Identifying genes for neuropsychiatric lupus

描述（由申请人提供）：系统性红斑狼疮（SLE）是一种慢性、特发性自身免疫性疾病，其特征为发作性发作和疾病进展、严重的发病率和死亡率（1，2）。它是一种多系统风湿性疾病，伴有多种相关的临床神经和精神综合征，包括认知、行为、情感和/或运动表现，可影响高达75%的SLE患者（3）。由于对中枢神经系统（CNS）功能异常相关的潜在机制缺乏了解，发病率和死亡率仍然很高。此外，由于缺乏具体的诊断方法和治疗方案，进展受到阻碍。一个长期存在的挑战是发现可以通过抑制正在进行的病理性免疫应答同时维持生理性免疫监视来阻止疾病进展的药物。 一种理想的治疗方法将是改变有助于神经精神狼疮（NPLE）免疫发病机制的基因的表达。虽然导致SLE神经系统紊乱的基因尚未被详细分析，但在狼疮小鼠模型中的初步研究表明，海马和小脑中细胞因子基因的异常表达是导致神经功能缺损的原因（3-5）。我们的实验室最近证明，组蛋白脱乙酰酶（HDI）抑制剂曲古抑菌素A（TSA）逆转了SLE免疫发病机制中涉及的几个基因的偏斜表达（6）。TSA显著下调CD 154（CD 40-ligand）和IL-10 mRNA和蛋白，同时上调人SLE PBMC/T细胞中IFN-g信息和蛋白水平。此外，我们在狼疮的MRlJIPr小鼠模型中的初步数据表明，该抑制剂下调MRL/Ipr脾细胞中的IL-10、IL-6、IL-12 p30、IL-12 p40和IFN-γ mRNA和蛋白质分泌。由于IL-6、IL-10和IFN-g基因在MR/Ipr狼疮的小脑和海马中过表达，我们提出HDIs可能对预防或治疗神经精神狼疮有用的概念。

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is a chronic, idiopathic autoimmune disease characterized by episodic flares and progression of disease, substantial morbidity and mortality(l, 2). It is a multisystern rheumatic disease with a wide variety of associated clinical neurological and psychiatric syndromes including cognitive, behavioral, affective, and/or motor manifestations that may effect up to 75 percent of SLE patients(3). Both morbidity and mortality remain high because of lack of understanding of the underlying mechanisms related to abnormal central nervous system (CNS) function. In addition, progress has been hampered by the lack of specific diagnostic methods and therapeutic regimens. A long-standing challenge has been to discover drugs that can halt the progression of disease by inhibiting the ongoing pathologic immune responses while maintaining physiologic immune surveillance. An ideal therapeutic approach would be to modify the expression of the genes that contribute to immunopathogenesis of neuropsychiatric lupus (NPLE). Although the genes responsible for neurological disturbances in SLE is not finely dissected out, preliminary studies in mouse models of lupus suggests aberrant cytokine genes expression in hippocampus and cerebellum are responsible for the neurological deficit(3-5). Our laboratory has recently demonstrated that the histone deacetylase (HDI) inhibitor Trichostatin A (TSA) reverses the skewed expression of several genes implicated in the immunopathogenesis of SLE(6). TSA significantly down-regulated CD154 (CD40-ligand) and IL-10 mRNA and protein, while simultaneously up-regulating IFN-g message and protein levels in human SLE PBMC/T cells. Furthermore, our preliminary data in MRlJIpr mouse model of lupus demonstrates that this inhibitor down-regulates IL-10, IL-6, IL-12p30, IL-12p40 and IFN-g mRNA and protein secretion in MRL/Ipr splenocytes. Since IL-6, IL-10 and IFN-g genes are over expressed in cerebellum and hippocampus in MR/Ipr lupus, we propose the concept that HDIs may be useful for the prevention or treatment of neuropshychiatric lupus.