Cerebrospinal fluid chitinase 3-like 1 levels are associated with conversion to multiple sclerosis
Cerebrospinal fluid chitinase 3-like 1 levels are associated with conversion to multiple sclerosis
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DOI：
10.1093/brain/awq035
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发表时间：
2010-04-10
期刊：
影响因子：
14.5
通讯作者：
Montalban, Xavier
中科院分区：
文献类型：
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作者：
Comabella, Manuel;Fernandez, Marta;Montalban, Xavier
在大多数多发性硬化症患者中，疾病始于首次发作或临床孤立综合征。在这个阶段，磁共振成像是转化为多发性硬化症的重要预测指标。除了寡克隆区带，其他生物标志物在临床孤立综合征患者中的作用是有争议的。在本研究中，我们的目标是确定与临床孤立综合征患者转化为多发性硬化症相关的蛋白质。我们应用了基于质谱学的蛋白质组学方法(等压标记)来收集先前从临床隔离综合征患者收集的脑脊液样本，这些患者随后转变为临床明确的多发性硬化症(n=30)和仍然患有临床隔离综合征的患者(n=30)。接下来，我们选择了铜蓝蛋白、维生素D结合蛋白和几丁质酶3-样1这三个最具代表性的差异表达蛋白，通过酶联免疫吸附试验在单个脑脊液样本中进行验证。与继续表现为临床孤立综合征的患者(P=0.00002)和对照组(P=0.012)相比，转化为临床明确的多发性硬化症的患者仅验证了几丁质酶3-样1，脑脊液水平升高(P=0.012)。脑脊液中几丁质酶3-样1的高水平与基线脑磁共振扫描中所观察到的Gd强化病灶数目和T2病灶数目显著相关，并与随访中的残疾进展和临床确诊多发性硬化症的时间缩短相关(对数等级P值=0.003)。在第二次验证的临床隔离综合征队列中也检测了脑脊液几丁质酶3-样1的水平，发现转化为多发性硬化症的患者与仍然存在临床隔离综合征的患者相比，脑脊液几丁质酶3-样1水平升高(P=0.018)。我们的结果表明，通过脑脊液标本的蛋白质组学分析，可以将转化为临床明确的多发性硬化症的患者与仍为临床隔离综合征的患者区分开来。尽管在其他以慢性炎症为特征的疾病中，几丁质酶3样蛋白水平也会升高，但几丁质酶3样蛋白1可作为多发性硬化症转化和残疾发展的预后生物标志物，有助于提高对多发性硬化症早期发病机制的理解。
In most patients with multiple sclerosis, the disease initiates with a first attack or clinically isolated syndrome. At this phase, magnetic resonance imaging is an important predictor of conversion to multiple sclerosis. With the exception of oligoclonal bands, the role of other biomarkers in patients with clinically isolated syndrome is controversial. In the present study, we aimed to identify proteins associated with conversion to multiple sclerosis in patients with clinically isolated syndrome. We applied a mass spectrometry-based proteomic approach (isobaric labelling) to previously collected pooled cerebrospinal fluid samples from patients with clinically isolated syndrome, who subsequently converted to clinically definite multiple sclerosis (n = 30) and patients who remained as having clinically isolated syndrome (n = 30). Next, three of the most represented differentially expressed proteins, i.e. ceruloplasmin, vitamin D-binding protein and chitinase 3-like 1 were selected for validation in individual cerebrospinal fluid samples by enzyme-linked immunosorbent assay. Only chitinase 3-like 1 was validated and cerebrospinal fluid levels were increased in patients who converted to clinically definite multiple sclerosis compared with patients who continued as clinically isolated syndrome (P = 0.00002) and controls (P = 0.012). High cerebrospinal fluid levels of chitinase 3-like 1 significantly correlated with the number of gadolinium enhancing lesions and the number of T2 lesions observed in brain magnetic resonance imaging scans performed at baseline, and were associated with disability progression during follow-up and shorter time to clinically definite multiple sclerosis (log-rank P-value = 0.003). Cerebrospinal fluid chitinase 3-like 1 levels were also measured in a second validation clinically isolated syndrome cohort and found to be increased in patients who converted to multiple sclerosis compared with patients who remained as having clinically isolated syndrome (P = 0.018). Our results indicate that patients who will convert to clinically definite multiple sclerosis could be distinguished from those patients who will remain as clinically isolated syndrome by proteomic analysis of cerebrospinal fluid samples. Although protein levels are also increased in other disorders characterized by chronic inflammation, chitinase 3-like 1 may serve as a prognostic biomarker for conversion to multiple sclerosis and development of disability which may help to improve the understanding of the aetiopathogenesis in the early stages of multiple sclerosis.