LRP4 抗体在重症肌无力中的功能特征。
Functional Signature of LRP4 Antibodies in Myasthenia Gravis.
机构信息
From the Department of Neurology with Institute of Translational Neurology (O.C., C.W.K., H.W., J.D.L.), University Hospital Münster; Department of Neurology with Experimental Neurology (F.S., A.M.); Neuroscience Clinical Research Center (F.S., A.M.), Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Germany; Genos Glycoscience Research Laboratory (M.P.-B., A.-M.P., G.L.), Zagreb; Faculty of Pharmacy and Biochemistry (G.L.), University of Zagreb, Croatia; Tzartos NeuroDiagnostics (S.T.); Department of Neurobiology (S.T.), Hellenic Pasteur Institute, Athens, Greece; Nuffield Department of Clinical Neurosciences (N.W.), Weatherall Institute of Molecular Medicine, University of Oxford, United Kingdom; and Center for Stroke Research Berlin (A.G.M.), Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Germany.
出版信息
Neurol Neuroimmunol Neuroinflamm. 2024 May;11(3):e200220. doi: 10.1212/NXI.0000000000200220. Epub 2024 Mar 20.
BACKGROUND AND OBJECTIVES
Antibodies (Abs) specific for the low-density lipoprotein receptor-related protein 4 (LRP4) occur in up to 5% of patients with myasthenia gravis (MG). The objective of this study was to profile LRP4-Ab effector actions.
METHODS
We evaluated the efficacy of LRP4-specific compared with AChR-specific IgG to induce Ab-dependent cellular phagocytosis (ADCP), Ab-dependent cellular cytotoxicity (ADCC), and Ab-dependent complement deposition (ADCD). Functional features were additionally assessed in an independent AChR-Ab MG cohort. Levels of circulating activated complement proteins and frequency of Fc glycovariants were quantified and compared with demographically matched 19 healthy controls.
RESULTS
Effector actions that required binding of Fc domains to cellular FcRs such as ADCC and ADCP were detectable for both LRP4-specific and AChR-specific Abs. In contrast to AChR-Abs, LRP4-binding Abs showed poor efficacy in inducing complement deposition. Levels of circulating activated complement proteins were not substantially increased in LRP4-Ab-positive MG. Frequency of IgG glycovariants carrying 2 sialic acid residues, indicative for anti-inflammatory IgG activity, was decreased in patients with LRP4-Ab-positive MG.
DISCUSSION
LRP4-Abs are more effective in inducing cellular FcR-mediated effector mechanisms than Ab-dependent complement activation. Their functional signature is different from AChR-specific Abs.
背景与目的
针对低密度脂蛋白受体相关蛋白 4（LRP4）的抗体（Abs）在高达 5%的重症肌无力（MG）患者中出现。本研究旨在分析 LRP4-Ab 的效应子功能。
方法
我们评估了 LRP4 特异性 IgG 与 AChR 特异性 IgG 诱导 Ab 依赖性细胞吞噬（ADCP）、Ab 依赖性细胞细胞毒性（ADCC）和 Ab 依赖性补体沉积（ADCD）的效果。在独立的 AChR-Ab MG 队列中进一步评估了功能特征。定量检测和比较了循环中激活的补体蛋白水平和 Fc 糖型变体的频率，并与 19 名年龄匹配的健康对照者进行比较。
结果
需要 Fc 结构域与细胞 FcR 结合的效应子功能，如 ADCC 和 ADCP，在 LRP4 特异性和 AChR 特异性 Abs 中均能检测到。与 AChR-Abs 不同，LRP4 结合 Abs 在诱导补体沉积方面效果不佳。在 LRP4-Ab 阳性 MG 患者中，循环中激活的补体蛋白水平没有明显升高。携带 2 个唾液酸残基的 IgG 糖型变体频率降低，表明具有抗炎 IgG 活性。
讨论
LRP4-Abs 比 Ab 依赖性补体激活更有效地诱导细胞 FcR 介导的效应机制。其功能特征与 AChR 特异性 Abs 不同。
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