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，其特点是发作性发作和疾病进展，发病率和死亡率高（1,2）。它是一种多系统风湿性疾病，具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)。由于缺乏对中枢神经系统（CNS）功能异常相关的潜在机制的了解，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，进展也受到阻碍。一个长期的挑战是发现药物可以通过抑制正在进行的病理免疫反应来阻止疾病的进展，同时保持生理免疫监视。

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.