Increased interleukin 33 in patients with neuro-Behcet's disease: correlation with MCP-1 and IP-10 chemokines
Increased interleukin 33 in patients with neuro-Behcet's disease: correlation with MCP-1 and IP-10 chemokines
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DOI：
10.1038/cmi.2014.31
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发表时间：
2014-11-01
影响因子：
24.1
通讯作者：
Hamzaoui, Agnes
中科院分区：
文献类型：
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作者：
Hamzaoui, Kamel;Borhani-Haghighi, Afshin;Hamzaoui, Agnes
白塞氏病 (BD) 的神经系统受累，即神经白塞氏病 (NBD)，会导致毁灭性的中枢神经系统 (CNS) 并发症，并且存在于 5% 至 30% 的 BD 患者中。 1 NBD 涉及免疫学和分子途径，包括白细胞介素 (IL)-1、-6 和 -8 以及 TNF-a 和 IFN-c 释放到脑脊液 (CSF) 中，2 这反映了与自身炎症性疾病途径兼容的非特异性炎症模式。 IL-33 是 IL-1 家族的非常规成员，最近与多种炎症和自身免疫性疾病有关。 3 我们在此首次记录了 NBD 患者中枢神经系统中 IL-33 的表达上调。我们研究了 20 名 NBD 患者的脑脊液中 IL-33 水平和 IL-33 mRNA 表达及其与 IP-10 和 MCP-1 趋化因子水平的相关性，并与 12 名年龄匹配的非炎症性神经系统疾病 (NIND) 患者和 10 名白塞病头痛患者 (HaBD) 进行比较。与疾病对照相比，NBD 患者脑脊液中的 IL-33 升高。在mRNA水平上，IL-33在NBD中高表达。与此同时，与疾病对照相比，介导 IL-33 转录的核因子 kB (NF-kB) 也有所升高。与疾病对照相比，NBD 中趋化因子 mRNA（IP-10 和 MCP-1）高度表达。总之，NBD 患者的中枢神经系统中 IL-33 水平升高，表明 IL-33 与 BD 神经损伤有关。 BD 是一种病因不明的复杂的多系统炎症性疾病。这种疾病通常表现为复发性口腔和生殖器溃疡和葡萄膜炎，并不同程度地伴有影响皮肤、大血管、胃肠系统和中枢神经系统的症状。 BD 中组织破坏的确切机制尚未完全阐明。许多病毒，包括肝炎病毒、细小病毒 B19 和单纯疱疹病毒，都与 BD 的病因有关。所有研究的患者均符合国际双相情感障碍研究组的诊断标准。 4 22 例 NBD 患者中，10 例有实质受累（亚急性神经综合征；脑干受累；半球受累伴脊髓受累；双侧锥体征），12 例有脑静脉和动脉血栓形成。 5 治疗方式包括免疫抑制剂联合高剂量口服或静脉脉冲糖皮质激素。疾病对照包括两组。第一个是患有 HaBD 的 BD 患者，这种症状不被认为是 BD 的神经系统表现。第二个对照组包括 12 名患有 NIND（如中风或痴呆）的患者。突尼斯大学医学伦理委员会批准了该项目，并获得了所有参与者的知情同意。采集 NBD、HaBD 和 NIND 患者的血液和脑脊液；脑脊液是在初次就诊时采集的。正如最近报道的，通过夹心 ELISA 测量血清和脑脊液中的 IL-33。 6 使用 TransAM NF-kB p65 转录因子测定试剂盒（Active Motif，卡尔斯巴德，加利福尼亚州，美国）分析 NF-kB DNA 结合活性。 6 NBD 患者的脑脊液中 IL-33 水平（122643.43 pg/ml；范围：40-187 pg/ml）显着高于 HaBD（78.30619. 05 pg/ml；范围：50-105 pg/ml；P50. 005）和 NIND（74.50613. 45 pg/ml；范围： 55–98 pg/ml；P50。0001) 患者（图 1a）。此外，与 NBD 患者血清中的水平相比，NBD 患者的 CSF IL-33 水平有所增加 (84.63627. 74 pg/ml；P50. 0015)。增加...
Neurological involvement in Behçet’s disease (BD), namely, neuro-Behçet’s disease (NBD), causes devastating central nervous system (CNS) complications and is present in 5% to 30% of patients with BD. 1 Immunological and molecular pathways are involved in NBD and include the release of interleukin (IL)-1,-6 and-8, and TNF-a and IFN-c into cerebrospinal fluid (CSF), 2 which reflects a nonspecific inflammatory pattern that is compatible with auto-inflammatory disease pathways. IL-33 is an unconventional member of the IL-1 family that has been recently implicated in several inflammatory and autoimmune diseases. 3 We document here, for the first time, that IL-33 is upregulated in the CNS of patients with NBD. We studied the IL-33 level and IL-33 mRNA expression in CSF and their correlation with the levels of the IP-10 and MCP-1 chemokines in 20 NBD patients, compared with those of 12 age-matched, non-inflammatory neurological disease (NIND) patients and 10 patients with headache attributed to Behçet’s disease (HaBD). IL-33 was elevated in the CSF from NBD patients compared with those of disease controls. At the mRNA level, IL-33 was highly expressed in NBD. In parallel, nuclear factor kB (NF-kB), which mediates IL-33 transcription, was also elevated when compared with disease controls. Chemokine mRNA (IP-10 and MCP-1) was highly expressed in NBD compared with the disease controls. In summary, IL-33 levels are elevated in the central nervous system of patients with NBD, implicating IL-33 in BD neurological lesions. BD is a complex, multisystem inflammatory disorder of unknown etiology. This disease typically manifests as recurrent oral and genital ulcerations and uveitis that are variably accompanied by symptoms affecting the skin, large vessels, gastrointestinal system and CNS. The precise mechanisms of tissue destruction in BD have not been fully elucidated. A number of viruses, including hepatitis viruses, parvovirus B19 and herpes simplex virus, has been implicated in the etiology of BD. All studied patients fulfilled the diagnostic criteria of the International Study Group for BD. 4 Of the 22 NBD patients, 10 had parenchymal involvement (subacute neurological syndrome; brainstem involvement; hemispheric involvement with spinal cord involvement; bilateral pyramidal signs) and 12 patients had cerebral vein and arterial thrombosis. 5 The treatment modalities consisted of immunosuppressive agents in combination with high oral doses or intravenous pulses of glucocorticosteroids.The disease controls included two groups. The first was composed of BD patients suffering from HaBD, a symptom that is not considered a neurological manifestation of BD. The second control group included 12 patients with NIND, such as stroke or dementia. The Ethics Committee of Medicine at the University of Tunis approved the project, and informed consent was obtained from all participants. Blood and CSF were collected from NBD, HaBD and NIND patients; CSF was obtained at the time of initial presentation. IL-33 was measured in serum and CSF by sandwich ELISAs, as recently reported. 6 NF-kB DNA-binding activity was analyzed using the TransAM NF-kB p65 transcription factor assay kit (Active Motif, Carlsbad, CA, USA). 6 CSF from NBD patients had significantly higher levels of IL-33 (122643.43 pg/ml; range: 40–187 pg/ml) than that of HaBD (78.30619. 05 pg/ml; range: 50–105 pg/ml; P50. 005) and NIND (74.50613. 45 pg/ml; range: 55–98 pg/ml; P50. 0001) patients (Figure 1a). Moreover, CSF IL-33 levels from NBD patients were increased compared to those in serum from NBD patients (84.63627. 74 pg/ml; P50. 0015). Increased …