Department of Neurology, National Pediatric Myoclonus Center and Neuroimmunology Laboratory, and Southern Illinois University School of Medicine, PO Box 19643, Springfield, IL 62794-9643, USA.
J Neuroinflammation. 2013 Jan 16;10:10. doi: 10.1186/1742-2094-10-10.
B-cell dysregulation has been implicated but not fully characterized in pediatric opsoclonus-myoclonus syndrome (OMS), a neuroblastoma-associated neuroinflammatory disorder.
To assess the role of B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL), two critical B cell-modulating cytokines, as potential biomarkers of disease activity and treatment biomarkers in OMS.
Soluble BAFF and APRIL were measured in cerebrospinal fluid (CSF) and serum by ELISA in 433 children (296 OMS, 109 controls, 28 other inflammatory neurological disorders (OIND)). BAFF-R receptors on circulating CD19+ B cells were measured by flow cytometry. A blinded scorer rated motor severity on the OMS Evaluation Scale. Immunotherapies were evaluated cross-sectionally and longitudinally.
The mean CSF BAFF concentration, which was elevated in untreated OMS and OIND, correlated with OMS severity category (P = 0.006), and reduction by adrenocorticotropic hormone or corticotropin (ACTH) (-61%) or corticosteroids (-38%) was seen at each level of severity. In contrast, CSF APRIL was normal in OMS and OIND and unaffected by immunotherapy. When the entire OMS dataset was dichotomized into 'high' versus 'normal' CSF BAFF concentration, the phenotype of the high group included greater motor severity and number of CSF oligoclonal bands, and a higher concentration of inflammatory chemokines CXCL13 and CXCL10 in CSF and CXCL9 and CCL21 in serum. Serum APRIL was 6.7-fold higher in the intravenous immunoglobulins (IVIg) group, whereas serum BAFF was 2.6-fold higher in the rituximab group. The frequency of B cell BAFF-R expression was similar in untreated and treated OMS. Longitudinal studies of CSF BAFF revealed a significant decline in ACTH-treated patients (with or without rituximab) (P < 0.0001). Longitudinal studies of serum APRIL showed a 2.9-fold increase after 1 to 2 g/kg IVIg monotherapy (P = 0.0003).
Striking distinctions in BAFF/APRIL signaling were found. OMS displayed heterogeneity in CSF BAFF expression, which met many but not all criteria as a potential biomarker of disease activity. We speculate that CSF BAFF may have more utility in a biomarker panel than as a stand-alone biomarker, and that the selective upregulation of both serum APRIL by IVIg and BAFF by rituximab, as well as downregulation of CSF BAFF by ACTH/steroids, may have utility as treatment biomarkers.
B 细胞失调已被涉及，但在儿科眼震肌阵挛综合征（OMS）中尚未完全描述，这是一种与神经母细胞瘤相关的神经炎症性疾病。
评估 B 细胞激活因子（BAFF）和增殖诱导配体（APRIL）在 OMS 中的作用，这两种关键的 B 细胞调节细胞因子，作为疾病活动的潜在生物标志物和治疗生物标志物。
通过 ELISA 在 433 名儿童（296 名 OMS、109 名对照、28 名其他炎症性神经疾病（OIND））的脑脊液（CSF）和血清中测量可溶性 BAFF 和 APRIL。通过流式细胞术测量循环 CD19+B 细胞上的 BAFF-R 受体。一位盲法评分者根据 OMS 评估量表对运动严重程度进行评分。免疫疗法进行了横断面和纵向评估。
未经治疗的 OMS 和 OIND 中升高的 CSF BAFF 浓度与 OMS 严重程度类别相关（P=0.006），并且在每个严重程度水平上，ACTH 或促肾上腺皮质激素（ACTH）（-61%）或皮质类固醇（-38%）的降低均可见。相比之下，CSF APRIL 在 OMS 和 OIND 中是正常的，不受免疫疗法的影响。当整个 OMS 数据集分为“高”与“正常”CSF BAFF 浓度时，高组的表型包括更严重的运动严重程度和更多的 CSF 寡克隆带，以及更高浓度的炎症趋化因子 CXCL13 和 CXCL10 在 CSF 和 CXCL9 和 CCL21 在血清中。静脉注射免疫球蛋白（IVIg）组血清 APRIL 高 6.7 倍，而利妥昔单抗组血清 BAFF 高 2.6 倍。未经治疗和治疗的 OMS 中 B 细胞 BAFF-R 表达的频率相似。CSF BAFF 的纵向研究显示，ACTH 治疗的患者（无论是否使用利妥昔单抗）均显著下降（P<0.0001）。血清 APRIL 的纵向研究显示，1 至 2 g/kg IVIg 单药治疗后增加 2.9 倍（P=0.0003）。
在 BAFF/APRIL 信号中发现了明显的区别。OMS 在 CSF BAFF 表达中表现出异质性，这符合许多但不是所有疾病活动潜在生物标志物的标准。我们推测 CSF BAFF 在生物标志物组中可能比作为单一标志物更有用，并且 IVIg 引起的血清 APRIL 和利妥昔单抗引起的 BAFF 的选择性上调，以及 ACTH/皮质类固醇引起的 CSF BAFF 的下调，可能作为治疗生物标志物具有实用性。
