title: The immunodominant myeloperoxidase T-cell epitope induces local cell-mediated injury in antimyeloperoxidase glomerulonephritis.
abstract: Microscopic polyangiitis is an autoimmune small-vessel vasculitis that often manifests as focal and necrotizing glomerulonephritis and renal failure. Antineutrophil cytoplasmic Abs (ANCAs) specific for myeloperoxidase (MPO) play a role in this disease, but the role of autoreactive MPO-specific CD4(+) T cells is uncertain. By screening overlapping peptides of 20 amino acids spanning the MPO molecule, we identified an immunodominant MPO CD4(+) T-cell epitope (MPO(409-428)). Immunizing C57BL/6 mice with MPO(409-428) induced focal necrotizing glomerulonephritis similar to that seen after whole MPO immunization, when MPO was deposited in glomeruli. Transfer of an MPO(409-428)-specific CD4(+) T-cell clone to Rag1(-/-) mice induced focal necrotizing glomerulonephritis when glomerular MPO deposition was induced either by passive transfer of MPO-ANCA and LPS or by planting MPO(409-428) conjugated to a murine antiglomerular basement membrane mAb. MPO(409-428) also induced biologically active anti-MPO Abs in mice. The MPO(409-428) epitope has a minimum immunogenic core region of 11 amino acids, MPO(415-426), with several critical residues. ANCA-activated neutrophils not only induce injury but lodged the autoantigen MPO in glomeruli, allowing autoreactive anti-MPO CD4(+) cells to induce delayed type hypersensitivity-like necrotizing glomerular lesions. These studies identify an immunodominant MPO T-cell epitope and redefine how effector responses can induce injury in MPO-ANCA-associated microscopic polyangiitis.
authors.affiliation: Center for Inflammatory Diseases, Department of Medicine, Monash University, Clayton 3168, Victoria, Australia.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Ooi
authors.forename: Janet
authors.initials: J
authors.lastname: Chang
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hickey
authors.forename: Dorin-Bogdan
authors.initials: DB
authors.lastname: Borza
authors.forename: Lars
authors.initials: L
authors.lastname: Fugger
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Holdsworth
authors.forename: A Richard
authors.initials: AR
authors.lastname: Kitching
mesh_terms: D000818:Animals; D019268:Antibodies, Antineutrophil Cytoplasmic / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D001324:Autoantigens / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018604:Epitope Mapping; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D005921:Glomerulonephritis / Q000201:enzymology / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D007111:Immunity, Cellular; D051379:Mice; D018345:Mice, Knockout; D055953:Microscopic Polyangiitis / Q000201:enzymology / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D018375:Neutrophil Activation / Q000235:genetics / Q000276:immunology; D009504:Neutrophils / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D009195:Peroxidase / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D019268:Antibodies, Antineutrophil Cytoplasmic; D001324:Autoantigens; D018984:Epitopes, T-Lymphocyte; D009195:Peroxidase