Jan Novak, Colin Reily, Nicholas J Steers, Tillie Schumann, Dana V Rizk, Bruce A Julian, Krzysztof Kiryluk, Ali G Gharavi, Todd J Green
{"title":"Emerging Biochemical and Immunologic Mechanisms in the Pathogenesis of IgA Nephropathy.","authors":"Jan Novak, Colin Reily, Nicholas J Steers, Tillie Schumann, Dana V Rizk, Bruce A Julian, Krzysztof Kiryluk, Ali G Gharavi, Todd J Green","doi":"10.1016/j.semnephrol.2025.151565","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":21756,"journal":{"name":"Seminars in nephrology","volume":" ","pages":"151565"},"PeriodicalIF":2.8000,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Seminars in nephrology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.semnephrol.2025.151565","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"UROLOGY & NEPHROLOGY","Score":null,"Total":0}
引用次数: 0
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.
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.