Müller Norbert, Weidinger Elif, Leitner Bianka, Schwarz Markus J
Department of Psychiatry and Psychotherapy, Ludwig Maximilian University Munich, Germany.
Department of Laboratory Medicine, Ludwig Maximilian University Munich, Germany.
Front Neurosci. 2015 Oct 21;9:372. doi: 10.3389/fnins.2015.00372. eCollection 2015.
High levels of pro-inflammatory substances such as cytokines have been described in the blood and cerebrospinal fluid of schizophrenia patients. Animal models of schizophrenia show that under certain conditions an immune disturbance during early life, such as an infection-triggered immune activation, might trigger lifelong increased immune reactivity. A large epidemiological study clearly demonstrated that severe infections and autoimmune disorders are risk factors for schizophrenia. Genetic studies have shown a strong signal for schizophrenia on chromosome 6p22.1, in a region related to the human leucocyte antigen (HLA) system and other immune functions. Another line of evidence demonstrates that chronic (dis)stress is associated with immune activation. The vulnerability-stress-inflammation model of schizophrenia includes the contribution of stress on the basis of increased genetic vulnerability for the pathogenesis of schizophrenia, because stress may increase pro-inflammatory cytokines and even contribute to a lasting pro-inflammatory state. Immune alterations influence the dopaminergic, serotonergic, noradrenergic, and glutamatergic neurotransmission. The activated immune system in turn activates the enzyme indoleamine 2,3-dioxygenase (IDO) of the tryptophan/kynurenine metabolism which influences the serotonergic and glutamatergic neurotransmission via neuroactive metabolites such as kynurenic acid. The described loss of central nervous system volume and the activation of microglia, both of which have been clearly demonstrated in neuroimaging studies of schizophrenia patients, match the assumption of a (low level) inflammatory neurotoxic process. Further support for the inflammatory hypothesis comes from the therapeutic benefit of anti-inflammatory medication. Metaanalyses have shown an advantageous effect of cyclo-oxygenase-2 inhibitors in early stages of schizophrenia. Moreover, intrinsic anti-inflammatory, and immunomodulatory effects of antipsychotic drugs are known since a long time. Anti-inflammatory effects of antipsychotics, therapeutic effects of anti-inflammtory compounds, genetic, biochemical, and immunological findings point to a major role of inflammation in schizophrenia.
精神分裂症患者的血液和脑脊液中已发现存在高水平的促炎物质，如细胞因子。精神分裂症动物模型表明，在某些情况下，生命早期的免疫紊乱，如感染引发的免疫激活，可能会引发终身免疫反应性增强。一项大型流行病学研究清楚地表明，严重感染和自身免疫性疾病是精神分裂症的危险因素。基因研究显示，在与人类白细胞抗原（HLA）系统及其他免疫功能相关的6号染色体p22.1区域，存在与精神分裂症相关的强烈信号。另一系列证据表明，慢性（应激）压力与免疫激活有关。精神分裂症的易感性-应激-炎症模型认为，在精神分裂症发病机制中，基于遗传易感性增加，应激发挥了作用，因为应激可能会增加促炎细胞因子，甚至导致持久的促炎状态。免疫改变会影响多巴胺能、5-羟色胺能、去甲肾上腺素能和谷氨酸能神经传递。被激活的免疫系统进而激活色氨酸/犬尿氨酸代谢中的吲哚胺2,3-双加氧酶（IDO），该酶通过犬尿喹啉酸等神经活性代谢物影响5-羟色胺能和谷氨酸能神经传递。精神分裂症患者神经影像学研究已清楚证实的中枢神经系统体积减小和小胶质细胞激活，符合（低水平）炎症性神经毒性过程的假设。抗炎药物的治疗益处为炎症假说提供了进一步支持。荟萃分析表明，环氧化酶-2抑制剂在精神分裂症早期具有有益作用。此外，抗精神病药物的内在抗炎和免疫调节作用早已为人所知。抗精神病药物的抗炎作用、抗炎化合物的治疗作用、基因、生化和免疫学研究结果均表明，炎症在精神分裂症中起主要作用。
