Aging-dependent change in Th17 and cytokine response in multiple sclerosis.

IF 10.1 1区 医学 Q1 IMMUNOLOGY
Wen Zhu, Shankar Revu, Chenyi Chen, Megan Dahl, Archana Ramkumar, Conor Kelly, Mandy J McGeachy, Zongqi Xia
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引用次数: 0

Abstract

Background: Multiple sclerosis (MS) is a chronic autoimmune disease damaging the central nervous system. Diminished inflammatory disease activity (DA) as people with MS (pwMS) age motivated randomized clinical trials assessing disease-modifying therapy (DMT) discontinuation in older pwMS given the concern for risks outweighing benefits. This study aims to examine whether peripheral production of Myelin Basic Protein (MBP)-driven cytokine responses mediate the aging-associated decline in MS inflammatory DA.

Methods: We included the clinical data of 669 adult pwMS between 2017 and 2022 who enrolled in a clinic-based prospective cohort. From a subset of 80 participants, we isolated fresh peripheral blood mononuclear cells (PBMCs) and cultured with 50 µg/ml of MBP (or heat-killed Candida) for 24 h. We assayed cell culture supernatants for interleukin 17 (IL-17) and interferon gamma (IFN-γ) using Enzyme-Linked Immunosorbent Assay and a subset of the supernatant samples using a commercial human cytokine/chemokine array. We examined the associations between age and annualized relapse rate (ARR) as well as between age and MBP-stimulated cytokine production (by cultured PBMC) using covariate-adjusted linear regressions. We performed mediation analyses to determine the extent to which MBP-driven cytokine response drives the association between age and ARR.

Results: Among 669 pwMS (mean age 51.7 ± 12.7 years, 80.7% women, 89.4% non-Hispanic White), ARR declined with age (β=-0.003, p < 0.001). Among the subgroup of 80 pwMS whose cultured PBMCs underwent ex vivo MBP stimulation, IL-17 production declined with age in women (β=-0.27, p = 0.04) but not men (β=-0.1, p = 0.73). MBP-driven IL-17 response partially mediated the association between older age and lower ARR (24.6% in women, 15.3% in men). In exploratory analyses, older pwMS (≥ 50 years) had marginally lower (IL-4, MCP-2, MCP-3, PDGF-AA, PDGF-AB/BB) and higher (Fractalkine, MDC) concentrations of several cytokines than younger pwMS (< 50 years), while certain cytokines (MCP-2, MDC) mediated whereas others negated the effect of age on ARR.

Conclusion: Diminished peripheral IL-17 response as a potential biological mechanism underlying the aging-dependent decline in MS inflammatory DA warrants further investigation.

多发性硬化症中Th17的衰老依赖性变化和细胞因子反应。
背景:多发性硬化症(MS)是一种损害中枢神经系统的慢性自身免疫性疾病。随着MS (pwMS)患者年龄的增长,炎症性疾病活动性(DA)降低,随机临床试验评估了老年pwMS患者停止疾病改善治疗(DMT)的风险大于收益。本研究旨在研究外周产生髓鞘碱性蛋白(MBP)驱动的细胞因子反应是否介导MS炎症性DA的衰老相关下降。方法:我们纳入了2017年至2022年间669名成年pwMS患者的临床数据,这些患者加入了一个基于临床的前瞻性队列。从80名参与者中,我们分离了新鲜的外周血单核细胞(PBMCs),并用50µg/ml的MBP(或热杀假丝酵母)培养24小时。我们使用酶联免疫吸附法检测细胞培养上清中白细胞介素17 (IL-17)和干扰素γ (IFN-γ),并使用商业人类细胞因子/化因子阵列检测上清样本的亚群。我们使用协变量调整的线性回归检验了年龄与年复发率(ARR)之间的关系,以及年龄与mbp刺激的细胞因子产生(通过培养的PBMC)之间的关系。我们进行了中介分析,以确定mbp驱动的细胞因子反应在多大程度上驱动年龄和ARR之间的关联。结果:在669名pwMS患者(平均年龄51.7±12.7岁,80.7%为女性,89.4%为非西班牙裔白人)中,ARR随年龄的增长而下降(β=-0.003, p)。结论:外周IL-17反应降低是MS炎症性DA衰老依赖性下降的潜在生物学机制,值得进一步研究。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of Neuroinflammation
Journal of Neuroinflammation 医学-神经科学
CiteScore
15.90
自引率
3.20%
发文量
276
审稿时长
1 months
期刊介绍: The Journal of Neuroinflammation is a peer-reviewed, open access publication that emphasizes the interaction between the immune system, particularly the innate immune system, and the nervous system. It covers various aspects, including the involvement of CNS immune mediators like microglia and astrocytes, the cytokines and chemokines they produce, and the influence of peripheral neuro-immune interactions, T cells, monocytes, complement proteins, acute phase proteins, oxidative injury, and related molecular processes. Neuroinflammation is a rapidly expanding field that has significantly enhanced our knowledge of chronic neurological diseases. It attracts researchers from diverse disciplines such as pathology, biochemistry, molecular biology, genetics, clinical medicine, and epidemiology. Substantial contributions to this field have been made through studies involving populations, patients, postmortem tissues, animal models, and in vitro systems. The Journal of Neuroinflammation consolidates research that centers around common pathogenic processes. It serves as a platform for integrative reviews and commentaries in this field.
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