Determination of Severity of Murine IgA Nephropathy by Glomerular Complement Activation by Aberrantly Glycosylated IgA and Immune Complexes
Determination of Severity of Murine IgA Nephropathy by Glomerular Complement Activation by Aberrantly Glycosylated IgA and Immune Complexes
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DOI：
10.1016/j.ajpath.2012.06.038
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发表时间：
2012-10-01
影响因子：
6
通讯作者：
Tomino, Yasuhiko
中科院分区：
文献类型：
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作者：
Hashimoto, Azusa;Suzuki, Yusuke;Tomino, Yasuhiko
IgA 肾病 (IgAN) 中补体级联成分的肾小球沉积的致病作用尚未完全阐明。为了研究补体途径在 IgAN 中的病理作用，研究了两种易发生 IgAN 的小鼠模型。与高血清 IgA (HIGA) 小鼠相比，分组的 ddY (gddY) 小鼠表现出显着的高蛋白尿、严重肾小球病变和细胞外基质扩张，但肾小球 IgA 沉积强度相似。 gddY 小鼠中补体 (C)3、C5b-9、C1q、C4、甘露糖结合凝集素 (MBL)-A/C、MBL 相关丝氨酸蛋白酶-2、因子 B 和备解素的染色明显强于 HIGA 小鼠，证明了经典途径、凝集素和旁路途径的肾小球激活。同样，gddY 小鼠的 IgA-IgG2a/IgM 和 IgA-MBL-A/C 免疫复合物以及聚合 IgA 的血清水平显着高于 HIGA 小鼠。此外，gddY 小鼠中以接骨木树皮凝集素和蓖麻凝集素 I 结合为特征的异常糖基化 IgA 的血清水平显着高于 HIGA 小鼠。使用气液色谱法对纯化的 IgA 进行单糖成分分析，证实了这种糖基化异常。这项研究首次证明异常糖基化 IgA 可能会影响大分子 IgA（包括 IgA-IgG 免疫复合物）的形成以及随后的补体激活，从而导致 IgAN 的全面进展。 （Am J Pathol 2012 年，181：1338-1347；http://dx.doi.org/10.1016/j.ajpath.2012.06.038）
The pathogenic roles of glomerular deposition of components of the complement cascade in IgA nephropathy (IgAN) are not completely clarified. To investigate the pathologic role of complement pathways in IgAN, two IgAN-prone mouse models were examined. Grouped ddY (gddY) mice showed significant high proteinuria, severe glomerular lesions, and extracellular matrix expansion compared with high serum IgA (HIGA) mice but with similar intensity of glomerular IgA deposition. Glomerular activation of the classical, lectin, and alternative pathways was demonstrated by significantly stronger staining for complement (C)3, C5b-9, C1q, C4, mannose-binding lectin (MBL)-A/C, MBL-associated serine protease-2, and factor B and properdin in gddY mice than in HIGA mice. Similarly, the serum levels of IgA-IgG2a/IgM and IgA-MBL-A/C immune complexes and polymeric IgA were significantly higher in gddY mice than in HIGA mice. Moreover, the serum levels of aberrantly glycosylated IgA characterized by the binding of Sambucus nigra bark lectin and Ricinus communis agglutinin I were significantly higher in gddY mice than in HIGA mice. This aberrancy in glycosylation was confirmed by monosaccharide compositional analysis of purified IgA using gas-liquid chromatography. This study is the first to demonstrate that aberrantly glycosylated IgA may influence the formation of macromolecular IgA including IgA-IgG immune complexes and subsequent complement activation, leading to full progression of IgAN. (Am J Pathol 2012, 181:1338-1347; http://dx.doi.org/10.1016/j.ajpath.2012.06.038)