Alibrandi Sara, Aguiar Talita, Ausmeier Mattea, Molinari Paolo, Fiaccadori Enrico, Maggiore Umberto, Chun Nicholas, Lanau Maria, Perez-Arnedo Mario, Manrique Joaquin, Cravedi Paolo, Zorn Emmanuel
Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Department of Medicine and Surgery, University of Parma, Parma, Italy.
Kidney Int Rep. 2025 Apr 21;10(7):2414-2423. doi: 10.1016/j.ekir.2025.04.016. eCollection 2025 Jul.
IgA nephropathy (IgAN), the most prevalent glomerular disease worldwide, carries a significant risk of kidney failure. Its pathogenesis involves the presence of elevated levels of IgA and galactose-deficient IgA (Gd-IgA), deposition of these antibodies in the kidney mesangium, and complement-mediated glomerular injury, leading to progressive renal function loss. The source and specificity of IgA in this disease remain unclear. We hypothesized that pathogenic IgA results from an immune response to abnormal protein modifications.
We used an advanced enzyme-linked immunosorbent assay (ELISA) platform to assess serum IgA and Gd-IgA reactivity to 93 posttranslational modifications and other chemical adducts in 28 patients with biopsy-proven IgAN and 22 healthy controls.
Carboxymethyl-lysine (CML) was identified as the dominant target of IgA and Gd-IgA, but not IgG in patients with IgAN. This finding was validated in an independent cohort of 15 IgAN cases and 15 controls. In addition, a positive correlation was found between serum CML concentration and IgA reactivity in patients with IgAN, alongside albuminuria. Lastly, immunofluorescence staining observed elevated CML deposition in glomeruli of patients with IgAN than in controls.
Our studies identify CML as a primary target of circulating IgA in IgAN, suggesting that aberrant responses to this modified self-antigen contribute to disease pathophysiology.
IgA肾病（IgAN）是全球最常见的肾小球疾病，具有显著的肾衰竭风险。其发病机制涉及IgA和半乳糖缺乏型IgA（Gd-IgA）水平升高、这些抗体在肾脏系膜中的沉积以及补体介导的肾小球损伤，导致肾功能逐渐丧失。该疾病中IgA的来源和特异性仍不清楚。我们推测致病性IgA是对异常蛋白质修饰的免疫反应的结果。
我们使用先进的酶联免疫吸附测定（ELISA）平台，评估28例经活检证实的IgA肾病患者和22例健康对照者血清IgA和Gd-IgA对93种翻译后修饰和其他化学加合物的反应性。
在IgA肾病患者中，羧甲基赖氨酸（CML）被确定为IgA和Gd-IgA的主要靶点，但不是IgG的主要靶点。这一发现在一个由15例IgA肾病病例和15例对照组成的独立队列中得到了验证。此外，在IgA肾病患者中，血清CML浓度与IgA反应性之间以及与蛋白尿之间发现了正相关。最后，免疫荧光染色观察到IgA肾病患者肾小球中CML沉积高于对照组。
我们的研究确定CML是IgA肾病中循环IgA的主要靶点，表明对这种修饰的自身抗原的异常反应促成了疾病的病理生理学。
