Anti-myeloperoxidase pathogenic autoimmunity can be induced by a Staphylococcus aureus plasmid derived peptide.

Abstract

Microscopic polyangiitis is a small-vessel vasculitic autoimmune disease whereby autoreactivity to the neutrophil enzyme myeloperoxidase (MPO) causes rapidly progressive glomerulonephritis. It is unknown how tolerance is lost, but there are reports in patients that S aureus infections precede anti- MPO autoimmunity, and in other forms of vasculitis, molecular mimicry has been shown to induce cross-reactive pathogenic autoimmunity. This study tests the hypothesis that molecular mimicry induces cross-reactive pathogenic anti-MPO autoimmunity. A BLAST search was used to identify 5 candidate microbial peptides with homology to the immunodominant MPO T-cell epitope, MPO409-428. Anti-MPO T-cell responses were determined by immunizing C57BL/6 mice with candidate peptides then measuring recall responses ex vivo to MPO by 3 [H]-T proliferation and IFN-gamma and IL-17 ELISPOTs. Anti-MPO antibodies were measured by ELISA, immunofluorescence on ethanol-fixed neutrophils and by enumerating neutrophil glomerular recruitment after passive transfer of antibody. Disease was assessed by immunizing mice with peptide or whole bacteria followed by depositing MPO in the glomerulus using low-dose sheep anti-mouse glomerular basement membrane antibodies, then measuring functional and histological endpoints. Only 1 peptide induced cross-reactive T-cell responses to MPO. This peptide was derived from a S aureus plasmid. Antibodies from mice immunized with this peptide cross-reacted with MPO, bound to neutrophils in a perinuclear fashion, and induced neutrophil glomerular recruitment. Furthermore, mice immunized with either this peptide or a clinical strain of S aureus containing the plasmid, developed albuminuria and focal necrotizing glomerulonephritis. This shows that molecular mimicry by a S aureus plasmid derived peptide induces anti-MPO pathogenic autoimmunity.