Pathogenesis and significance of glomerular C4d deposition in lupus nephritis: activation of classical and lectin pathways

Abstract

Immune complex-mediated complement activation through the classic pathway plays a key role in the pathogenesis of lupus nephritis (LN). C4d deposition in renal tissue reflects the prognosis of systemic lupus erythematosus (SLE). The aim of the current study is to investigate the pathogenesis and clinicopathologic significance of glomerular C4d deposition in LN. We retrospectively analyzed clinical and histopathological data of 20 SLE patients with renal biopsy-proven LN and 10 non-SLE renal biopsy samples as control. LN biopsies showed varying degrees of glomerular C4d staining associated with immune complex deposits, IgG (p = 0.015), C1q (p = 0.032) and C3 (p = 0.049). 7 LN biopsies had all of C4d, C1q and C3 deposits in their glomeruli, indicative of the activation of the classical pathway, whereas 2 LN biopsies had C4d and C3 deposits without accompanying C1q deposits, indicating the activation of the lectin pathway. Glomerular C4d deposition was correlated with the LN subtype (p < 0.001). In particular, a diffusely intense and coarsely granular pattern of C4d deposition in all glomeruli was detected in class V membranous LN. However, glomerular C4d deposition was correlated with neither disease activity of SLE nor histological activity and chronicity of LN. In conclusion, the activation of the lectin pathway as well as the classical pathway seems to play a crucial role in the pathogenesis of LN. Glomerular C4d staining could be helpful for diagnosing class V membranous LN, although glomerular C4d deposition does not reflect SLE disease activity and histological activity and chronicity.

Keywords: C4d; Lupus nephritis; classical pathway; disease activity; lectin pathway.

Figure 1

A representative renal biopsy specimen showing activation of the lectin pathway in lupus nephritis (case No. 9). A: Light microscopy in class IV diffuse LN shows increased mesangial cellularity with focally lobular accentuation, hyaline thrombi (arrow) and a few areas of glomerular leukocytic infiltration (hematoxylin and eosin, x 400). B: Mild glomerular C4d staining in the same case is observed along the glomerular capillary loops, represented by +1 (anti-C4d, x 400). C: No C1q deposition in the same case is observed in the glomerulus (anti-C1q immunofluorescence, x 400). D: Immunofluorescence microscopy in the same case reveals trace staining of C3 in the peripheral capillary walls (anti-C3 immunofluorescence, x 400). E: Immunofluorescence microscopy in the same case reveals a weak and granular pattern of IgG deposition in the peripheral capillary walls (anti-IgG immunofluorescence, x 400). F: Electron microscopy in the same case reveals subendothelial deposits (arrow) with effacement of foot processes (transmission electron microscopy, x 8,000).

Figure 2

A representative renal biopsy specimen showing activation of the classical pathway in lupus nephritis (case No. 1). A: Light microscopy in class IV LN shows increased mesangial cellularity with focal lobular accentuation, hyaline thrombi (arrow) and glomerular leukocytic infiltration. A greater degree of periglomerular interstitial inflammation is also noted (hematoxylin and eosin, x 400). B: Moderate glomerular C4d staining in the same case is observed along the glomerular capillary loops and in the mesangium (anti-C4d, x 400). C-E: Immunofluorescence microscopy in the same case reveals granular deposition of C1q (C), C3 (D) and IgG (E) both in the measangium and in the peripheral capillary walls (original magnification x 400). F: Electron microscopy in the same case shows subendothelial deposits along the capillary loops. Loss of foot processes is also observed (transmission electron microscopy, x 8,000).

Figure 3

Glomerular C4d staining in class V membranous lupus nephritis (case No. 4). A: Light microscopy in class V membranous LN shows diffuse thickening of the capillary walls or “wire loop” lesions (arrow) (hematoxylin and eosin, x 400). B: Intense glomerular C4d staining in the same case shows a uniformly strong, diffusely intense and coarsely granular pattern along the glomerular capillary loops, represented by +++. Inset: C4d deposits along the glomerular capillary loops resemble the spikes (anti-C4d, x 400). C: Immunofluorescence microscopy in the same case reveals a granular pattern of IgG deposition in the peripheral capillary walls (anti-IgG immunofluorescence, x 400). D: Markedly thickened glomerular basement membrane and small spikes are seen. Inset: Well-developed spikes are present (periodic acid methanemine silver, x 400). E: Electron microscopy in the same case reveals numerous subepithelial deposits (arrow) scattered throughout the capillary loops (transmission electron microscopy, x 8,000). F: The pattern of glomerular C4d staining in membranous nephropathy (positive control) is similar to the C4d staining pattern in case No. 5 class V membranous LN (anti-C4d, x 400).