Cole Michael A, Ranjan Nikhil, Gerber Gloria F, Pan Xiang-Zuo, Flores-Guerrero Daniel, McNamara George, Chaturvedi Shruti, Sperati C John, McCrae Keith R, Brodsky Robert A
Division of Hematology, Department of Medicine, Johns Hopkins University, Baltimore, MD.
Ross Fluorescence Imaging Center, Division of Gastroenterology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
Blood. 2024 Dec 12;144(24):2528-2545. doi: 10.1182/blood.2024025850.
Complement-mediated thrombotic microangiopathy (CM-TMA) or hemolytic uremic syndrome, previously identified as atypical hemolytic uremic syndrome, is a TMA characterized by germ line variants or acquired antibodies to complement proteins and regulators. Building upon our prior experience with the modified Ham (mHam) assay for ex vivo diagnosis of complementopathies, we have developed an array of cell-based complement "biosensors" by selective removal of complement regulatory proteins (CD55 and CD59, CD46, or a combination thereof) in an autonomously bioluminescent HEK293 cell line. These biosensors can be used as a sensitive method for diagnosing CM-TMA and monitoring therapeutic complement blockade. Using specific complement pathway inhibitors, this model identifies immunoglobulin M (IgM)-driven classical pathway stimulus during both acute disease and in many patients during clinical remission. This provides a potential explanation for ∼50% of patients with CM-TMA who lack an alternative pathway "driving" variant and suggests at least a subset of CM-TMA is characterized by a breakdown of IgM immunologic tolerance.
补体介导的血栓性微血管病（CM-TMA）或溶血尿毒综合征，以前被认定为非典型溶血尿毒综合征，是一种血栓性微血管病，其特征为补体蛋白和调节因子的种系变异或获得性抗体。基于我们之前使用改良哈姆（mHam）试验进行补体病体外诊断的经验，我们通过在自主生物发光的人胚肾293（HEK293）细胞系中选择性去除补体调节蛋白（CD55和CD59、CD46或其组合），开发了一系列基于细胞的补体“生物传感器”。这些生物传感器可作为诊断CM-TMA和监测补体治疗性阻断的灵敏方法。利用特定的补体途径抑制剂，该模型在急性疾病期间以及许多临床缓解期患者中均识别出免疫球蛋白M（IgM）驱动的经典途径刺激。这为约50%缺乏替代途径“驱动”变异的CM-TMA患者提供了一种潜在解释，并表明至少一部分CM-TMA的特征是IgM免疫耐受的破坏。
