皮质激素抵抗性Th17/Tc-17细胞对TLR-2和TLR-4配体的高反应性是多发性硬化症患者治疗失败风险较高的一个特征。

Hyperresponsiveness of Corticoid-Resistant Th17/Tc-17 Cells to TLR-2 and TLR-4 Ligands is a Feature of Multiple Sclerosis Patients at Higher Risk of Therapy Failure.

作者信息

Hygino Joana, Sales Marisa C, Sacramento Priscila M, Kasahara Taissa M, da Silva Júlio César Costa, Bilhão Rafaela, Andrade Regis M, Vasconcelos Cláudia Cristina Ferreira, Bento Cleonice A M

机构信息

Post-Graduate Program in Neurology, Federal University of the State of Rio de Janeiro, Rio de Janeiro City, Brazil.

Post-Graduate Program in Microbiology, University of the State of Rio de Janeiro, Rio de Janeiro City, Brazil.

出版信息

J Inflamm Res. 2024 Nov 14;17:8775-8797. doi: 10.2147/JIR.S476110. eCollection 2024.

DOI:10.2147/JIR.S476110

PMID:39564547

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11573880/

Abstract

PURPOSE

The presence of T cells expressing TLR-2 and TLR-4 has been associated with relapsing-remitting multiple sclerosis (RRMS) pathogenesis. Here, we evaluated whether the effectiveness of DMT in controlling clinical activity of the disease would be associated with modulation of proportion of TLRs T cells.

PATIENTS AND METHODS

Whole peripheral blood mononuclear cells, purified CD4 and CD8 T cells from RRMS patients were cultured with different stimuli. The frequency of IL-17-secreting CD4 and CD8 T cells positive for TLR-2 and TLR-4 was determined by flow cytometry. The cytokine profile of these T cells following TLR-2 and TLR-4 stimulation was determined by Multiplex. Some of these T cell cultures were treated with hydrocortisone. The levels of LPS-binding protein (LBP) were dosed by ELISA. Clinical (occurrence of relapses) and radiological (number of active brain lesions) activity were evaluated during the 1-year follow-up.

RESULTS

Despite DMT, high intensity of TLR-2 and TLR-4 expression on (CD4 and CD8) T-cells, as well as the frequency of IL-17-secreting (CD4 and CD8) T-cells, are predictive of future RRMS relapses. Moreover, higher cytokine production related to Th17/Tc-17 phenotypes in response to TLR-2 and TLR-4 agonists was observed in DMT-treated patients and displayed an elevated number of brain lesions. The hyperresponsiveness of MS-derived T-cells to TLR-2 and TLR-4 ligands, with high levels of IL-1β, IL-6, IL-17, IFN-γ and GM-CSF in response to both TLR agonists, positively correlated with plasma LBP levels. Interestingly, corticoid was less efficient in reducing Th17 and Tc-17 cytokine production induced by TLR-2 and TLR-4 ligands in DMT-treated patients who relapsed during follow-up.

CONCLUSION

Collectively, the data suggested that persistence of circulating Th17 and Tc17 cells expressing elevated levels of functional TLR-2 and TLR-4 could indicate high disease activity and lower therapeutic efficacy in RRMS patients.

摘要

目的

表达Toll样受体2（TLR-2）和Toll样受体4（TLR-4）的T细胞的存在与复发缓解型多发性硬化症（RRMS）的发病机制相关。在此，我们评估了疾病修饰治疗（DMT）在控制疾病临床活动方面的有效性是否与TLR T细胞比例的调节相关。

患者和方法

将RRMS患者的全外周血单核细胞、纯化的CD4和CD8 T细胞用不同刺激物培养。通过流式细胞术确定分泌白细胞介素-17（IL-17）且TLR-2和TLR-4呈阳性的CD4和CD8 T细胞的频率。通过多通道技术确定这些T细胞在TLR-2和TLR-4刺激后的细胞因子谱。其中一些T细胞培养物用氢化可的松处理。通过酶联免疫吸附测定法（ELISA）测定脂多糖结合蛋白（LBP）的水平。在1年随访期间评估临床（复发情况）和放射学（活跃脑病变数量）活动。

结果

尽管采用了DMT，但（CD4和CD8）T细胞上TLR-2和TLR-4的高表达强度以及分泌IL-17的（CD4和CD8）T细胞频率可预测RRMS患者未来的复发。此外，在接受DMT治疗的患者中，观察到对TLR-2和TLR-4激动剂产生的与辅助性T细胞17（Th17）/细胞毒性T细胞17（Tc-17）表型相关的细胞因子产生增加，且脑病变数量增多。MS来源的T细胞对TLR-2和TLR-4配体反应过度，对两种TLR激动剂均产生高水平的白细胞介素-1β（IL-1β）、白细胞介素-6（IL-6）、IL-17、干扰素-γ（IFN-γ）和粒细胞-巨噬细胞集落刺激因子（GM-CSF），这与血浆LBP水平呈正相关。有趣的是，在随访期间复发的接受DMT治疗的患者中，皮质类固醇在降低由TLR-2和TLR-4配体诱导的Th17和Tc-17细胞因子产生方面效果较差。