Emerging Biochemical and Immunologic Mechanisms in the Pathogenesis of IgA Nephropathy.

IF 2.8 3区 医学 Q2 UROLOGY & NEPHROLOGY Seminars in nephrology Pub Date : 2025-03-13 DOI:10.1016/j.semnephrol.2025.151565
Jan Novak, Colin Reily, Nicholas J Steers, Tillie Schumann, Dana V Rizk, Bruce A Julian, Krzysztof Kiryluk, Ali G Gharavi, Todd J Green
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Abstract

IgA nephropathy is a mesangioproliferative glomerular disease with significant morbidity and mortality. Most patients with IgA nephropathy develop kidney failure in their lifetime, reducing their life expectancy by a decade. Since its first description in 1968, it has been established that kidneys of IgA nephropathy patients are injured as "innocent bystanders" by nephritogenic IgA1-containing immune complexes. Results from clinical, biochemical, immunologic, and genetic studies suggest a multistep pathogenetic mechanism. In genetically predisposed individuals, this process results in formation of circulating immune complexes due to the binding of IgG/IgA autoantibodies to the polymeric IgA1 molecules with incomplete O-glycosylation. This event is followed by the addition of other proteins, such as complement C3, resulting in the formation of nephritogenic immune complexes. These complexes are not effectively removed from the circulation, and some of them pass through the fenestration of glomerular endothelial cells to enter the mesangial space and activate mesangial cells. It is thought that the process is initiated by soluble immune complexes and that their accumulation results in the formation of immunodeposits that further amplify glomerular injury. Here we summarize current understanding of the pathogenesis of IgA nephropathy and discuss experimental model systems that can inform development of new therapeutic strategies and targets.

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IgA 肾病是一种间质增生性肾小球疾病,发病率和死亡率都很高。大多数 IgA 肾病患者终生都会出现肾衰竭,从而使预期寿命缩短十年。自 1968 年首次描述 IgA 肾病以来,人们已经确定,IgA 肾病患者的肾脏作为 "无辜的旁观者 "受到了肾炎原 IgA1 免疫复合物的伤害。临床、生化、免疫学和遗传学研究结果表明,IgA 肾病的发病机制有多个步骤。在易感基因携带者中,由于 IgG/IgA 自身抗体与 O-糖基化不完全的聚合 IgA1 分子结合,形成循环免疫复合物。随后,其他蛋白质(如补体 C3)也会加入,从而形成致肾炎免疫复合物。这些复合物不能有效地从血液循环中清除,其中一些通过肾小球内皮细胞的栅栏进入系膜空间,激活系膜细胞。有人认为,这一过程是由可溶性免疫复合物启动的,它们的积累会形成免疫沉积物,进一步扩大肾小球损伤。在此,我们总结了目前对 IgA 肾病发病机制的理解,并讨论了可为开发新的治疗策略和靶点提供信息的实验模型系统。
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来源期刊
Seminars in nephrology
Seminars in nephrology 医学-泌尿学与肾脏学
CiteScore
5.60
自引率
0.00%
发文量
27
审稿时长
6-12 weeks
期刊介绍: Seminars in Nephrology is a timely source for the publication of new concepts and research findings relevant to the clinical practice of nephrology. Each issue is an organized compendium of practical information that serves as a lasting reference for nephrologists, internists and physicians in training.
期刊最新文献
Current Biomarkers of IgA Nephropathy. Emerging Biochemical and Immunologic Mechanisms in the Pathogenesis of IgA Nephropathy. Post-transplant IgA Nephropathy. The Genetics of IgA Nephropathy: Implications for Future Therapies. IgA Nephropathy: Epidemiology and Disease Risk Across the World.
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