Updating the mild encephalitis hypothesis of schizophrenia
Updating the mild encephalitis hypothesis of schizophrenia
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DOI：
10.1016/j.pnpbp.2012.06.019
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发表时间：
2013-04-05
影响因子：
5.6
通讯作者：
Bechter, K.
中科院分区：
文献类型：
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作者：
Bechter, K.
精神分裂症似乎是一种异质性疾病。新出现的证据表明，低水平神经炎症（LLNI）可能并不罕见。许多总体致病性较低的传染性病原体是精神病（包括精神分裂症）和自身免疫性疾病的危险因素。根据轻度脑炎（ME）假说，LLNI代表了精神分裂症亚组的核心发病机制，该亚组与其他精神疾病有症状重叠。ME可由感染、自身免疫、毒性或创伤触发。一个“迟来的打击”和基因-环境相互作用需要解释精神分裂症的主要发现，这两个方面都与ME假说一致。精神分裂症风险基因在群体内保持相当恒定，尽管由此产生的后代数量较少;这可能是由于与风险基因相关的优势，例如，改善免疫反应，这可能会在不断变化的环境中发挥保护作用，尽管它们与增加对精神障碍的易感性的缺点有关。特定的精神分裂症症状可能会出现与LLNI的情况下，当某些脑功能系统参与，除了被预先存在的责任因素塑造。前驱症状阶段和向疾病状态的转变可能与LLNI过程的出现和随时间的变化有关。精神分裂症病程的变异性类似于自身免疫性疾病的不同病程，这是由三个必要因素造成的：基因、环境和免疫系统。提供了神经发育、遗传、ME和其他类型精神分裂症亚组的初步标准。在博尔纳病病毒感染中可以观察到ME精神分裂症的一个罕见例子。其他人估计，由早期感染引起的神经发育性精神分裂症可以解释约30%的病例，但转变为疾病的潜在病理机制仍存在疑问。可能涉及LLNI（例如，来自与持续性感染相关的再激活）和其他病理机制，包括血脑屏障或血CSF屏障的功能障碍、CNS-内源性免疫和平衡布线传输的体积传输模式（后者主要由突触传输表示，其通常被描述为在精神分裂症中受到干扰）。容量传输与CSF信号传导有关;并且一起可以代表在精神分裂症中观察到的分布式脑功能障碍、连接障碍和脑结构异常的共同发病联系。此外，CSF信号传导可以经由CSF流出通路沿着脑神经和外周神经延伸到外周组织中，并且它可以解释在嗅觉功能障碍、自主神经功能障碍中发现的神经元功能障碍的外周拓扑结构，甚至在外周组织中，即，在50%的病例中发现的肌肉损伤。精神分裂症的调节因素，如压力，激素和饮食，也是免疫反应的调节因素。考虑到最近对CSF的研究，ME精神分裂症亚组可能占病例的约40%。(C)2012 Elsevier Inc. All rights reserved.
Schizophrenia seems to be a heterogeneous disorder. Emerging evidence indicates that low level neuroinflammation (LLNI) may not occur infrequently. Many infectious agents with low overall pathogenicity are risk factors for psychoses including schizophrenia and for autoimmune disorders. According to the mild encephalitis (ME) hypothesis, LLNI represents the core pathogenetic mechanism in a schizophrenia subgroup that has syndromal overlap with other psychiatric disorders. ME may be triggered by infections, autoimmunity, toxicity, or trauma. A 'late hit' and gene-environment interaction are required to explain major findings about schizophrenia, and both aspects would be consistent with the ME hypothesis. Schizophrenia risk genes stay rather constant within populations despite a resulting low number of progeny; this may result from advantages associated with risk genes, e.g., an improved immune response, which may act protectively within changing environments, although they are associated with the disadvantage of increased susceptibility to psychotic disorders. Specific schizophrenic symptoms may arise with instances of LLNI when certain brain functional systems are involved, in addition to being shaped by pre-existing liability factors. Prodrome phase and the transition to a diseased status may be related to LLNI processes emerging and varying over time. The variability in the course of schizophrenia resembles the varying courses of autoimmune disorders, which result from three required factors: genes, the environment, and the immune system. Preliminary criteria for subgrouping neurodevelopmental, genetic, ME, and other types of schizophrenias are provided. A rare example of ME schizophrenia may be observed in Borna disease virus infection. Neurodevelopmental schizophrenia due to early infections has been estimated by others to explain approximately 30% of cases, but the underlying pathomechanisms of transition to disease remain in question. LLNI (e.g. from reactivation related to persistent infection) may be involved and other pathomechanisms including dysfunction of the blood-brain barrier or the blood-CSF barrier, CNS-endogenous immunity and the volume transmission mode balancing wiring transmission (the latter represented mainly by synaptic transmission, which is often described as being disturbed in schizophrenia). Volume transmission is linked to CSF signaling; and together could represent a common pathogenetic link for the distributed brain dysfunction, dysconnectivity, and brain structural abnormalities observed in schizophrenia. In addition, CSF signaling may extend into peripheral tissues via the CSF outflow pathway along brain nerves and peripheral nerves, and it may explain the peripheral topology of neuronal dysfunctions found, like in olfactory dysfunction, dysautonomia, and even in peripheral tissues, i.e., the muscle lesions that were found in 50% of cases. Modulating factors in schizophrenia, such as stress, hormones, and diet, are also modulating factors in the immune response. Considering recent investigations of CSF, the ME schizophrenia subgroup may constitute approximately 40% of cases. (C) 2012 Elsevier Inc. All rights reserved.