria, Australia

Anton Y. Peleg,

• Holdsworth, Stephen R., Monash University, Clayton, Victoria, Australia

Stephen R. Holdsworth,

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 (MPO_409-428), relevant to several MHCII and lying within an MPO epitope hot spot, would induce anti-MPO autoimmunity.

Methods

Immunity to MPO and MPO_409-428 was studied in microbial peptide immunized C57BL/6 (B/6, I-A^b), BALB/c (I-A^d/E^d) 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-A^b/MPO_415-428 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 MPO_409-428 in B/6, BALB/c and DR15+ mice, found in some S.aureus strains, induced expansion of MPO_415-428 tetramer+CD4+ cells, anti-MPO T cell autoimmunity (to MPO_408-428 and whole MPO) and bioactive MPO-ANCA in B/6 mice. 6PGDp induced anti-MPO autoreactivity in mice with different MHCII (I-A^d/E^d 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.