Pharmacology Department, National University of Ireland,Galway, Ireland.
Expert Rev Clin Immunol. 2005 May;1(1):103-12. doi: 10.1586/1744666X.1.1.103.
The cause of schizophrenia remains an enigma despite the development of effective antipsychotic drugs that act by modulating the dopaminergic and serotonergic systems in the limbic region of the brain. Although such drugs are undoubtedly clinically effective, many patients do not fully benefit from such treatments, and the side effects, such as weight gain and the exacerbation of insulin-dependent diabetes mellitus, are often problematic. In recent years, the possible cause of schizophrenia has switched from an emphasis on neurotransmitter dysfunction to possible genetic and neurodevelopmental abnormalities. The close link between the loci for insulin-dependent diabetes mellitus, human lymphocyte antigen system and schizophrenia may indicate an immune component for this disorder. This hypothesis gains further credibility from epidemiologic studies showing a link between viral infections in utero and the subsequent development of schizophrenia; the negative correlation between rheumatoid arthritis and schizophrenia gives further support to the hypothesis. Thus, the immune hypothesis of schizophrenia has developed from an understanding of the genetic, environmental and infectious sequelae that underlie the immune changes involving the cellular and humoral components of the adaptive immune system. The changes in the types of T-lymphocytes that are involved in the adaptive immune response are of particular importance. The T-helper 1 cells, that secrete interleukin-2 and interferon-gamma for example, are reduced in activity while the T-helper 2 cells, together with the macrophages, show an increased secretion of interleukins-6 and -10. As these immune changes are normalized following effective antipsychotic drug treatment, new types of antipsychotics could be developed that act directly on the imbalance in the components of the adaptive immune system. The finding that some anti-inflammatory drugs can exhibit modest antipsychotic activity is further evidence of the validity of the autoimmune nature of schizophrenia and an indication that drug development based on this concept may be a fruitful area for future research.
尽管开发了有效的抗精神病药物，通过调节大脑边缘区域的多巴胺能和 5-羟色胺能系统来发挥作用，但精神分裂症的病因仍然是个谜。尽管这些药物在临床上无疑是有效的，但许多患者并没有从这些治疗中完全受益，而且副作用，如体重增加和胰岛素依赖型糖尿病的恶化，往往是个问题。近年来，精神分裂症的可能病因已经从强调神经递质功能障碍转变为可能的遗传和神经发育异常。胰岛素依赖型糖尿病、人类淋巴细胞抗原系统和精神分裂症的基因座之间的紧密联系可能表明这种疾病存在免疫成分。这一假设从流行病学研究中得到了进一步的可信度，这些研究表明宫内病毒感染与随后发生的精神分裂症之间存在关联；类风湿关节炎与精神分裂症之间的负相关关系进一步支持了这一假设。因此，精神分裂症的免疫假说从对遗传、环境和感染后果的理解发展而来，这些后果涉及到适应性免疫系统的细胞和体液成分的免疫变化。参与适应性免疫反应的 T 淋巴细胞类型的变化尤其重要。例如，分泌白细胞介素-2 和干扰素-γ的 T 辅助 1 细胞的活性降低，而 T 辅助 2 细胞与巨噬细胞一起，白细胞介素-6 和 -10 的分泌增加。随着有效的抗精神病药物治疗后这些免疫变化得到正常化，可能会开发出新型的直接作用于适应性免疫系统成分失衡的抗精神病药物。一些抗炎药物可以表现出适度的抗精神病活性的发现进一步证明了精神分裂症自身免疫性质的有效性，并表明基于这一概念的药物开发可能是未来研究的一个富有成效的领域。
