Tomita Michiyo, Khan Raza L, Blehm Benjamin H, Santoro Thomas J
Department of Internal Medicine, University of North Dakota School of Medicine, 1919 North Elm Street, Fargo, ND 58102, USA.
Med Hypotheses. 2004;62(3):325-35. doi: 10.1016/j.mehy.2003.10.009.
Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown etiology. Neuropsychiatric disturbances unexplained by drugs or by other untoward manifestations of disease are present in up to one-half of SLE patients and have profound economic and social impact. In patients with neuropsychiatric SLE, structural lesions have been identified in the hippocampus and proinflammatory cytokines have been detected in the cerebrospinal fluid. Similarly, murine models of lupus, such as MRL-lpr/lpr mice display behavioral disturbances which map to the hippocampus and exhibit overexpression of proinflammatory cytokine genes in hippocampal homogenates. Neuropsychiatric SLE typically occurs in the presence of serologically and clinically active lupus. In animal models of SLE, such as MRL-lpr/lpr, NZB, BXSB, and [NZB x NZW]F(1), uncontrolled autoreactivity in the periphery is accompanied by behavioral disturbances that are chronic and progressive. These observations suggest the hypothesis that central nervous system disease in SLE is driven by cross-talk between the peripheral immune system and the brain's innate immune system, which results in the inexorable activation of astrocytes, microglia, and/or neurons within the hippocampus. This leads to overproduction of brain cytokines, which induce the synthesis of pro-oxidant molecules, such as eicosanoids and reactive oxygen species, with resultant tissue injury. The cascade becomes self-perpetuating and eventuates in neuronal death, which is followed by impaired cognition. A better understanding of the molecular events that operate in the pathogenesis of neuropsychiatric SLE may provide the basis for a more rational therapeutic approach to this incompletely understood disease.
系统性红斑狼疮（SLE）是一种病因不明的自身免疫性疾病。高达一半的SLE患者存在无法用药物或疾病的其他不良表现解释的神经精神障碍，这些障碍具有深远的经济和社会影响。在神经精神性SLE患者中，已在海马体中发现结构病变，并且在脑脊液中检测到促炎细胞因子。同样，狼疮的小鼠模型，如MRL-lpr/lpr小鼠表现出行为障碍，这些障碍定位于海马体，并且在海马匀浆中表现出促炎细胞因子基因的过表达。神经精神性SLE通常在血清学和临床活动性狼疮存在的情况下发生。在SLE的动物模型中，如MRL-lpr/lpr、NZB、BXSB和[NZB×NZW]F(1)，外周的不受控制的自身反应性伴随着慢性和进行性的行为障碍。这些观察结果提出了一个假设，即SLE中的中枢神经系统疾病是由外周免疫系统和大脑固有免疫系统之间的相互作用驱动的，这导致海马体内星形胶质细胞、小胶质细胞和/或神经元的不可阻挡的激活。这导致脑内细胞因子过度产生，进而诱导促氧化分子如类花生酸和活性氧的合成，从而导致组织损伤。这个级联反应会自我持续下去，最终导致神经元死亡，随后认知功能受损。更好地理解在神经精神性SLE发病机制中起作用的分子事件，可能为这种尚未完全理解的疾病提供更合理的治疗方法的基础。
