New developments in the genetics, pathogenesis, and therapy of IgA nephropathy.
New developments in the genetics, pathogenesis, and therapy of IgA nephropathy.
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DOI：
10.1038/ki.2015.252
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发表时间：
2015-11
影响因子：
19.6
通讯作者：
Kiryluk K
中科院分区：
文献类型：
--
作者：
Magistroni R;D'Agati VD;Appel GB;Kiryluk K
近年来，伊加肾病领域取得了显著进展。在这里，我们强调了重要的新方向和最新进展，包括成功发现了几个遗传易感基因座，制定了多击发病机制模型，该模型整合了半乳糖缺陷型IgA 1、抗聚糖反应和免疫复合物诱导的肾损伤的研究结果，引入了牛津病理学评分系统，以及肾脏疾病改善全球结局（KDIGO）共识治疗指南的正式化。我们专注于最新的遗传学发现，这些发现证实了遗传因素的强大贡献，并解释了疾病易感性的一些地理种族差异。迄今为止发现的大多数伊加肾病易感基因编码的基因参与维持肠上皮屏障和对粘膜病原体的反应。跨所有全基因组关联研究（GWAS）位点的群体间等位基因分化的一致模式与疾病患病率平行，并与当地病原体的变异相关，这表明多位点适应可能塑造了当今伊加肾病的景观。重要的是，“伊加产生的肠道免疫网络”成为潜在治疗干预的新靶点之一。我们把这些发现的背景下，多击中发病机制模型和现有的知识伊加免疫生物学。最后，我们提供了我们对现有治疗方案的看法，讨论了临床不确定性的领域，并概述了正在进行的临床试验和转化研究。
Recent years have brought notable progress in the field of IgA nephropathy. Here, we highlight important new directions and latest developments, including successful discovery of several genetic susceptibility loci, formulation of the multi-hit pathogenesis model that integrates findings from studies of galactose-deficient IgA1, anti-glycan response and immune complex-induced kidney injury, introduction of the Oxford pathology scoring system, and formalization of the Kidney Disease Improving Global Outcomes (KDIGO) consensus treatment guidelines. We focus on the latest genetic findings that confirm a strong contribution of inherited factors and explain some of the geo-ethnic disparities in disease susceptibility. Most IgA nephropathy susceptibility loci discovered to date encode genes involved in the maintenance of the intestinal epithelial barrier and response to mucosal pathogens. The concerted pattern of inter-population allelic differentiation across all Genome Wide Association Studies (GWAS) loci parallels the disease prevalence and correlates with variation in local pathogens, suggesting that multi-locus adaptation might have shaped the present-day landscape of IgA nephropathy. Importantly, the “Intestinal Immune Network for IgA Production” emerged as one of the new targets for potential therapeutic intervention. We place these findings in the context of the multi-hit pathogenesis model and existing knowledge of IgA immunobiology. Lastly, we provide our perspective on the existing treatment options, discuss areas of clinical uncertainty, and outline ongoing clinical trials and translational studies.