Pathogenesis of glomerulonephritis (IgA nephropathy and FcαR)

Ig A肾病患者最重要的表现之一是肾小球系膜沉积，目前尚不清楚系膜细胞的激活是否由Ig A直接触发，FcαR是多种细胞中Ig A结合的主要受体，在结合时表现出多种免疫学反应。尽管通过FcαR分析肾小球系膜功能在α肾病的发病机制中具有重要意义，但对其是否在系膜细胞上表达仍存在争议。在此期间，我们建立了表达FcαR和FcRγ链的系膜细胞，并对其生物学功能进行了分析。我们证实了FcαR具有激活系膜细胞的潜能(酪氨酸磷酸化、SYK激活和单核细胞趋化蛋白-1的产生)。这些结果表明，FcαR及其γ链可能参与了系膜细胞对免疫球蛋白沉积的反应。由于FcαR表达改变可能与免疫球蛋白A肾病有关，我们研究了这种疾病中这些启动子的多态性。研究表明，IgA肾病患者的+56C等位基因频率和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。而在其他原发性肾小球肾炎患者中，+56CC等位基因和+56C等位基因频率与正常成人相比无显著差异。IgA肾病患者的114CC基因频率也显著高于两个对照组。提示FcαR基因启动子区的多态性与IgA肾病的易感性有关，提示FcαR基因及其表达在本病中的重要作用。

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.