CSF-Derived CD4(+) T-Cell Diversity Is Reduced in Patients With Alzheimer Clinical Syndrome.
CSF-Derived CD4(+) T-Cell Diversity Is Reduced in Patients With Alzheimer Clinical Syndrome.
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DOI：
10.1212/nxi.0000000000001106
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发表时间：
2022-01
期刊：
影响因子：
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通讯作者：
Monson N
中科院分区：
文献类型：
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作者：
Joshi C;Sivaprakasam K;Christley S;Ireland S;Rivas J;Zhang W;Sader D;Logan R;Lambracht-Washington D;Rosenberg R;Cullum M;Hitt B;Li QZ;Barber R;Greenberg B;Cowell L;Zhang R;Stowe A;Huebinger R;Kelley B;Monson N
阿尔茨海默病患者表现出淀粉样蛋白相关的神经变性的证据。我们的重点是确定这些患者是否也表现出由CD4+T细胞介导的疾病靶向适应性免疫反应的证据。为了验证这一假设，我们评估了阿尔茨海默病临床综合征(ACS)患者的脑脊液免疫特征，这些患者表现出临床上明确的痴呆症。应用多色流式细胞术检测急性冠脉综合征患者的先天免疫和获得性免疫水平。使用下一代测序技术测量脑脊液来源的CD4+和CD8+T细胞受体谱系遗传学。脑脊液来源抗体库的脑特异性自身抗体特征用阵列技术或酶联免疫吸附试验测量。以同龄健康对照组(HCS)的脑脊液作为对照队列。与正常对照组比较，急性冠脉综合征患者脑脊液中天然细胞增多，且随着年龄的增长，先天性细胞的扩张率增加，但与正常对照组比较差异无统计学意义。在急性冠脉综合征患者中，尽管脑脊液中有天然细胞的增殖，但总的CD4+T细胞的频率随着年龄的增长而降低。T细胞受体谱系遗传学研究表明，与同龄HCS相比，急性冠脉综合征患者T细胞克隆性增殖增强，多样性降低。脑脊液检查显示，急性冠脉综合征患者的CD4+T细胞介导的适应性免疫反应发生了改变。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衰退的目标前进。
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.