Abstract
Linear deposition of IgG and complement 3 (C3) along glomerular basement membrane (GBM) is generally revealed in the kidneys of human anti-GBM disease. Our recent studies demonstrated the pathogenic role of complement activation in renal damage of this disease. However, the pathways of complement activation were still paradoxical. In this study, renal biopsy tissues from 10 patients with anti-GBM disease were used to investigate the pathways of complement activation by detecting the deposition of various complement components, including C1q, factor B, factor P (properdin), mannose-binding lectin (MBL), C3d, C4d and C5b-9, using immunohistochemistry and immunofluorescence. We found that C1q, factor B, properdin, C3d, C4d and C5b-9 were detected in all the glomeruli of our patients, along GBM with a linear and/or granular staining pattern. Furthermore, C1q, factor B and properdin co-localized well with C5b-9. The properdin also co-localized well with C3d. However, the deposition of MBL was diffusive in mesangium, GBM, Bowman's capsule and within crescents and was not co-localized with C5b-9 but partially co-localized with C4d. The intensity of factor B deposition (3.3 vs. 1.2, P<0.001) and C5b-9 deposition (3.2 vs. 1.6, P<0.001) was significantly stronger in the glomeruli with crescent formation, compared with the glomeruli without crescents. The complement system is overall activated via both the alternative pathway and classical pathway in the kidneys of human anti-GBM disease. The alternative pathway might play an important role in complement activation induced renal damage.
Highlights
Anti-glomerular basement membrane (GBM) disease is a rare but life-threatening autoimmune disease, which clinically manifests rapidly progressive glomerulonephritis with or without pulmonary hemorrhage [1,2]
In the renal biopsy of patients, linear deposition of IgG is often accompanied by complement 3 (C3) deposits, on glomerular capillary wall (GCW) in linear or granular staining pattern, which indicates that complement activation is involved in the kidney injury [5]
C3d deposition on glomerular capillary wall was shown in each glomerulus of all patients with anti-GBM disease, even in those C3c negative cases, which indicated that the complement system was activated after the binding of anti-GBM IgG to the target antigens
Summary
Anti-glomerular basement membrane (GBM) disease is a rare but life-threatening autoimmune disease, which clinically manifests rapidly progressive glomerulonephritis with or without pulmonary hemorrhage [1,2]. Our recent study in human anti-GBM disease identified that the plasma level of the terminal component of complement activation, C5b-9, named as membrane attack complex, was closely associated with the severity of kidney damage and was the predictor for renal failure during patient follow up [6]. The pathways of complement activation in anti-GBM disease are largely studied by passive injection of heterologous antibodies against GBM. Anti-GBM disease is a well-known autoantibody induced disease, C1q, the key component of classical pathway, is seldom found deposit in the renal biopsy specimens [5]. We investigated the deposition of various complement components in the renal biopsy specimens from patients with anti-GBM disease, with the aim to clarify the pathways of complement activation in the kidney injury of human anti-GBM disease
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