Experimental evidence of pathogenic role of IgG autoantibodies in IgA nephropathy.
Experimental evidence of pathogenic role of IgG autoantibodies in IgA nephropathy.
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IgG自身抗体在伊加肾病中致病作用的实验证据
DOI：
10.1016/j.jaut.2021.102593
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发表时间：
2021-03
影响因子：
12.8
通讯作者：
Novak J
中科院分区：
文献类型：
--
作者：
Moldoveanu Z;Suzuki H;Reily C;Satake K;Novak L;Xu N;Huang ZQ;Knoppova B;Khan A;Hall S;Yanagawa H;Brown R;Winstead CJ;O'Quinn DB;Weinmann A;Gharavi AG;Kiryluk K;Julian BA;Weaver CT;Suzuki Y;Novak J
IgA 肾病被认为是一种自身免疫性疾病，其中半乳糖缺陷型 IgA1 (Gd-IgA1) 被 IgG 自身抗体识别，导致肾炎性免疫复合物的形成和肾脏积聚。尽管这一假设得到了最近发现的支持，即在 IgA 肾病患者的肾脏免疫沉积物中，IgG 富含 Gd-IgA1 特异性自身抗体，但仍缺乏实验证据。从 IgA 肾病患者血清中分离的 IgG 或作为重组 IgG (rIgG) 生产的 IgG 与人 Gd-IgA1 混合，形成免疫复合物。来自健康个体的 IgG 作为对照。裸鼠和 SCID 小鼠被注射免疫复合物或单独的人 IgG 和 Gd-IgA1，并通过免疫荧光确定它们在肾脏中的存在。通过定量形态测定法评估肾小球的病理变化，并通过 RNA-Seq 进行探索性转录组分析。注射 Gd-IgA1 与来自 IgA 肾病患者的 IgG 自身抗体混合的免疫缺陷小鼠，而不是注射 Gd-IgA1 与来自健康个体的 IgG 混合的免疫缺陷小鼠，显示出 IgA、IgG 和小鼠补体 C3 肾小球沉积以及伴有血尿和蛋白尿的系膜增生性肾小球损伤。未复合的Gd-IgA1或IgG不引起病理变化。此外，将 Gd-IgA1-rIgG 免疫复合物注射到免疫缺陷小鼠体内会诱导人类疾病特征的组织病理学变化。小鼠肾组织的探索性转录组分析表明，这些免疫复合物改变了多种途径的基因表达，与 IgA 肾病患者肾活检中观察到的变化一致。这项研究为 Gd-IgA1 特异性 IgG 自身抗体在 IgA 肾病发病机制中的致病作用提供了第一个体内证据。
IgA nephropathy is thought to be an autoimmune disease wherein galactose-deficient IgA1 (Gd-IgA1) is recognized by IgG autoantibodies, resulting in formation and renal accumulation of nephritogenic immune complexes. Although this hypothesis is supported by recent findings that, in renal immunodeposits of IgA nephropathy patients, IgG is enriched for Gd-IgA1-specific autoantibodies, experimental proof is still lacking. IgG isolated from sera of IgA nephropathy patients or produced as a recombinant IgG (rIgG) was mixed with human Gd-IgA1 to form immune complexes. IgG from healthy individuals served as a control. Nude and SCID mice were injected with human IgG and Gd-IgA1, in immune complexes or individually, and their presence in kidneys was ascertained by immunofluorescence. Pathologic changes in the glomeruli were evaluated by quantitative morphometry and exploratory transcriptomic profiling was performed by RNA-Seq. Immunodeficient mice injected with Gd-IgA1 mixed with IgG autoantibodies from patients with IgA nephropathy, but not Gd-IgA1 mixed with IgG from healthy individuals, displayed IgA, IgG, and mouse complement C3 glomerular deposits and mesangioproliferative glomerular injury with hematuria and proteinuria. Un-complexed Gd-IgA1 or IgG did not induce pathological changes. Moreover, Gd-IgA1-rIgG immune complexes injected into immunodeficient mice induced histopathological changes characteristic of human disease. Exploratory transcriptome profiling of mouse kidney tissues indicated that these immune complexes altered gene expression of multiple pathways, in concordance with the changes observed in kidney biopsies of patients with IgA nephropathy. This study provides the first in vivo evidence for a pathogenic role of IgG autoantibodies specific for Gd-IgA1 in the pathogenesis of IgA nephropathy.
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影响因子：
15.9
作者：
CONLEY, ME;COOPER, MD;MICHAEL, AF
通讯作者：
MICHAEL, AF
内科毛细血管增殖的分子表型：IgA肾病的新型治疗靶标。
影响因子：
3.7
作者：
Hodgin JB;Berthier CC;John R;Grone E;Porubsky S;Gröne HJ;Herzenberg AM;Scholey JW;Hladunewich M;Cattran DC;Kretzler M;Reich HN
通讯作者：
Reich HN
影响因子：
19.6
作者：
Coppo, Rosanna;Fonsato, Valentina;Camussi, Giovanni
通讯作者：
Camussi, Giovanni
DOI：
10.4049/jimmunol.1103031
发表时间：
2012-07-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Berthier CC;Bethunaickan R;Gonzalez-Rivera T;Nair V;Ramanujam M;Zhang W;Bottinger EP;Segerer S;Lindenmeyer M;Cohen CD;Davidson A;Kretzler M
通讯作者：
Kretzler M
影响因子：
13.6
作者：
Berthoux, Francois;Suzuki, Hitoshi;Novak, Jan
通讯作者：
Novak, Jan