Identifying genes for neuropsychiatric lupus

描述(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，以发作性红斑和疾病进展为特征，显著的发病率和死亡率(L，2)。它是一种多系统的风湿性疾病，具有多种相关的临床神经和精神症状，包括认知、行为、情感和/或运动表现，可能影响多达75%的SLE患者(3)。由于缺乏对中枢神经系统(CNS)功能异常的潜在机制的了解，发病率和死亡率都居高不下。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一种药物，可以通过抑制正在进行的病理免疫反应，同时保持生理免疫监测来阻止疾病的进展。 一个理想的治疗方法是改变参与神经精神性狼疮(NPLE)免疫病理机制的基因的表达。尽管导致系统性红斑狼疮神经功能障碍的基因尚未被仔细剖析，但对狼疮小鼠模型的初步研究表明，在海马体和小脑中异常表达的细胞因子基因是导致神经功能障碍的原因(3-5)。我们的实验室最近证明，组蛋白脱乙酰酶(HDI)抑制剂曲古抑素A(TSA)逆转了与SLE免疫发病机制有关的几个基因的倾斜表达。TSA显著下调人SLE PBMC/T细胞CD154(CD40配体)和IL-10mRNA和蛋白的表达，同时上调PBMC/T细胞干扰素-g的信息和蛋白水平。此外，我们在MR1JIpr小鼠狼疮模型上的初步数据表明，该抑制剂下调MRL/IPR脾细胞IL-10、IL-6、IL-12p30、IL-12p40和干扰素-g的mRNA和蛋白的分泌。由于IL-6、IL-10和IFN-g基因在MR/IPR狼疮的小脑和海马区过度表达，我们提出HDIs可能有助于神经性精神病狼疮的预防或治疗。

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.