Fc receptor-mediated accumulation of macrophages in crescentic glomerulonephritis induced by anti-glomerular basement membrane antibody administration in WKY rats
Fc receptor-mediated accumulation of macrophages in crescentic glomerulonephritis induced by anti-glomerular basement membrane antibody administration in WKY rats
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DOI：
10.1093/intimm/dxh058
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发表时间：
2004-05-01
影响因子：
4.4
通讯作者：
Yamamoto, T
中科院分区：
文献类型：
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作者：
Kovalenko, P;Fujinaka, H;Yamamoto, T
WKY大鼠诱导的抗肾小球基底膜(GBM)肾小球肾炎以CD8(+)T细胞和单核/巨噬细胞在肾小球内积聚为特征，并伴有新月体形成。抗体与GBM结合后白细胞聚集的机制尚不清楚。为了揭示FcGamma受体(FcGammaR)在白细胞募集中的作用，我们检测了FcGammaR在肾小球中的表达，以及应用抗GBM抗体F(ab‘)(2)片段或阻断FcGammaR对该模型的发生和发展的影响。随着病程的延长，肾小球FcGammaR mRNA的表达逐渐增加，提示其在肾炎的发生发展中具有重要意义。仅注射完整抗GBM抗体的大鼠肾小球病变和蛋白尿，而不注射F(ab‘)(2)片段。体内应用热聚合型Ig G阻断FcGammaR可降低各型FcGammaR(1、2和3型)的mRNA表达，并显著改善肾小球肾炎的临床表现。经流式细胞术和免疫组织化学鉴定，肾小球内表达FcGammaR2的细胞为巨噬细胞，而不是CD8(+)T细胞。CD8(+)T细胞耗竭大鼠FcGammaR1和FcGammaR2的表达显著降低，FcGammaR2的表达消失。因此，CD8(+)T细胞可能刺激巨噬细胞表面FcGammaR的表达，从而促进其在肾小球的聚集和损伤。这些研究为免疫球蛋白Fc-FcGammaR相互作用在肾小球巨噬细胞募集和诱导WKY大鼠抗肾小球基底膜肾炎中发挥重要作用提供了直接证据。
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 Fcgamma receptors (FcgammaR) in leukocytes recruitment we examined the expression of FcgammaR in glomeruli and the effects of the administration of F(ab')(2) fragment of anti-GBM antibody or FcgammaR blocking on the initiation and progression of this model. A gradual increase of FcgammaR 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 FcgammaR by administering heat-aggregated IgG led to the decrease of mRNA expression for all types of FcgammaR (types 1, 2 and 3) and a significant amelioration of glomerulonephritis manifestations. By flow cytometry and immunohistochemistry FcgammaR2-expressing cells in glomeruli were identified as macrophages, but not CD8(+) T cells. The expression of FcgammaR1 and 3 was significantly decreased, and that of FcgammaR2 became undetectable in CD8(+) T cell-depleted rats. Thus, CD8(+) T cells may stimulate FcgammaR expression on macrophages, contributing to their glomerular accumulation and injury. These studies provide direct evidence for a crucial involvement of IgG Fc-FcgammaR interaction in glomerular recruitment of macrophages and following induction of anti-GBM glomerulonephritis in WKY rats.