title: Complement activation in pauci-immune necrotizing and crescentic glomerulonephritis: results of a proteomic analysis.
abstract: BACKGROUND
  Complement activation plays an important role in the pathophysiology of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), although it remains unclear which pathway is activated. Whether pauci-immune necrotizing crescentic glomerulonephritis (pauci-immune GN) with negative ANCA serology is part of the spectrum of AAV or a different disease entity is essentially unknown.
  
  
  METHODS
  We used proteomic analysis to delineate the complement profile in a series of 13 kidney biopsies of patients with pauci-immune GN, with either proteinase 3 (PR3) (five patients) or myeloperoxidase (MPO) antibodies (four patients) or with consistently negative ANCA serology (four patients). Immunofluorescence staining of glomeruli was essentially negative in the PR3-ANCA and MPO-ANCA groups, while a mild staining for C3 was seen in the ANCA-negative cases. No electron-dense deposits were found in the PR3-ANCA and MPO-ANCA groups, but mesangial and few subepithelial deposits were clearly present in the ANCA-negative specimens.
  
  
  RESULTS
  Mass spectrometry revealed low spectra numbers for C3 and immunoglobulins in both PR3-positive and MPO-positive patients with minimal or no C4 and C9. In contrast, larger spectra numbers for C3, moderate spectra numbers for C9, complement factor H-related protein-1 and low spectra numbers for C4, C5 and immunoglobulins were found in the ANCA-negative cases.
  
  
  CONCLUSIONS
  While complement activation is noted in AAV, the complement activation appears to be more prominent in the ANCA-negative glomerulonephritis. The larger amount of C3 and moderate amount of C9 in the ANCA-negative glomerulonephritis implies activation of the alternate and terminal pathway of complement, suggesting that this entity may be caused or promoted by a genetic or acquired defect in the alternative pathway.
authors.affiliation: Division of Anatomic Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Sethi
authors.affiliation: Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: Ladan
authors.initials: L
authors.lastname: Zand
authors.affiliation: Division of Nephrology, AZ Sint-Jan Brugge-Oostende AV, Brugge, Belgium.
authors.forename: An S
authors.initials: AS
authors.lastname: De Vriese
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Specks
authors.affiliation: Division of Anatomic Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Vrana
authors.affiliation: University of Wisconsin, Madison, WI, USA.
authors.forename: Siddak
authors.initials: S
authors.lastname: Kanwar
authors.affiliation: Division of Anatomic Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Kurtin
authors.affiliation: Division of Anatomic Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Theis
authors.affiliation: Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Angioi
authors.affiliation: Division of Anatomic Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Lynn
authors.initials: L
authors.lastname: Cornell
authors.affiliation: Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: Fernando C
authors.initials: FC
authors.lastname: Fervenza
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis / Q000276:immunology*; D015415:Biomarkers / Q000378:metabolism; D003167:Complement Activation / Q000276:immunology*; D005260:Female; D005921:Glomerulonephritis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D053146:Myeloblastin / Q000276:immunology*; D009195:Peroxidase / Q000276:immunology*; D020543:Proteome / Q000032:analysis*; D040901:Proteomics / Q000379:methods; D055815:Young Adult
chemical_list: D015415:Biomarkers; D020543:Proteome; D009195:Peroxidase; D053146:Myeloblastin
keywords: alternative pathway; anti-neutrophil cytoplasmic antibody; complement; crescentic glomerulonephritis; mass spectrometry; pauci-immune