Pathogenesis of glomerulonephritis (IgA nephropathy and FcαR)

伊加肾病患者肾小球系膜细胞的伊加沉积是其最重要的表现之一，但系膜细胞的活化是否由伊加直接触发尚不清楚，FcαR是伊加在各种细胞中结合的主要受体，并对结合表现出不同的免疫反应。尽管Fc α R在伊加肾病发病机制中对分析系膜功能具有重要意义，但其是否在系膜细胞上表达仍存在争议。本研究建立了表达FcαR和Fc γ R的系膜细胞转染株，并对其生物学功能进行了初步研究。我们证实了系膜细胞具有细胞活化的潜力这些结果表明，FcαR与FcRγ链可能有助于系膜对伊加沉积的反应。我们最近发现了两种新的多态性，FcαR基因功能性启动子区的-114 T/C和+56 T/C（相对于主要转录起始位点）。由于FcαR表达的改变可能与伊加肾病相关，我们检测了这种疾病中的这些启动子多态性。伊加肾病患者的+56C等位基因和CC基因型频率显著高于其他原发性肾小球肾炎患者和健康成人。与此相反，在其他原发性肾小球肾炎患者和健康成人之间未观察到+56CC基因型和+56C等位基因的频率的显着差异。伊加肾病患者114 CC基因型频率也显著高于对照组。FcαR启动子区多态性与伊加肾病易感性相关，提示FcαR基因及其表达在IgA肾病中的重要性。

One of the most critical findings in patients with IgA nephropathy is glomerular mesangial deposition of IgA.It is still unknown whether the activation of mesangial cells is directly triggered by IgA.FcαR is the major receptor for binding of IgA in various cells, and displays various immunological responses on binding. There is controversy as to whether FcαR is expressed on mesangial cells, although it is important to analyze the mesangial functions via FcαR in the pathogenesis of IgA nephropathy. In this time, we established mesangial transfectants which expressed FcαR and FcR γ chain, and then analyzed the biological function. We confirmed that mesangial cells had potential for cell-activation (tyrosine phosphorylation, syk activation arid MCP-1 production) with FcαR cross-linking.These results suggested that FcαR with the FcRγ, chain may contribute to the mesangial response to IgA deposition.Next, we have recently identified two novel polymorphisms (-114T/C and +56T/C relative to the major transcription start site) in the functional promoter region of the FcαR gene. Since altered FcαR expression may be associated with IgA nephropathy, we examined these promoter polymorphisms in this disease. The study demonstrated that the frequency of the +56C allele and CC genotype in patients with IgA nephropathy was significantly higher than that in patients with other primary glomerulonephritis and healthy adults. In contrast, no significant difference in the frequencies of the +56CC genotype and +56C allele was observed between other primary glomerulonephritis patients and healthy adults. The frequency of the 114CC genotype in patients with IgA nephropathy was also significantly increased, compared with those in both control groups. It appears that polymorphisms of the FcαR promoter region are associated with susceptibility to IgA nephropathy, suggesting the importance of the FcαR gene and its expression in this disease.