From the Department of Neurology (C.J., S.I., J.R., W.Z., D.S., R.L., D.L.-W., R.R., M.C., B.H., B.G., R.Z., B.K., N.M.), Department of Neuroscience (K.S.), Department of Population and Data Sciences, (S.C., L.C.), Department of Psychiatry (M.C.), Department of Immunology (Q-Z.L, N.M.) and Department of Surgery (R.H.), UT Southwestern Medical Center UNT Health Science Center (R.B.), Department of Pharmacology and Neuroscience, Department of Neurology (A.S.), University of Kentucky, Lexington, KY.
Neurol Neuroimmunol Neuroinflamm. 2021 Nov 30;9(1). doi: 10.1212/NXI.0000000000001106. Print 2022 Jan.
Patients with Alzheimer dementia display evidence of amyloid-related neurodegeneration. Our focus was to determine whether such patients also display evidence of a disease-targeting adaptive immune response mediated by CD4 T cells. To test this hypothesis, we evaluated the CSF immune profiles of patients with Alzheimer clinical syndrome (ACS), who display clinically defined dementia.
Innate and adaptive immune profiles of patients with ACS were measured using multicolor flow cytometry. CSF-derived CD4 and CD8 T-cell receptor repertoire genetics were measured using next-generation sequencing. Brain-specific autoantibody signatures of CSF-derived antibody pools were measured using array technology or ELISA. CSF from similar-age healthy controls (HCs) was used as a comparator cohort.
Innate cells were expanded in the CSF of patients with ACS in comparison to HCs, and innate cell expansion increased with age in the patients with ACS, but not HCs. Despite innate cell expansion in the CSF, the frequency of total CD4 T cells reduced with age in the patients with ACS. T-cell receptor repertoire genetics indicated that T-cell clonal expansion is enhanced, and diversity is reduced in the patients with ACS compared with similar-age HCs.
Examination of CSF indicates that CD4 T cell-mediated adaptive immune responses are altered in patients with ACS. Understanding the underlying mechanisms affecting adaptive immunity will help move us toward the goal of slowing cognitive decline.
阿尔茨海默病患者表现出与淀粉样蛋白相关的神经退行性变的证据。我们的重点是确定这些患者是否也表现出由 CD4 T 细胞介导的针对疾病的适应性免疫反应的证据。为了验证这一假设，我们评估了具有阿尔茨海默临床综合征（ACS）的患者的 CSF 免疫特征，这些患者表现出临床定义的痴呆。
使用多色流式细胞术测量 ACS 患者的固有和适应性免疫特征。使用下一代测序测量 CSF 来源的 CD4 和 CD8 T 细胞受体库遗传学。使用阵列技术或 ELISA 测量 CSF 来源的抗体池的脑特异性自身抗体特征。使用类似年龄的健康对照（HC）的 CSF 作为比较队列。
与 HCs 相比，ACS 患者的 CSF 中固有细胞扩张，并且在 ACS 患者中，固有细胞的扩张随年龄增加，而在 HCs 中则不增加。尽管 CSF 中有固有细胞扩张，但 ACS 患者的总 CD4 T 细胞频率随年龄增长而降低。T 细胞受体库遗传学表明，与相似年龄的 HCs 相比，ACS 患者的 T 细胞克隆扩增增强，多样性降低。
对 CSF 的检查表明，ACS 患者的 CD4 T 细胞介导的适应性免疫反应发生改变。了解影响适应性免疫的潜在机制将有助于我们朝着减缓认知能力下降的目标前进。
