Pathogenesis of glomerulonephritis (IgA nephropathy and FcαR)

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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.