Panzer Sarah E, Laskowski Jennifer, Renner Brandon, Kulik Liudmila, Ljubanovic Danica, Huber Kendra M, Zhong Weixiong, Pickering Matthew C, Holers V Michael, Thurman Joshua M
Division of Nephrology, Department of Medicine, University of Wisconsin Madison, Madison, Wisconsin, USA.
Department of Medicine, University of Colorado Denver, Aurora, Colorado, USA.
Kidney Int. 2015 Sep;88(3):528-37. doi: 10.1038/ki.2015.120. Epub 2015 May 6.
Although glomerular immunoglobulin M (IgM) deposition occurs in a variety of glomerular diseases, the mechanism of deposition and its clinical significance remain controversial. Some have theorized IgM becomes passively trapped in areas of glomerulosclerosis. However, recent studies found that IgM specifically binds damaged glomeruli. Therefore, we tested whether natural IgM binds to neo-epitopes exposed after insults to the glomerulus and exacerbates disease in mice deficient in the complement regulatory protein factor H; a model of non-sclerotic and nonimmune-complex glomerular disease. Immunofluorescence microscopy demonstrated mesangial and capillary loop deposition of IgM, whereas ultrastructural analysis found IgM deposition on endothelial cells and subendothelial areas. Factor H-deficient mice lacking B cells were protected from renal damage, as evidenced by milder histologic lesions on light and electron microscopy. IgM, but not IgG, from wild-type mice bound to cultured murine mesangial cells. Furthermore, injection of purified IgM into mice lacking B cells bound within the glomeruli and induced proteinuria. A monoclonal natural IgM-recognizing phospholipids also bound to glomeruli in vivo and induced albuminuria. Thus, our results indicate specific IgM antibodies bind to glomerular epitopes and that IgM contributes to the progression of glomerular damage in this mouse model of non-sclerotic glomerular disease.
尽管肾小球免疫球蛋白M（IgM）沉积见于多种肾小球疾病，但沉积机制及其临床意义仍存在争议。一些人推测IgM被动滞留于肾小球硬化区域。然而，最近的研究发现IgM特异性结合受损的肾小球。因此，我们检测了天然IgM是否结合肾小球损伤后暴露的新表位，并在缺乏补体调节蛋白H因子的小鼠中加重疾病；这是一种非硬化性和非免疫复合物性肾小球疾病模型。免疫荧光显微镜检查显示IgM在系膜和毛细血管袢沉积，而超微结构分析发现IgM沉积在内皮细胞和内皮下区域。缺乏B细胞的H因子缺陷小鼠可免受肾损伤，光镜和电镜下组织学损伤较轻即证明了这一点。野生型小鼠的IgM而非IgG可结合培养的小鼠系膜细胞。此外，将纯化的IgM注射到缺乏B细胞的小鼠体内，IgM在肾小球内结合并诱导蛋白尿。一种识别磷脂的单克隆天然IgM在体内也可结合肾小球并诱导白蛋白尿。因此，我们的结果表明特异性IgM抗体结合肾小球表位，并且在这种非硬化性肾小球疾病小鼠模型中IgM促进肾小球损伤的进展。
