Cerebrospinal Fluid Cytokine and Chemokine Profiles in Central Nervous System Sarcoidosis: Diagnostic and Immunopathologic Insights

IF 8.1 1区医学 Q1 CLINICAL NEUROLOGY Annals of Neurology Pub Date : 2024-07-19 DOI:10.1002/ana.27024

Georgios Mangioris MD, Sean J. Pittock MD, Binxia Yang PhD, James P. Fryer MS, William S. Harmsen MS, Divyanshu Dubey MBBS, Eoin P. Flanagan MB, BCh, Sebastian A. Lopez-Chiriboga MD, Andrew McKeon MB, BCh, John R. Mills PhD, Ivana Vodopivec MD, PhD, W. Oliver Tobin MB, BCh, BAO, PhD, Michel Toledano MD, Allen J. Aksamit MD, Anastasia Zekeridou MD, PhD

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Abstract

Objective

To evaluate the cerebrospinal fluid (CSF) cytokine/chemokine profile of central nervous system (CNS) neurosarcoidosis (NS), and its utility in differential diagnosis, treatment, and prognostication.

Methods

In this case–control study, we validated 17 cytokines/chemokines (interleukin [IL]-1-beta, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p70, IL-13, IL-17A, BAFF, IL-8/CXCL8, CXCL9, CXCL10, CXCL13, GM-CSF, interferon-gamma, and tumor necrosis factor [TNF]-alpha) in a multiplexed automated immunoassay system (ELLA; Bio-Techne, Minneapolis, MN, USA), and assessed them in CSF and serum of symptomatic patients with probable or definite CNS NS (01/2011–02/2023) with gadolinium enhancement and/or CSF pleocytosis. Patients with multiple sclerosis, primary CNS lymphoma, aquaporin-4 immunoglobulin G positivity, non-inflammatory disorders, and healthy individuals were used as controls.

Results

A total of 32 NS patients (59% women; median age, 59 years [19–81]) were included; concurrent sera were available in 12. CSF controls consisted of 26 multiple sclerosis, 8 primary CNS lymphoma, 84 aquaporin-4 immunoglobulin G positive, and 34 patients with non-inflammatory disorders. Gadolinium enhancement was present in 31 of 32 NS patients, and CSF pleocytosis in 27 of 32 (84%). CSF IL-2, IL-6, IL-10, IL-13, BAFF, IL-8/CXCL8, CXCL9, CXCL10, CXCL13, GM-CSF, interferon-gamma, and TNF-alpha levels were significantly higher in NS patients compared with non-inflammatory controls (p ≤ 0.02); elevations were more common in CSF than serum. Concurrent elevation of IL-6, CXCL9, CXCL10, GM-CSF, interferon-gamma, and TNF-alpha was present in 18 of 32 NS patients, but only in 1 control. Elevated IL-6, IL-10, IL-13, CXCL9, CXL10, GM-CSF, and TNF-alpha associated with measures of disease activity.

Interpretation

NS CSF cytokine/chemokine profiles suggest T cell (mainly T helper cell type 1), macrophage, and B-cell involvement. These signatures aid in NS diagnosis, indicate disease activity, and suggest therapeutic avenues. ANN NEUROL 2024;96:704–714

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中枢神经系统肉样瘤病的脑脊液细胞因子和趋化因子谱：诊断和免疫病理学的启示。

目的评估中枢神经系统（CNS）神经肉芽肿病（NS）的脑脊液（CSF）细胞因子/趋化因子谱，及其在鉴别诊断、治疗和预后中的作用：在这项病例对照研究中，我们在多重自动免疫分析系统（ELLA.Bio-Techne，明尼苏达州）中验证了 17 种细胞因子/趋化因子（白细胞介素 [IL]-1-beta、IL-2、IL-4、IL-5、IL-6、IL-10、IL-12p70、IL-13、IL-17A、BAFF、IL-8/CXCL8、CXCL9、CXCL10、CXCL13、GM-CSF、γ 干扰素和肿瘤坏死因子 [TNF]- α）；Bio-Techne，Minneapolis，MN，USA），并对可能或确定患有中枢神经系统疾病（01/2011-02/2023）、伴有钆增强和/或脑脊液多细胞的有症状患者的脑脊液和血清进行评估。多发性硬化症、原发性中枢神经系统淋巴瘤、水光素-4免疫球蛋白G阳性、非炎症性疾病患者和健康人作为对照：共纳入 32 名 NS 患者（59% 为女性；中位年龄为 59 岁 [19-81]），其中 12 人有同期血清。CSF 对照组包括 26 名多发性硬化症患者、8 名原发性中枢神经系统淋巴瘤患者、84 名水肿素-4 免疫球蛋白 G 阳性患者和 34 名非炎症性疾病患者。32 名 NS 患者中有 31 人出现钆增强，32 人中有 27 人（84%）出现 CSF 多形性。与非炎症性对照组相比，NS 患者的 CSF IL-2、IL-6、IL-10、IL-13、BAFF、IL-8/CXCL8、CXCL9、CXCL10、CXCL13、GM-CSF、γ 干扰素和 TNF-α 水平显著升高（P ≤ 0.02）；CSF 水平升高比血清水平升高更为常见。32 例 NS 患者中有 18 例同时出现 IL-6、CXCL9、CXCL10、GM-CSF、γ 干扰素和 TNF-α 升高，但只有 1 例对照组出现这种情况。IL-6、IL-10、IL-13、CXCL9、CXL10、GM-CSF和TNF-α的升高与疾病活动相关：NS CSF细胞因子/趋化因子图谱提示T细胞（主要是T辅助细胞1型）、巨噬细胞和B细胞受累。这些特征有助于 NS 诊断、显示疾病活动性并提示治疗途径。ann neurol 2024.

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来源期刊

Annals of Neurology 医学-临床神经学

CiteScore

18.00

自引率

1.80%

发文量

270

审稿时长

3-8 weeks

期刊介绍： Annals of Neurology publishes original articles with potential for high impact in understanding the pathogenesis, clinical and laboratory features, diagnosis, treatment, outcomes and science underlying diseases of the human nervous system. Articles should ideally be of broad interest to the academic neurological community rather than solely to subspecialists in a particular field. Studies involving experimental model system, including those in cell and organ cultures and animals, of direct translational relevance to the understanding of neurological disease are also encouraged.