Lieber Institute for Brain Development, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Bloomberg School of Public Health, Department of Mental Health, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Mol Psychiatry. 2018 May;23(5):1251-1260. doi: 10.1038/mp.2017.89. Epub 2017 May 9.
The role of the immune system in schizophrenia remains controversial despite numerous studies to date. Most studies have profiled expression of select genes or proteins in peripheral blood, but none have focused on the expression of canonical pathways that mediate overall immune response. The current study used a systematic genetic approach to investigate the role of the immune system in a large sample of post-mortem brain of patients with schizophrenia: RNA sequencing was performed to assess the differential expression of 561 immune genes and 20 immune pathways in dorsolateral prefrontal cortex (DLPFC) (144 schizophrenia and 196 control subjects) and hippocampus (83 schizophrenia and 187 control subjects). The effect of RNA quality on gene expression was found to be highly correlated with the effect of diagnosis even after adjustment for observable RNA quality parameters (i.e. RNA integrity), thus this confounding relationship was statistically controlled using principal components derived from the gene expression matrix. In DLPFC, 23 immune genes were found to be differentially expressed (false discovery rate <0.05), of which seven genes replicated in both directionality and at nominal significance (P<0.05) in an independent post-mortem DLPFC data set (182 schizophrenia and 212 control subjects), although notably at least five of these genes have prominent roles in pathways other than immune function and overall the effect sizes were minimal (fold change <1.1). In the hippocampus, no individual immune genes were identified to be differentially expressed, and in both DLPFC and hippocampus none of the individual immune pathways were relatively differentially expressed. Further, genomic schizophrenia risk profiles scores were not correlated with the expression of individual immune pathways or differentially expressed genes. Overall, past reports claiming a primary pathogenic role of the immune system intrinsic to the brain in schizophrenia could not be confirmed.
尽管迄今为止已有大量研究，但免疫系统在精神分裂症中的作用仍存在争议。大多数研究都对特定基因或蛋白质在外周血中的表达进行了分析，但没有一项研究关注介导整体免疫反应的规范途径的表达。本研究使用系统遗传学方法来研究免疫系统在大量精神分裂症患者死后大脑样本中的作用：对 561 个免疫基因和 20 个免疫途径在背外侧前额叶皮层（DLPFC）（144 例精神分裂症和 196 例对照）和海马（83 例精神分裂症和 187 例对照）中的差异表达进行了 RNA 测序。发现 RNA 质量对基因表达的影响与诊断的影响高度相关，即使在调整了可观察到的 RNA 质量参数（即 RNA 完整性）后也是如此，因此使用源自基因表达矩阵的主成分来对这种混杂关系进行了统计学控制。在 DLPFC 中，发现 23 个免疫基因的表达存在差异（错误发现率<0.05），其中 7 个基因在独立的死后 DLPFC 数据集（182 例精神分裂症和 212 例对照）中以相同的方向和名义显著性（P<0.05）复制，尽管值得注意的是，其中至少有 5 个基因在免疫功能以外的途径中发挥着重要作用，而且总体而言，这些基因的效应大小很小（倍数变化<1.1）。在海马体中，没有发现单个免疫基因的表达存在差异，并且在 DLPFC 和海马体中，没有任何一个单独的免疫途径存在相对差异表达。此外，基因组精神分裂症风险谱评分与单个免疫途径或差异表达基因的表达无关。总体而言，过去声称免疫系统内在的大脑在精神分裂症中具有主要致病作用的报告无法得到证实。
