德国汉堡埃彭多夫大学医学中心Tobias B. Huber团队研究了足细胞病变中靶向肾病蛋白的自身抗体。该项研究成果发表在2024年5月25日出版的《新英格兰医学杂志》上。

成人的微小病变性肾病和原发性局灶节段性肾小球硬化，以及儿童的特发性肾病综合征，是免疫介导的足细胞病变，可导致肾病综合征。针对肾病蛋白的自身抗体已在微小病变性肾病患者中发现，但其临床和病理生理作用尚不清楚。

研究组进行了一项多中心研究，以分析患有肾小球疾病（包括微小病变性肾病、局灶节段性肾小球硬化、膜性肾病、IgA肾病、抗中性粒细胞胞浆抗体相关肾小球肾炎和狼疮性肾炎）的成人以及特发性肾病综合征儿童和对照组参与者的抗肾上腺素自身抗体。还通过重组鼠肾病蛋白的主动免疫建立了实验小鼠模型。

该研究包括539名患者（357名成人和182名儿童）和117名对照组参与者。在成年人中，105名患有微小病变性肾病的患者中有46名（44%）、74名原发性局灶节段性肾小球硬化患者中有7名（9%）发现了抗肾上腺素自身抗体，而在患有其他疾病的患者当中，只有极少数病例发现了这种自身抗体。在182名患有特发性肾病综合征的儿童中，94名（52%）有可检测的抗肾上腺素自身抗体。在未接受免疫抑制治疗的活动性微小病变性肾病或特发性肾病综合征患者亚组中，抗肾上腺素自身抗体的患病率分别高达69%和90%。在纳入研究和随访期间，抗肾上腺素自身抗体水平与疾病活动性相关。实验免疫在小鼠中诱导了肾病综合征、一种微小变化的疾病样表型、IgG定位于足细胞狭缝隔膜、肾病蛋白磷酸化和严重的细胞骨架变化。

在这项研究中，循环抗肾上腺素自身抗体在微小病变性肾病或特发性肾病综合征患者中很常见，似乎是疾病活动的标志物。它们在狭缝隔膜处的结合诱导足细胞功能障碍和肾病综合征，这突出了其病理生理意义。

附：英文原文

Title: Autoantibodies Targeting Nephrin in Podocytopathies

Author: Felicitas E. Hengel, Silke Dehde, Morit Lassé, Gunther Zahner, Larissa Seifert, Annabel Schnarre, Oliver Kretz, Fatih Demir, Hans O. Pinnschmidt, Florian Grahammer, Renke Lucas, Lea Maxima Mehner, Tom Zimmermann, Anja M. Billing, Jun Oh, Adele Mitrotti, Paola Pontrelli, Hanna Debiec, Claire Dossier, Manuela Colucci, Francesco Emma, William E. Smoyer, Astrid Weins, Franz Schaefer, Nada Alachkar, Anke Diemert, Julien Hogan, Elion Hoxha, Thorsten Wiech, Markus M. Rinschen, Pierre Ronco, Marina Vivarelli, Loreto Gesualdo, Nicola M. Tomas, Tobias B. Huber

Issue&Volume: 2024-05-25

Abstract:

BACKGROUND

Minimal change disease and primary focal segmental glomerulosclerosis in adults, along with idiopathic nephrotic syndrome in children, are immune-mediated podocytopathies that lead to nephrotic syndrome. Autoantibodies targeting nephrin have been found in patients with minimal change disease, but their clinical and pathophysiological roles are unclear.

METHODS

We conducted a multicenter study to analyze antinephrin autoantibodies in adults with glomerular diseases, including minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, IgA nephropathy, antineutrophil cytoplasmic antibody–associated glomerulonephritis, and lupus nephritis, as well as in children with idiopathic nephrotic syndrome and in controls. We also created an experimental mouse model through active immunization with recombinant murine nephrin.

RESULTS

The study included 539 patients (357 adults and 182 children) and 117 controls. Among the adults, antinephrin autoantibodies were found in 46 of the 105 patients (44%) with minimal change disease, 7 of 74 (9%) with primary focal segmental glomerulosclerosis, and only in rare cases among the patients with other conditions. Of the 182 children with idiopathic nephrotic syndrome, 94 (52%) had detectable antinephrin autoantibodies. In the subgroup of patients with active minimal change disease or idiopathic nephrotic syndrome who were not receiving immunosuppressive treatment, the prevalence of antinephrin autoantibodies was as high as 69% and 90%, respectively. At study inclusion and during follow-up, antinephrin autoantibody levels were correlated with disease activity. Experimental immunization induced a nephrotic syndrome, a minimal change disease–like phenotype, IgG localization to the podocyte slit diaphragm, nephrin phosphorylation, and severe cytoskeletal changes in mice.

CONCLUSIONS

In this study, circulating antinephrin autoantibodies were common in patients with minimal change disease or idiopathic nephrotic syndrome and appeared to be markers of disease activity. Their binding at the slit diaphragm induced podocyte dysfunction and nephrotic syndrome, which highlights their pathophysiological significance.

DOI: NJ202405250000003

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2314471