Feinberg Cardiovascular and Renal Research Institute, Department of Medicine - Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Department of Nephrology, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, PR China.
J Pathol. 2021 Jun;254(2):159-172. doi: 10.1002/path.5658. Epub 2021 Apr 9.
IgA nephropathy (IgAN) is the most common type of glomerulonephritis worldwide, which follows a chronic but nonetheless highly variable course of progression. IgA immune complexes are the primary source of renal deposits in IgAN. Apart from the presence of granular IgA1 deposits in the glomerular mesangium and mesangial hypercellularity as common features, the detailed process of IgA1 deposition and clearance in the kidney remains unclear. We sought to examine the dynamics of IgA deposition and tissue plasticity in response to deposits including their intrarenal clearance. We followed a synthetic approach to produce a recombinant fusion between IgA Fc (rIgA) and a biotin tag, which was subsequently induced with streptavidin (SA) to form an oligomeric poly-IgA mimic. Both uninduced rIgA (mono-rIgA) and polymeric SA-rIgA (poly-rIgA) were injected intravenously into Wistar rats. Plasma IgA levels and renal and liver histology were examined in a time series. In contrast to mono-rIgA, this synthetic poly-rIgA analog formed renal deposits exclusively in the glomerulus and were mostly cleared in 3 h. However, repeated daily injections for 12 days caused long-lasting and stronger glomerular IgA deposition together with IgG and complement C3, in association with mesangial cell proliferation, matrix expansion, and variable degrees of albuminuria and hematuria that phenocopied IgAN. Ex vivo, poly-rIgA bound cultured mesangial cells and elicited cytokine production, in addition to activating plasma C3 that was consistent with the actions of IgA immune complexes in IgAN pathogenesis. Remarkably, the kidneys were able to reverse all pathologic manifestations and restore normal glomerular histology 2 weeks after injections were halted. The synthetic model showed the kinetics between the intricate balance of renal deposition and clearance, as well as glomerular plasticity towards healing. Together, the results revealed a priming effect of existing deposits in promoting stronger and longer-lasting IgA deposition to cause renal damage. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
IgA 肾病（IgAN）是全球最常见的肾小球肾炎类型，其具有慢性但高度可变的进展过程。IgA 免疫复合物是 IgAN 中肾脏沉积物的主要来源。除了肾小球系膜中颗粒状 IgA1 沉积物和系膜细胞增多症等常见特征外，IgA1 沉积在肾脏中的详细清除过程仍不清楚。我们试图研究 IgA 沉积和组织可塑性的动力学，以响应包括其在肾脏内清除在内的沉积物。我们采用一种综合方法，在 IgA Fc（rIgA）和生物素标签之间产生重组融合物，然后用链霉亲和素（SA）诱导形成寡聚多 IgA 模拟物。将未诱导的 rIgA（单 rIgA）和聚合的 SA-rIgA（多 rIgA）静脉内注射到 Wistar 大鼠中。在时间序列中检查血浆 IgA 水平和肾脏和肝脏组织学。与单 rIgA 相比，这种合成的多 rIgA 类似物仅在肾小球中形成肾脏沉积物，并且在 3 小时内大部分被清除。然而，重复每日注射 12 天会导致肾小球 IgA 沉积持续时间更长且更强，同时伴有 IgG 和补体 C3，与系膜细胞增殖、基质扩张以及不同程度的白蛋白尿和血尿有关，这些表现与 IgAN 相似。在体外，多 rIgA 结合培养的系膜细胞并引发细胞因子产生，除了激活血浆 C3 外，这与 IgAN 发病机制中 IgA 免疫复合物的作用一致。值得注意的是，在停止注射后 2 周，肾脏能够逆转所有病理表现并恢复正常肾小球组织学。该合成模型显示了肾脏沉积和清除之间复杂平衡以及肾小球向愈合方向的可塑性之间的动力学关系。总之，这些结果揭示了现有沉积物在促进更强和更持久的 IgA 沉积以引起肾脏损伤方面的启动作用。2021 年英国和爱尔兰病理学会。John Wiley & Sons，Ltd. 出版。
