Role of T-bet in the pathogenesis of experimental autoimmune encephalomyelitis

T-bet 在实验性自身免疫性脑脊髓炎发病机制中的作用

• 批准号: 8763519
• 负责人: Vanja Lazarevic
• 金额: $ 35.8万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8763519
• 关键词: Affect; Animal Model; Autoimmune Diseases; CD4 Positive T Lymphocytes; Candidate Disease Gene; Cell Differentiation process; Cells; Central Nervous System Diseases; Complex; Demyelinations; Development; Disease; Disease remission; Encephalomyelitis; Etiology; Exhibits; Experimental Autoimmune Encephalomyelitis; Gene Targeting; Genes; Genetic Programming; Goals; Immune; Immunity; Impairment; Individual; Inflammatory; Injury; Intervention; Investigation; Laboratories; Lead; Mediating; Modeling; Multiple Sclerosis; Nature; Nervous System Trauma; Neuraxis; Neurologic; Pathogenesis; Pathogenicity; Patients; Primary Progressive Multiple Sclerosis; Process; Progressive Disease; Proteins; Relapse; Research; Role; Secondary Progressive Multiple Sclerosis; Signal Transduction; T-bet protein; Th1 Cells; environmental agent; genome-wide; interleukin-23; neuroinflammation; new therapeutic target; programs; response; transcription factor; treatment strategy

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) of uncertain etiology. It is a complex disease in which one or more environmental agents predispose genetically susceptible individuals to develop immunologically mediated CNS demyelination and axonal injury. In 80-90% of cases, MS starts with a relapsing-remitting course (RR-MS), but most patients develop progressive neurological deficits (i.e. secondary progressive MS; SP-MS). In 10-20% of cases, MS patients exhibit a more progressive disease without remission, namely primary progressive MS (PP-MS). Despite intense investigation into the pathological changes of MS, many questions regarding the nature of immunological dysregulation that lead to the development of MS remain unanswered. Most of our understanding of the pathogenesis of multiple sclerosis comes from investigations using experimental autoimmune encephalomyelitis animal model. In this model, both CD4+ T helper type 1 (TH1) and T helper type 17 (TH17) cells contribute to the pathogenesis of the disease. The transcription factor T-bet (encoded by the Tbx21 gene) drives the development of TH1 cells and inhibits the differentiation of TH17 cells. Interestingly, despite its role as a negative regulator of TH17 differentiation program in naive CD4+ T cells, T-bet is critical for the function of mature TH17 cells. T-bet is re-expressed in TH17 cells in response to IL-23, which drives the pathogenesis of several autoimmune diseases. T-bet deficient TH17 cells treated with IL-23 are not pathogenic in the setting of neuroinflammation. This observation raised important questions: (a) What makes TH17 cells pathogenic? (b) Is it the genetic program regulated by T-bet in response to IL-23 signaling? To answer these questions, we have performed genome-wide profiling of wild-type and T-bet deficient TH17 cells. In the process, an intriguing panel of candidate genes has been uncovered. Identifying the T-bet target genes in CD4+ T cells responsible for conferring pathogenicity and understanding how these gene products lead to CNS damage will lead to novel therapeutic targets. Treatment strategies directed at a specific subset of T-bet target genes, rather than T-bet itself, will provide selective intervention without causing global impairment of Type 1 immunity. Ultimately, the goal of this research is to lead to the development of new therapies for multiple sclerosis.

多发性硬化症（MS）是不确定病因的中枢神经系统（CNS）的炎症性疾病。这是一种复杂的疾病，其中一种或多种环境药物易感遗传易感的个体会发展出免疫学介导的中枢神经系统脱髓鞘和轴突损伤。在80-90％的病例中，MS始于复发过程（RR-MS），但大多数患者会出现进行性神经系统缺陷（即次要进行性MS; SP-MS）。在10-20％的病例中，MS患者表现出更为进行性疾病而没有缓解的疾病，即主要进行性MS（PP-MS）。尽管对MS的病理变化进行了严格的调查，但导致MS发展的免疫失调性质的许多问题仍未得到答复。我们对多发性硬化症发病机理的大部分理解都来自使用实验性自身免疫性脑脊髓炎动物模型的研究。在此模型中，CD4+ T辅助器类型1（TH1）和T辅助型17（Th17）细胞都有助于该疾病的发病机理。转录因子T-bet（由TBX21基因编码）驱动Th1细胞的发育并抑制Th17细胞的分化。有趣的是，尽管在幼稚的CD4+ T细胞中它是Th17分化程序的负调节剂，但T-bet对于成熟Th17细胞的功能至关重要。响应IL-23，T-BET在TH17细胞中重新表达，这驱动了几种自身免疫性疾病的发病机理。在神经炎症的情况下，用IL-23处理的T-bet缺乏TH17细胞不是致病性的。这种观察提出了重要的问题：（a）是什么使Th17细胞致病？ （b）这是由T-BET响应IL-23信号传导的遗传程序吗？为了回答这些问题，我们对野生型和T-bet缺乏Th17细胞进行了全基因组分析。在此过程中，已经发现了一个有趣的候选基因小组。确定负责赋予致病性并了解这些基因产物如何导致中枢神经系统损伤的CD4+ T细胞中的T-BET靶基因将导致新的治疗靶标。针对特定T-BET靶基因的特定子集而不是T-BET本身的治疗策略将提供选择性干预措施，而不会引起1型免疫力的全球损害。最终，这项研究的目的是导致开发多发性硬化症的新疗法。