Dynamic changes of MMP-9 plasma levels correlate with JCV reactivation and immune activation in natalizumab-treated multiple sclerosis patients
Dynamic changes of MMP-9 plasma levels correlate with JCV reactivation and immune activation in natalizumab-treated multiple sclerosis patients
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DOI：
10.1038/s41598-018-36535-5
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发表时间：
2019-01-22
影响因子：
4.6
通讯作者：
Ciardi, Maria Rosa
中科院分区：
文献类型：
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作者：
Iannetta, Marco;Zingaropoli, Maria Antonella;Ciardi, Maria Rosa
本研究旨在探讨34例复发缓解型多发性硬化症(RRMS)患者外周血中基质金属蛋白酶(MMP2)和MMP9水平的变化及其与JC病毒(JCV)激活和T淋巴细胞表型改变的关系。用酶谱法检测血浆中的基质金属蛋白酶-9水平。用实时荧光定量聚合酶链式反应检测血浆中的JCV-DNA。用流式细胞仪检测T淋巴细胞表型。结果血浆基质金属蛋白酶-9水平从12次滴注那他珠单抗增加到24次。根据JCV-DNA检测对血浆样本进行分层，JCV-DNA阳性患者的血浆MMP9水平明显高于JCV-DNA阴性患者。血浆MMP9水平与JCV病毒载量呈正相关。CD8免疫衰老率、CD8免疫激活率、CD8效应者百分率与血浆MMP9水平呈正相关，CD8初始百分率与MMP9水平呈负相关。我们的数据表明，在注射12到24次那他珠单抗之间，血浆中的基质金属蛋白酶-9水平升高，并且与血浆中JCV-DNA检测、T淋巴细胞免疫激活和衰老有关。这些发现可能有助于理解在那他珠单抗治疗下PML的发病机制，提示MMP9可能作为RRMS患者PML的预测标记物。
The aim of the study was to investigate the changes of matrix metalloproteinase (MMP)-2 and MMP-9 plasma levels during natalizumab treatment and their correlation with JC virus (JCV) reactivation and T-lymphocyte phenotypic modifications in peripheral blood samples from 34 relapsing-remitting multiple sclerosis (RRMS) patients. MMP-9 levels were assessed by zymography in plasma samples. JCV-DNA was detected through quantitative real time PCR in plasma samples. T-lymphocyte phenotype was assessed with flow cytometry. MMP-9 plasma levels resulted increased from 12 to 24 natalizumab infusions. Stratifying plasma samples according to JCV-DNA detection, MMP-9 plasma levels were significantly increased in JCV-DNA positive than JCV-DNA negative samples. MMP-9 plasma levels resulted positively correlated with JCV viral load. CD4 immune senescence, CD8 immune activation and CD8 effector percentages were positively correlated to MMP-9 plasma levels, whereas a negative correlation between CD8 naive percentages and MMP-9 plasma levels was found. Our data indicate an increase of MMP-9 plasma levels between 12 and 24 natalizumab infusions and a correlation with JCV-DNA detection in plasma, T-lymphocyte immune activation and senescence. These findings could contribute to understand PML pathogenesis under natalizumab treatment, suggesting a potential role of MMP-9 as a predictive marker of PML in RRMS patients.