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Complement activation in pauci-immune necrotizing and crescentic glomerulonephritis: results of a proteomic analysis
Sanjeev Sethi1, Ladan Zand2, An S De Vriese3
1Division of Anatomic Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
Insights
Complement activation is key in anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). This study found more complement activation in ANCA-negative glomerulonephritis, suggesting alternative pathway involvement.
Area of Science:
- Nephrology
- Immunology
- Pathophysiology
Background:
- Complement activation significantly impacts anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) pathogenesis.
- The specific complement pathway involved in AAV remains unclear.
- The relationship between pauci-immune necrotizing crescentic glomerulonephritis (pauci-immune GN) with negative ANCA serology and AAV is not well-defined.
Purpose of the Study:
- To investigate the complement profiles in kidney biopsies of patients with pauci-immune GN.
- To compare complement activation patterns between ANCA-positive (PR3-ANCA, MPO-ANCA) and ANCA-negative pauci-immune GN.
- To elucidate the role of complement in ANCA-negative pauci-immune GN.
Main Methods:
- Proteomic analysis of 13 kidney biopsies from patients with pauci-immune GN.
- Categorization into PR3-ANCA positive, MPO-ANCA positive, and ANCA-negative groups.
- Immunofluorescence staining and electron microscopy to assess glomerular findings and complement deposition.
Main Results:
- Low complement C3 and immunoglobulin spectra in PR3-ANCA and MPO-ANCA groups, with minimal C4 and C9.
- Higher C3 and moderate C9 spectra in ANCA-negative cases, alongside complement factor H-related protein-1.
- Immunofluorescence showed mild C3 staining in ANCA-negative cases, while electron microscopy revealed deposits absent in ANCA-positive groups.
Conclusions:
- Complement activation is more pronounced in ANCA-negative glomerulonephritis compared to ANCA-associated vasculitis.
- Elevated C3 and C9 in ANCA-negative cases suggest alternative and terminal complement pathway activation.
- This points to a potential genetic or acquired defect in the alternative pathway contributing to ANCA-negative glomerulonephritis.
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.
Conclusion:
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.