Peripheral Immune Cell Populations Associated with Cognitive Deficits and Negative Symptoms of Treatment-Resistant Schizophrenia.
Peripheral Immune Cell Populations Associated with Cognitive Deficits and Negative Symptoms of Treatment-Resistant Schizophrenia.
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DOI：
10.1371/journal.pone.0155631
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Bullmore ET
中科院分区：
文献类型：
--
作者：
Fernandez-Egea E;Vértes PE;Flint SM;Turner L;Mustafa S;Hatton A;Smith KG;Lyons PA;Bullmore ET
假设，精神障碍可能是由免疫机制引起或调节的。如果是这样的话，人们可能会期望存在外周免疫系统表型，这些表型可以在血细胞中测量，作为精神病状态的生物标志物。采用多参数流式细胞术检测18例慢性精神分裂症患者（其中17例接受氯氮平治疗）和18例年龄、性别、BMI和吸烟相匹配的健康志愿者静脉血中73种免疫细胞亚群的活化状态。我们使用多变量方法（偏最小二乘法）来降低维数，并定义与对照组相比，病例中差异共表达细胞计数的群体。精神分裂症患者的NK细胞、幼稚B细胞、CXCR 5+记忆T细胞和经典单核细胞的相对数量增加;树突状细胞（DC）、HLA-DR+调节性T细胞（T细胞）和CD 4+记忆T细胞的数量减少。同样，在患者组中，更严重的阴性和认知症状与树突状细胞、HLA-DR+ T细胞和CD 4+记忆T细胞的相对数量减少相关。受中枢神经系统多巴胺信号对精神病的重要性的启发，我们测量了分离的CD 4+细胞中多巴胺受体基因的表达。多巴胺D3（DRD 3）受体的表达显着增加氯氮平治疗的精神分裂症和共变显着分化的T细胞类的CD 4+谱系。氯氮平治疗的精神分裂症患者外周免疫细胞群和多巴胺能信号传导被破坏免疫表型可以提供外周可及的和机制上特异性的生物标志物，用于该耐药患者亚组中残留的认知和阴性症状。
Hypothetically, psychotic disorders could be caused or conditioned by immunological mechanisms. If so, one might expect there to be peripheral immune system phenotypes that are measurable in blood cells as biomarkers of psychotic states. We used multi-parameter flow cytometry of venous blood to quantify and determine the activation state of 73 immune cell subsets for 18 patients with chronic schizophrenia (17 treated with clozapine), and 18 healthy volunteers matched for age, sex, BMI and smoking. We used multivariate methods (partial least squares) to reduce dimensionality and define populations of differentially co-expressed cell counts in the cases compared to controls. Schizophrenia cases had increased relative numbers of NK cells, naïve B cells, CXCR5+ memory T cells and classical monocytes; and decreased numbers of dendritic cells (DC), HLA-DR+ regulatory T-cells (Tregs), and CD4+ memory T cells. Likewise, within the patient group, more severe negative and cognitive symptoms were associated with decreased relative numbers of dendritic cells, HLA-DR+ Tregs, and CD4+ memory T cells. Motivated by the importance of central nervous system dopamine signalling for psychosis, we measured dopamine receptor gene expression in separated CD4+ cells. Expression of the dopamine D3 (DRD3) receptor was significantly increased in clozapine-treated schizophrenia and covaried significantly with differentiated T cell classes in the CD4+ lineage. Peripheral immune cell populations and dopaminergic signalling are disrupted in clozapine-treated schizophrenia. Immuno-phenotypes may provide peripherally accessible and mechanistically specific biomarkers of residual cognitive and negative symptoms in this treatment-resistant subgroup of patients.