TFE3 and TFEB in CD40L Dependent Murine Autoimmunity and Human Lupus

TFE3 和 TFEB 在 CD40L 依赖性小鼠自身免疫和人类狼疮中的作用

• 批准号: 7415148
• 负责人: CHRISTOPHER AJ ROMAN
• 金额: $ 34.43万
• 依托单位: SUNY DOWNSTATE MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-15 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7415148
• 关键词: Address; Affinity; Antibodies; Antigens; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Autoimmunity; B-Lymphocytes; Backcrossings; Binding; Biological; Biological Assay; CD28 gene; CD40 Ligand; Cessation of life; Collaborations; Condition; Dendritic cell activation; Development; Disease; Dominant-Negative Mutation; Embryo; Enlargement of lymph nodes; Etiology; Exhibits; Functional disorder; Gene Expression; Gene Proteins; Gene Transfer Techniques; Genetic; Genetic Transcription; Goals; Human; Immune; Immune response; Immunity; Immunoglobulin Class Switching; Immunoglobulin G; Immunoglobulin M; Inbred MRL lpr Mice; Inflammatory; Interleukin-15; Interleukin-2; Interleukins; Knowledge; Lupus; Lymphatic Diseases; Lymphocyte; Microphthalmos; Modeling; Molecular; Mus; Pathology; Pathway interactions; Patients; Peripheral Blood Lymphocyte; Phosphorylation; Physiological; Production; Prognostic Marker; Proteins; Publications; Purpose; Regulation; Reporter Genes; Research Personnel; Resected; Rheumatoid Arthritis; Role; Running; Structure of germinal center of lymph node; Syndrome; Systemic Lupus Erythematosus; T memory cell; T-Cell Receptor; T-Lymphocyte; TFE3 gene; TNFSF5 gene; Testing; Thinking; Thymus Gland; Transgenic Organisms; base; cohort; immune function; in vivo; interest; macrophage; promoter; receptor; research study; response; transcription factor

DESCRIPTION (provided by applicant): CD40L (CD154; gp39) is a critical effector molecule of activated T cells, necessary for production of isotype switched and affinity matured antibodies by B cells, and macrophage and dendritic cell activation. Abnormal CD40L expression by T and B cells is thought to drive multiple human immunological and inflammatory diseases of which systemic lupus erythematosus (Lupus, SLE) and rheumatoid arthritis are most prominent. Consequently, identification of factors that regulate CD40L is necessary to better understand the etiology of these diseases and possibly develop new treatment strategies. Studies from the applicant now show that the related transcription factors TFE3 and TFEB are physiological and direct activators of CD40L gene expression in T cells. Simultaneous inactivation of TFE3 and TFEB exclusively in T cells in mice resulted in an immune deficiency resembling human Hyper IgM syndrome caused by CD40L deficiency, characterized by defective humoral immune responses to thymus (T)-dependent antigens, poor germinal center formation, but normal T-independent humoral responses. T cells from such mice exhibited impaired CD40L expression. This discovery was possible by expressing a transdominant-negative (TON) inhibitory protein that simultaneously blocked TFE3 and TFEB activity in T cells via transgenesis. This was necessary because genetic TFEB-deficiency causes early embryonic death and TFE3 and TFEB are functionally redundant with respect to CD40L. The purpose of the proposed studies is to further define how TFE3 and TFEB contribute to immune function and the autoimmune disease SLE primarily via their role in governing CD40L expression in lymphocytes. Experiments in Aim 1 will molecularly define the conditions and means by which TFE3 and TFEB control CD40L expression in response to T cell stimulation in mouse and human T cells. In Aim 2, we will evaluate the contribution of TFE3- and TFEB-dependent CD40L expression to the development of autoimmune disease in the Lupus-prone MRL/lpr mouse. In Aim 3, collaborative studies with Dr. E. Ginzler, who runs the SUNY-Downstate Lupus Cohort, will evaluate the status and contribution of TFE3 and TFEB to abnormal CD40L expression in lymphocytes from patients with SLE. Such information is important to fully understand the molecular basis of this immune pathology, to devise new treatment strategies, and possibly identify new prognostic markers.

描述(由申请人提供)：CD40L(CD154；gp39)是激活的T细胞的关键效应分子，对于B细胞产生同型转换和亲和力成熟的抗体以及巨噬细胞和树突状细胞的激活是必需的。T、B细胞CD40L的异常表达被认为是多种人类免疫性和炎症性疾病的诱因，其中以系统性红斑狼疮(SLE)和类风湿关节炎最为突出。因此，识别调节CD40L的因素对于更好地了解这些疾病的病因并可能开发新的治疗策略是必要的。申请人目前的研究表明，相关转录因子TFE3和TFEB是T细胞CD40L基因表达的生理性和直接激活剂。TFE3和TFEB在小鼠T细胞中同时失活，导致类似于CD40L缺乏引起的人类Hyper IgM综合征的免疫缺陷，其特征是对胸腺(T)依赖抗原的体液免疫反应缺陷，生发中心形成不良，但T非依赖性体液反应正常。这些小鼠的T细胞表现出CD40L表达受损。这一发现是可能的，因为表达了一种跨显性负(TON)抑制蛋白，通过转基因同时阻断了T细胞中TFE3和TFEB的活性。这是必要的，因为遗传的TFEB缺乏导致早期胚胎死亡，并且TFE3和TFEB相对于CD40L在功能上是多余的。本研究的目的是进一步明确TFE3和TFEB如何主要通过调节淋巴细胞中CD40L的表达来促进免疫功能和自身免疫性疾病SLE。目标1中的实验将从分子上确定TFE3和TFEB控制CD40L表达的条件和方法，以响应小鼠和人类T细胞的T细胞刺激。在目的2中，我们将评估依赖TFE3和TFEB的CD40L表达在狼疮易感MRL/LPR小鼠自身免疫性疾病发生中的作用。在目标3中，与纽约州立大学北部狼疮队列负责人E.Ginzler博士的合作研究将评估TFE3和TFEB在SLE患者淋巴细胞中异常CD40L表达的状况和作用。这些信息对于充分理解这种免疫病理的分子基础，设计新的治疗策略，并可能识别新的预后标记物是重要的。