Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL..
Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, UK.
Semin Nephrol. 2018 Sep;38(5):461-476. doi: 10.1016/j.semnephrol.2018.05.016.
IgA nephropathy, the most common primary glomerulonephritis in the world and a frequent cause of end-stage renal disease, is characterized by typical mesangial deposits of IgA1, as described by Berger and Hinglaise in 1968. Since then, it has been discovered that aberrant IgA1 O-glycosylation is involved in disease pathogenesis. Progress in glycomic, genomic, clinical, analytical, and biochemical studies has shown autoimmune features of IgA nephropathy. The autoimmune character of the disease is explained by a multihit pathogenesis model, wherein overproduction of aberrantly glycosylated IgA1, galactose-deficient in some O-glycans, by IgA1-secreting cells leads to increased levels of circulatory galactose-deficient IgA1. These glycoforms induce production of autoantibodies that subsequently bind hinge-region of galactose-deficient IgA1 molecules, resulting in the formation of nephritogenic immune complexes. Some of these complexes deposit in the kidney, activate mesangial cells, and incite glomerular injury. Thus, galactose-deficient IgA1 is central to the disease process. In this article, we review studies concerning IgA1 O-glycosylation that have contributed to the current understanding of the role of IgA1 in the pathogenesis of IgA nephropathy.
IgA 肾病是世界上最常见的原发性肾小球肾炎，也是终末期肾病的常见病因，其特征是 Berger 和 Hinglaise 于 1968 年描述的典型系膜 IgA1 沉积。从那时起，人们发现异常的 IgA1 O-糖基化参与了疾病的发病机制。糖组学、基因组学、临床、分析和生化研究的进展表明 IgA 肾病具有自身免疫特征。疾病的自身免疫特征可以用多打击发病机制模型来解释，即在 IgA1 分泌细胞中，异常糖基化 IgA1 的过度产生和某些 O-聚糖中的半乳糖缺乏导致循环中半乳糖缺乏 IgA1 的水平升高。这些糖型诱导产生自身抗体，随后与半乳糖缺乏 IgA1 分子的铰链区结合，导致肾炎性免疫复合物的形成。其中一些复合物沉积在肾脏中，激活系膜细胞，并引发肾小球损伤。因此，半乳糖缺乏的 IgA1 是疾病过程的核心。本文综述了有关 IgA1 O-糖基化的研究，这些研究有助于我们当前对 IgA1 在 IgA 肾病发病机制中的作用的理解。
