评估多发性硬化症患者的年龄相关免疫特征。
Evaluation of Age-Dependent Immune Signatures in Patients With Multiple Sclerosis.
机构信息
From the Department of Neurology with Institute of Translational Neurology (M. Eschborn, M.P., T.W., S.P., A.S.-M., L.L., C.C.G., H.W., L.K.), University Hospital Münster, Münster, Germany; Department of Neurology with Institute of Translational Neurology (C.N., L.R., T.R., S.G.M.), University Hospital Münster, Münster, Germany; present address: Department of Neurology, University Hospital Düsseldorf, Düsseldorf, Germany; Department of Neurology (K.P., S.B.), Focus Program Translational Neuroscience (FTN) and Immunotherapy (FZI), Rhine Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany; Institute of Biostatistics and Clinical Research (M. Eveslage), University of Münster, Münster, Germany; and Brain and Mind Centre (H.W.), Medical Faculty, University of Sydney, Sydney, Camperdown, NSW, Australia.
出版信息
Neurol Neuroimmunol Neuroinflamm. 2021 Oct 19;8(6). doi: 10.1212/NXI.0000000000001094. Print 2021 Nov.
BACKGROUND AND OBJECTIVES
In MS, an age-related decline in disease activity and a decreased efficacy of disease-modifying treatment have been linked to immunosenescence, a state of cellular dysfunction associated with chronic inflammation.
METHODS
To evaluate age-related immunologic alterations in MS, we compared immune signatures in peripheral blood (PB) and CSF by flow cytometry in patients with relapsing-remitting (RR) (PB n = 38; CSF n = 51) and primary progressive (PP) MS (PB n = 40; CSF n = 36) and respective controls (PB n = 40; CSF n = 85).
RESULTS
Analysis revealed significant age-related changes in blood immune cell composition, especially in the CD8 T-cell compartment of healthy donors (HDs) and patients with MS. However, HDs displayed a strong age-dependent decline in the expression of the immunoregulatory molecules KLRG1, LAG3, and CTLA-4 on memory CD8 T cells, whereas this age-dependent reduction was completely abrogated in patients with MS. An age-dependent increase in the expression of the costimulatory molecule CD226 on memory CD8 T cells was absent in patients with MS. CD226 expression correlated with disability in younger (≤50 years) patients with MS. CSF analysis revealed a significant age-dependent decline in various immune cell populations in PPMS but not RRMS, suggesting a differential effect of aging on the intrathecal compartment in PPMS.
DISCUSSION
Our data illustrate that aging in MS is associated with a dysbalance between costimulatory and immunoregulatory signals provided by CD8 T cells favoring a proinflammatory phenotype and, more importantly, a pattern of premature immune aging in the CD8 T-cell compartment of young patients with MS with potential implications for disease severity.
背景与目的
在多发性硬化症（MS）中，疾病活动的年龄相关性下降和疾病修正治疗的疗效降低与免疫衰老有关，免疫衰老即与慢性炎症相关的细胞功能障碍状态。
方法
为了评估 MS 中与年龄相关的免疫学改变，我们通过流式细胞术比较了复发缓解型 MS（RRMS）（PB n=38；CSF n=51）和原发进展型 MS（PPMS）（PB n=40；CSF n=36）患者外周血（PB）和脑脊液（CSF）中的免疫特征，并与相应的对照者（PB n=40；CSF n=85）进行比较。
结果
分析显示，血液免疫细胞组成存在显著的年龄相关性变化，尤其是在健康供者（HDs）和 MS 患者的 CD8 T 细胞中。然而，HDs 的记忆 CD8 T 细胞上的免疫调节分子 KLRG1、LAG3 和 CTLA-4 的表达随年龄呈强烈的依赖性下降，而 MS 患者中这种年龄相关的减少完全被阻断。记忆 CD8 T 细胞上共刺激分子 CD226 的表达随年龄增加，而 MS 患者中这种增加则不存在。CD226 的表达与年轻（≤50 岁）MS 患者的残疾程度相关。CSF 分析显示，PPMS 中各种免疫细胞群体随年龄的依赖性下降，但 RRMS 中则没有，这表明衰老对 PPMS 鞘内隔室的影响存在差异。
讨论
我们的数据表明，MS 中的衰老与 CD8 T 细胞提供的共刺激和免疫调节信号之间的失衡有关，这种失衡有利于促炎表型，更重要的是，在年轻 MS 患者的 CD8 T 细胞中存在一种早衰的免疫衰老模式，这可能对疾病严重程度有影响。
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