Fc receptor-mediated accumulation of macrophages in crescentic glomerulonephritis induced by anti-glomerular basement membrane antibody administration in WKY rats

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Abstract
Anti‐glomerular basement membrane (GBM) glomerulonephritis induced in WKY rats is characterized by glomerular accumulation of CD8+ T cells and monocytes/macrophages, followed by crescent formation. The mechanism of leukocyte accumulation after antibody binding to GBM is still unclear. To unveil an involvement of Fcγ receptors (FcγR) in leukocytes recruitment we examined the expression of FcγR in glomeruli and the effects of the administration of F(ab′)2 fragment of anti‐GBM antibody or FcγR blocking on the initiation and progression of this model. A gradual increase of FcγR mRNA expression in glomeruli during the time course of disease suggested their significance in the development of glomerulonephritis. Glomerular lesions and proteinuria were induced only in rats injected with intact IgG of anti‐GBM antibody, but not with the F(ab′)2 fragment. In vivo blocking of FcγR by administering heat‐aggregated IgG led to the decrease of mRNA expression for all types of FcγR (types 1, 2 and 3) and a significant amelioration of glomerulonephritis manifestations. By flow cytometry and immunohistochemistry FcγR2‐expressing cells in glomeruli were identified as macrophages, but not CD8+ T cells. The expression of FcγR1 and 3 was significantly decreased, and that of FcγR2 became undetectable in CD8+ T cell‐depleted rats. Thus, CD8+ T cells may stimulate FcγR expression on macrophages, contributing to their glomerular accumulation and injury. These studies provide direct evidence for a crucial involvement of IgG Fc–FcγR interaction in glomerular recruitment of macrophages and following induction of anti‐GBM glomerulonephritis in WKY rats.

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