Glomerular cells do not express the C5a receptor in human glomerulonephritis

K. Lhotta1, P. König1, G. Mayer1 and M. Oppermann2

1 Department of Clinical Nephrology, Innsbruck University Hospital, Austria, 2 Department of Immunology, University of Göttingen, Germany

Sir,

Complement is a major mediator of glomerular inflammation in several form of glomerulonephritis such as lupus nephritis, membranous nephritis, anti-GBM nephritis, or IgA nephropathy. Activation of the terminal pathway leads to cleavage of C5 and release of the potent anaphylatoxin C5a. C5a and its catabolite C5a(desArg) mediate their potent pro-inflammatory effects through binding to the C5a receptor CD88. The G-protein-coupled receptor is expressed mainly by cells of myeloid origin such as macrophages and neutrophils. CD88 expression has also been reported in lung, liver, and brain tissue [1]. A recent report describes expression of CD88 on cultured human mesangial cells. Stimulation of the receptor caused mildly enhanced proliferation and synthesis of MCP-1 and platelet-derived growth factor (PDGF) [2]. The C5a receptor has also been described on proximal tubular cells and macrophages in normal renal tissue [3].

These reports prompted us to investigate CD88 expression in human renal diseases, mainly glomerulonephritis. Thirty-one consecutive renal biopsies and one normal control tissue from a kidney removed for renal-cell carcinoma were investigated. The diagnostic groups are shown in Table 1Go. Of the four patients with rapidly progressive glomerulonephritis (RPGN), two had anti-GBM nephritis, one an antineutrophilic cytoplasmic antibody (ANCA)-associated nephritis, and one suffered from Henoch–Schönlein purpura. The biopsies were investigated using the direct immunofluorescence method. Five-micrometre-thick acetone-fixed cryostat section were incubated with two well-characterized monoclonal anti-CD88 antibodies P12/11 (2 µg/ml) and D12/1 (4 µg/ml) for 30 min [3]. In addition, a mouse monoclonal anti-leukocyte common antigen–antibody was used to stain all leukocytes. After washing in phosphate-buffered saline a fluorescein isothiocyanate (FITC)-conjugated polyclonal rabbit-anti-mouse immunoglobulin antibody was applied.


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Table 1 CD88 expression of leukocytes per glomerular cross-section

 
In normal renal tissue we found CD88 on proximal tubular epithelial cells with some predominance on the basolateral membrane (Figure 1aGo). In addition a few interstitial cells were CD88 positive. No staining of intrinsic glomerular cells was observed in normal renal tissue or in all cases of glomerulonephritis or interstitial nephritis. Tubular staining was unaltered in most biopsies and reduced only in areas of severe tubular damage. The only cells in the glomeruli expressing CD88 were infiltrating leukocytes (Figure 1bGo). The total leukocyte counts and CD88-positive leukocyte counts per glomerular cross-section are shown in Table 1Go. Most of the intraglomerular leukocytes are CD88 positive. These cells are likely to be macrophages, which comprise the majority of intraglomerular cells in glomerulonephritis. In addition, a great proportion of cells infiltrating the interstitium in severe proliferative glomerulonephritis and interstitial nephritis also express CD88.



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Fig. 1 (a) Expression of CD88 on proximal tubular epithelial cells in a case of membranous nephropathy (x200). (b) Staining of intraglomerular leukocytes in a case of Goodpasture's syndrome (x400).

 
Based on our results we propose that the anaphylatoxin C5a exerts no direct effect on intrinsic glomerular cells in glomerulonephritis. C5a rather has an indirect proinflammatory effect by attracting and activating leukocytes, predominantly macrophages, in the glomeruli. The physiological and pathophysiological consequences of CD88 on proximal tubular epithelial cells are unknown. Usually complement activation is not a predominant feature of interstitial nephritis or interstitial infiltration in glomerulonephritis. C5a generated by complement activation in the glomeruli might enter the urine and bind to its receptor on the luminal membrane of the tubular epithelial cells. Investigation of the effects of C5a on tubular epithelial cells is expected to provide interesting new insights into the pathogenesis of tubulointerstitial involvement in glomerulonephritis.

References

  1. Ember JA, Jagels MA, Hugly TE. Characterization of complement anaphylatoxins and their biological responses. In: Volonakis JE, Frank MM, eds. The Human Complement System in Health and Disease. Marcel Dekker, New York, 1998; 241–284
  2. Braun M, Davis AE. Cultured human glomerular mesangial cells express the C5a receptor. Kidney Int1998; 54: 1542–1549[ISI][Medline]
  3. Fayyazi A, Scheel O, Werfel T et al. The C5a receptor is expressed in normal renal proximal tubular but not in normal pulmonary or hepatic epithelial cells. Immunology2000; 99: 38–45[ISI][Medline]




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