Glycosylation and size of IgA1 are essential for interaction with mesangial transferrin receptor in IgA nephropathy
Glycosylation and size of IgA1 are essential for interaction with mesangial transferrin receptor in IgA nephropathy
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DOI：
10.1097/01.asn.0000115401.07980.0c
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发表时间：
2004-03-01
影响因子：
13.6
通讯作者：
Monteiro, RC
中科院分区：
文献类型：
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作者：
Moura, IC;Arcos-Fajardo, M;Monteiro, RC
转铁蛋白受体(TFR)是一种表达于人肾小球系膜细胞(HMC)的候选IgA1受体。TfR与IgA1结合，但不与IgA2结合，与血管内沉积的IgA1共定位，在IgA肾病(IgAN)患者中高表达。在这里，分析了免疫球蛋白A1与系膜TFR相互作用的结构要求。聚合的而非单体的IgA1与培养的HMC上的TFR相互作用，并介导内化。可溶性TfR1和TfR2均能显著抑制IgA1的结合(>；50%)，证实TfR是系膜上的IgA1受体。IgAN患者的低半乳糖化血清IgA1与TFR的结合比健康人的IgA1更有效。与正常人相比，糖基化异常的IgA肾病患者的血清IgA免疫复合物与TFR结合的能力更强。这种结合被可溶性TFR显著抑制，突显了TFR在系膜IgA1沉积中的作用。为了阐明糖基化位点在IgA1-TFR相互作用中的潜在作用，我们使用了多种重组二聚体IgA1分子来研究TFR与只表达TFR作为IgA受体的Daudi细胞的结合。N-或O-连接的糖基化位点的缺失取消了IgA1与TFR的结合，表明糖对IgA1的结合是必不可少的。然而，唾液酸酶和β-半乳糖苷酶处理的IgA1显著增强了IgA1/TFR的相互作用。这些结果表明，IgA1的异常糖基化和免疫复合体的形成是促使TFR-IgA1相互作用的基本因素，是IgAN发病的初始步骤。
Transferrin receptor (TfR) has been identified as a candidate IgA1 receptor expressed on human mesangial cells (HMC). TfR binds IgA1 but not IgA2, co-localizes with inesangial IgA1 deposits, and is overexpressed in patients with IgA nephropathy (IgAN). Here, structural requirements of IgA1 for its interaction with mesangial TfR were analyzed. Polymeric but not monomeric IgA1 interacted with TfR on cultured HMC and mediates internalization. IgA1 binding was significantly inhibited (>50%) by soluble forms of both TfR1 and TfR2, confirming that TfR serves as mesangial IgA1 receptor. Hypogalactosylated serum IgA1 from patients with IgAN bound TfR more efficiently than IgA1 from healthy individuals. Serum IgA immune complexes from patients with IgAN containing aberrantly glycosylated IgA1 bound more avidly to TfR than those from normal individuals. This binding was significantly inhibited by soluble TfR, highlighting the role of TfR in mesangial IgA1 deposition. For addressing the potential role of glycosylation sites in IgA1-TfR interaction, a variety of recombinant dimeric IgA1 molecules were used in binding studies on TfR with Daudi cells that express only TfR as IgA receptor. Deletion of either N- or O-linked glycosylation sites abrogated IgA1 binding to TfR, suggesting that sugars are essential for IgA1 bindincy. However, sialidase andbeta-galactosidase treatment of IgA1 significantly enhanced IgA1/TfR interaction. These results indicate that aberrant glycosylation of IgA1 as well as immune complex formation constitute essential factors favoring inesangial TfR-IgA1 interaction as initial steps in IgAN pathogenesis.