University of Alabama at Birmingham, Birmingham, AL, USA.
University of Alabama at Birmingham, Birmingham, AL, USA; Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan.
J Autoimmun. 2021 Mar;118:102593. doi: 10.1016/j.jaut.2021.102593. Epub 2021 Jan 25.
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.
IgA 肾病被认为是一种自身免疫性疾病，其中半乳糖缺乏的 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蓄积。尽管最近的研究发现，在 IgA 肾病患者的肾免疫沉积物中，IgG 富含 Gd-IgA1 特异性自身抗体，支持了这一假说，但仍缺乏实验证据。
从 IgA 肾病患者的血清中分离出 IgG 或作为重组 IgG（rIgG）产生，与人类 Gd-IgA1 混合形成免疫复合物。健康个体的 IgG 作为对照。裸鼠和 SCID 小鼠分别注射人 IgG 和 Gd-IgA1 免疫复合物或单独注射，并通过免疫荧光法确定其在肾脏中的存在。通过定量形态计量学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。
用来自 IgA 肾病患者的 IgG 自动抗体混合 Gd-IgA1 免疫缺陷小鼠，但不是用健康个体的 IgG 混合 Gd-IgA1，显示 IgA、IgG 和小鼠补体 C3 肾小球沉积物和系膜增生性肾小球损伤，伴有血尿和蛋白尿。未复合的 Gd-IgA1 或 IgG 不会引起病理变化。此外，将 Gd-IgA1-rIgG 免疫复合物注入免疫缺陷小鼠，会引起与 IgA 肾病患者肾活检观察到的变化特征一致的组织病理学变化。对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个途径的基因表达，与 IgA 肾病患者肾活检观察到的变化一致。
这项研究提供了 IgG 自动抗体特异性针对 Gd-IgA1 在 IgA 肾病发病机制中的致病作用的第一个体内证据。
