Aberrantly glycosylated IgA1 in IgA nephropathy patients is recognized by IgG antibodies with restricted heterogeneity
Aberrantly glycosylated IgA1 in IgA nephropathy patients is recognized by IgG antibodies with restricted heterogeneity
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DOI：
10.1172/jci38468
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发表时间：
2009-06-01
影响因子：
15.9
通讯作者：
Novak, Jan
中科院分区：
文献类型：
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作者：
Suzuki, Hitoshi;Fan, Run;Novak, Jan
伊加肾病（IgAN）的特征在于由半乳糖缺陷型IgA1和聚糖特异性IgG抗体组成的循环免疫复合物。这些免疫复合物存款在肾小球系膜中并诱导IgAN特征性的系膜增生性肾小球肾炎。为了确定IgG抗体的精确特异性和分子特性，我们从IgAN患者中产生EBV永生化IgG分泌淋巴细胞，并发现分泌的IgG以聚糖依赖性方式与半乳糖缺陷型IgA 1形成复合物。我们克隆和测序的重链和轻链的抗原结合域的特异性半乳糖缺乏的IgA 1和确定的A到S的替代在互补决定区3的可变区的基因编码的IgG重链的IgAN患者。此外，定点诱变，恢复残基丙氨酸减少了半乳糖缺陷型IgA 1的重组IgG的结合。最后，我们开发了一种斑点印迹法检测聚糖特异性IgG抗体，该抗体将IgAN患者与健康和疾病对照区分开来，特异性为88%，灵敏度为95%，并发现IgAN患者血清中该抗体水平升高与蛋白尿相关。总的来说，这些发现表明聚糖特异性抗体与IgAN的发展相关，并可能代表疾病特异性标志物和潜在的治疗靶点。
IgA nephropathy (IgAN) is characterized by circulating immune complexes composed of galactose-deficient IgA1 and a glycan-specific IgG antibody. These immune complexes deposit in the glomerular mesangium and induce the mesangioproliferadve glomerulonephritis characteristic of IgAN. To define the precise specificities and molecular properties of the IgG antibodies, we generated EBV-immortalized IgG-secreting lymphocytes from patients with IgAN and found that the secreted IgG formed complexes with galactose-deficient IgA1 in a glycan-dependent manner. We cloned and sequenced the heavy- and light-chain antigen-binding domains of IgG specific for galactose-deficient IgA1 and identified an A to S substitution in the complementarity-determining region 3 of the variable region of the gene encoding the IgG heavy chain in IgAN patients. Furthermore, site-directed mutagenesis that reverted the residue to alanine reduced the binding of recombinant IgG to galactose-deficient IgA1. Finally, we developed a dot-blot assay for the glycan-specific IgG antibody that differentiated patients with IgAN from healthy and disease controls with 88% specificity and 95% sensitivity and found that elevated levels of this antibody in the sera of patients with IgAN correlated with proteinuria. Collectively, these findings indicate that glycan-specific antibodies are associated with the development of IgAN and may represent a disease-specific marker and potential therapeutic target.