From the Arthritis and Clinical Immunology Research Program (S.G., G.K., R.M.K., K.M., J.M.G., Y.M.-D., G.P., R.C.A.), Oklahoma Medical Research Foundation; Department of Microbiology and Immunology (S.G., R.C.A.), Oklahoma University Health Science Center; NeuroCure Clinical Research Center and Experimental and Clinical Research Center (N.S., K.R., P.S., M.H., F.P.), Max Delbrueck Center for Molecular Medicine and Charité Universitätsmedizin Berlin; and Department of Neurology (N.S., K.R., P.S., M.H., F.P.), Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany.
Neurol Neuroimmunol Neuroinflamm. 2024 Jul;11(4):e200268. doi: 10.1212/NXI.0000000000200268. Epub 2024 Jun 17.
AQP4 antibody-positive NMOSD (AQP4-NMOSD), MOG antibody-associated disease (MOGAD), and seronegative NMOSD (SN-NMOSD) are neuroautoimmune conditions that have overlapping clinical manifestations. Yet, important differences exist in these diseases, particularly in B-cell depletion (BCD) efficacy. Yet, the biology driving these differences remains unclear. Our study aims to clarify biological pathways distinguishing these diseases beyond autoantibodies and investigate variable BCD effects through proteomic comparisons.
In a retrospective study, 1,463 serum proteins were measured in 53 AQP4-NMOSD, 25 MOGAD, 18 SN-NMOSD, and 49 healthy individuals. To identify disease subtype-associated signatures, we examined serum proteins in patients without anti-CD20 B-cell depletion (NoBCD). We then assessed the effect of BCD treatment within each subtype by comparing proteins between BCD-treated and NoBCD-treated patients.
In NoBCD-treated patients, serum profiles distinguished the 3 diseases. AQP4-NMOSD showed elevated type I interferon-induced chemokines (CXCL9 and CXCL10) and TFH chemokine (CXCL13). MOGAD exhibited increased cytotoxic T-cell proteases (granzyme B and granzyme H), while SN-NMOSD displayed elevated Wnt inhibitory factor 1, a marker for nerve injury. Across all subtypes, BCD-treated patients showed reduction of B-cell-associated proteins. In AQP4-NMOSD, BCD led to a decrease in several inflammatory pathways, including IL-17 signaling, cytokine storm, and macrophage activation. By contrast, BCD elevated these pathways in patients with MOGAD. BCD had no effect on these pathways in SN-NMOSD.
Proteomic profiles show unique biological pathways that distinguish AQP4-NMOSD, MOGAD, or SN-NMOSD. Furthermore, BCD uniquely affects inflammatory pathways in each disease type, providing an explanation for the disparate therapeutic response in AQP4-NMOSD and MOGAD.
AQP4 抗体阳性 NMOSD（AQP4-NMOSD）、MOG 抗体相关疾病（MOGAD）和血清阴性 NMOSD（SN-NMOSD）是具有重叠临床表现的神经自身免疫性疾病。然而，这些疾病之间存在重要差异，特别是在 B 细胞耗竭（BCD）疗效方面。然而，驱动这些差异的生物学机制仍不清楚。我们的研究旨在阐明超越自身抗体的区分这些疾病的生物学途径，并通过蛋白质组学比较研究可变的 BCD 效应。
在一项回顾性研究中，我们测量了 53 例 AQP4-NMOSD、25 例 MOGAD、18 例 SN-NMOSD 和 49 例健康个体的 1463 种血清蛋白。为了识别疾病亚型相关的特征，我们检查了未接受抗 CD20 B 细胞耗竭（NoBCD）治疗的患者的血清蛋白。然后，我们通过比较 BCD 治疗和 NoBCD 治疗患者之间的蛋白质，评估了每个亚型内 BCD 治疗的效果。
在 NoBCD 治疗的患者中，血清谱区分了这 3 种疾病。AQP4-NMOSD 表现出升高的 I 型干扰素诱导的趋化因子（CXCL9 和 CXCL10）和 TFH 趋化因子（CXCL13）。MOGAD 表现出细胞毒性 T 细胞蛋白酶（颗粒酶 B 和颗粒酶 H）的增加，而 SN-NMOSD 则显示出升高的 Wnt 抑制因子 1，这是神经损伤的标志物。在所有亚型中，BCD 治疗的患者均表现出 B 细胞相关蛋白的减少。在 AQP4-NMOSD 中，BCD 导致包括 IL-17 信号、细胞因子风暴和巨噬细胞激活在内的几个炎症途径的减少。相比之下，BCD 在 MOGAD 患者中增加了这些途径。BCD 对 SN-NMOSD 中这些途径没有影响。
蛋白质组学谱显示了独特的生物学途径，可区分 AQP4-NMOSD、MOGAD 或 SN-NMOSD。此外，BCD 独特地影响每种疾病类型的炎症途径，为 AQP4-NMOSD 和 MOGAD 中不同的治疗反应提供了解释。
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