Laboratório de Pesquisa Clínica em Neuroinfecções, Instituto Nacional de Infectologia Evandro Chagas (INI), Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro, Brazil.
Seção de Imunodiagnóstico, Instituto Nacional de Infectologia Evandro Chagas (INI), Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro, Brazil.
Front Immunol. 2021 Oct 26;12:737941. doi: 10.3389/fimmu.2021.737941. eCollection 2021.
Human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a neurodegenerative disease due to axonal damage of the corticospinal secondary to an inflammatory response against infected T-cells. In the present work, we aimed to evaluate biomarkers of neurodegeneration and neuroinflammation in the definition of HAM/TSP prognosis. Neurofilament light (NfL) and phosphorylated heavy (pNfH) chains, total Tau protein, cellular prion protein (PrPc), inflammatory chemokines, and neopterin were quantified in paired cerebrospinal fluid (CSF) and serum samples from HAM/TSP patients (n=21), HTLV-1 asymptomatic carriers (AC) (n=13), and HTLV-1 seronegative individuals with non-inflammatory non-degenerative neurological disease (normal-pressure hydrocephalus) (n=9) as a control group. HTLV-1 proviral load in peripheral blood mononuclear cells and the expression of chemokine receptors CCR4, CCR5, and CXCR3 in infected CD4 T-cells (HTLV-1 Tax cells) were also assessed. CSF levels of Tau, NfL, and pNfH were similar between groups, but PrPc and neopterin were elevated in HAM/TSP patients. Most individuals in the control group and all HTLV-1 AC had CSF/serum neopterin ratio < 1.0, and two-thirds of HAM/TSP patients had ratio values > 1.0, which positively correlated with the speed of disease progression and pNfH levels, indicating active neuroinflammation. HAM/TSP patients showed high serum levels of CXCR3-binding chemokines (CXCL9, CXCL10, and CXCL11) and elevated CSF levels of CCL2, CCL3, CCL4, CCL17, CXCL5, CXCL10, and CXCL11. Indeed, CXCL10 concentration in CSF of HAM/TSP patients was 5.8-fold and 8.7-fold higher in than in HTLV-1 AC and controls, respectively, and correlated with CSF cell counts. HAM/TSP patients with typical/rapid disease progression had CSF/serum CXCL10 ratio > 1.0 and a higher frequency of CXCR3TaxCD4 T-cells in blood, which indicated a positive gradient for the migration of infected cells and infiltration into the central nervous system. In conclusion, the slow progression of HAM/TSP abrogates the usefulness of biomarkers of neuronal injury for the disease prognosis. Thus, markers of inflammation provide stronger evidence for HAM/TSP progression, particularly the CSF/serum neopterin ratio, which may contribute to overcome differences between laboratory assays.
人类 T 淋巴细胞病毒 1 型（HTLV-1）相关的脊髓病/热带痉挛性截瘫（HAM/TSP）是一种神经退行性疾病，由于对感染的 T 细胞的炎症反应导致皮质脊髓的轴突损伤。在本工作中，我们旨在评估神经退行性变和神经炎症的生物标志物在 HAM/TSP 预后中的定义。在 HAM/TSP 患者（n=21）、HTLV-1 无症状携带者（AC）（n=13）和 HTLV-1 血清阴性、无炎症性非退行性神经疾病（正常压力脑积水）的脑脊液（CSF）和血清样本中定量测定神经丝轻链（NfL）和磷酸化重链（pNfH）、总 Tau 蛋白、细胞朊蛋白（PrPc）、炎性趋化因子和新蝶呤。还评估了外周血单个核细胞中的 HTLV-1 前病毒载量和感染 CD4 T 细胞（HTLV-1 Tax 细胞）中趋化因子受体 CCR4、CCR5 和 CXCR3 的表达。各组间 Tau、NfL 和 pNfH 的 CSF 水平相似，但 HAM/TSP 患者的 PrPc 和新蝶呤升高。对照组中的大多数个体和所有 HTLV-1 AC 的 CSF/血清新蝶呤比值<1.0，三分之二的 HAM/TSP 患者的比值>1.0，这与疾病进展速度和 pNfH 水平呈正相关，表明存在活跃的神经炎症。HAM/TSP 患者的血清 CXCR3 结合趋化因子（CXCL9、CXCL10 和 CXCL11）水平较高，CSF 中 CCL2、CCL3、CCL4、CCL17、CXCL5、CXCL10 和 CXCL11 水平升高。实际上，HAM/TSP 患者的 CSF 中 CXCL10 浓度比 HTLV-1 AC 和对照组分别高 5.8 倍和 8.7 倍，与 CSF 细胞计数相关。具有典型/快速疾病进展的 HAM/TSP 患者的 CSF/血清 CXCL10 比值>1.0，血液中 CXCR3TaxCD4 T 细胞频率更高，这表明感染细胞的迁移和浸润中枢神经系统呈正梯度。总之，HAM/TSP 的缓慢进展削弱了神经元损伤生物标志物对疾病预后的作用。因此，炎症标志物为 HAM/TSP 进展提供了更强的证据，特别是 CSF/血清新蝶呤比值，这可能有助于克服实验室检测之间的差异。
