title: Renal participation of myeloperoxidase in antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis.
abstract: Myeloperoxidase (MPO) is an important neutrophil lysosomal enzyme, a major autoantigen, and a potential mediator of tissue injury in MPO-ANCA-associated vasculitis (MPO-AAV) and glomerulonephritis. Here we examined MPO deposition in kidney biopsies from 47 patients with MPO-AAV. Leukocyte accumulation and fibrin deposition consistent with cell-mediated immunity was a major feature. Tubulointerstitial macrophage, CD4+ and CD8+ T-cell, and neutrophil numbers correlated with low presenting eGFR. MPO was not detected in kidneys from patients with minimal change or thin basement membrane disease, but was prominent in glomerular, periglomerular, and tubulointerstitial regions in MPO-AAV. Extracellular MPO released from leukocytes was pronounced in all MPO-AAV patients. Similar numbers of neutrophils and macrophages expressed MPO in the kidneys, but colocalization studies identified neutrophils as the major source of extracellular MPO. Extraleukocyte MPO was prominent in neutrophil extracellular traps in the majority of patients; most of which had traps in half or more glomeruli. These traps were associated with more neutrophils and more MPO within glomeruli. Glomerular MPO-containing macrophages generated extracellular trap-like structures. MPO also localized to endothelial cells and podocytes. The presence of the most active glomerular lesions (both segmental necrosis and cellular crescents) correlated with intraglomerular CD4+ cells and MPO+ macrophages. Thus, cellular and extracellular MPO may cause glomerular and interstitial injury.
authors.affiliation: Centre for Inflammatory Diseases, Monash University Department of Medicine, Clayton, Victoria, Australia.
authors.forename: Kim M
authors.initials: KM
authors.lastname: O'Sullivan
authors.affiliation: Monash Micro Imaging, Monash University, Clayton, Victoria, Australia.
authors.forename: Camden Y
authors.initials: CY
authors.lastname: Lo
authors.affiliation: Centre for Inflammatory Diseases, Monash University Department of Medicine, Clayton, Victoria, Australia.|Department of Nephrology, Monash Health, Clayton Victoria, Australia.
authors.forename: Shaun A
authors.initials: SA
authors.lastname: Summers
authors.affiliation: Monash Micro Imaging, Monash University, Clayton, Victoria, Australia.
authors.forename: Kirstin D
authors.initials: KD
authors.lastname: Elgass
authors.affiliation: Department of Biochemistry and Molecular Biology, BIO21 Institute, University of Melbourne, Parkville, Victoria, Australia.|Biological Optical Microscopy Platform, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: McMillan
authors.affiliation: Department of Pathology, Monash Health, Clayton, Victoria, Australia.
authors.forename: Anthony
authors.initials: A
authors.lastname: Longano
authors.affiliation: Centre for Inflammatory Diseases, Monash University Department of Medicine, Clayton, Victoria, Australia.|Department of Nephrology, Monash Health, Clayton Victoria, Australia.
authors.forename: Sharon L
authors.initials: SL
authors.lastname: Ford
authors.affiliation: Centre for Inflammatory Diseases, Monash University Department of Medicine, Clayton, Victoria, Australia.
authors.forename: Poh-Yi
authors.initials: PY
authors.lastname: Gan
authors.affiliation: Department of Nephrology, Monash Health, Clayton Victoria, Australia.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Kerr
authors.affiliation: Centre for Inflammatory Diseases, Monash University Department of Medicine, Clayton, Victoria, Australia.|Department of Nephrology, Monash Health, Clayton Victoria, Australia.
authors.forename: A Richard
authors.initials: AR
authors.lastname: Kitching
authors.affiliation: Centre for Inflammatory Diseases, Monash University Department of Medicine, Clayton, Victoria, Australia.|Department of Nephrology, Monash Health, Clayton Victoria, Australia.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Holdsworth
mesh_terms: D000368:Aged; D019268:Antibodies, Antineutrophil Cytoplasmic / Q000276:immunology; D001327:Autoimmune Diseases / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes; D018414:CD8-Positive T-Lymphocytes; D003713:Dendritic Cells / Q000201:enzymology; D042783:Endothelial Cells / Q000201:enzymology; D045604:Extracellular Fluid / Q000201:enzymology; D065206:Extracellular Traps / Q000201:enzymology*; D005260:Female; D005919:Glomerular Filtration Rate; D005921:Glomerulonephritis / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D006801:Humans; D007678:Kidney Glomerulus / Q000201:enzymology / Q000473:pathology; D008264:Macrophages / Q000201:enzymology; D008297:Male; D009504:Neutrophils / Q000201:enzymology; D009195:Peroxidase / Q000378:metabolism*; D050199:Podocytes / Q000201:enzymology
chemical_list: D019268:Antibodies, Antineutrophil Cytoplasmic; D009195:Peroxidase