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: 7618022
• 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/7618022
• 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; Dendritic cell activation; Development; Disease; Dominant-Negative Mutation; Embryo; 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; 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; Thymus Gland; Transgenic Organisms; base; cohort; immune function; in vivo; interest; lupus-like; macrophage; promoter; receptor; research study; response; systemic autoimmune disease; transcription factor; treatment strategy

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）：CD 40 L（CD 154; gp 39）是活化T细胞的关键效应分子，是B细胞产生同种型转换和亲和力成熟抗体以及巨噬细胞和树突细胞活化所必需的。T和B细胞的异常CD 40 L表达被认为驱动多种人类免疫和炎性疾病，其中系统性红斑狼疮（Lupus，SLE）和类风湿性关节炎是最突出的。因此，鉴定调节CD 40 L的因子对于更好地理解这些疾病的病因并可能开发新的治疗策略是必要的。申请人的研究现在表明，相关的转录因子TFE 3和TFEB是T细胞中CD 40 L基因表达的生理和直接激活剂。小鼠T细胞中TFE 3和TFEB的同时失活导致类似于由CD 40 L缺乏引起的人高IgM综合征的免疫缺陷，其特征在于对胸腺（T）依赖性抗原的体液免疫应答缺陷，生发中心形成不良，但正常的T非依赖性体液应答。来自这些小鼠的T细胞表现出受损的CD 40 L表达。这一发现是可能的，通过表达一种反式显性负（TON）抑制蛋白，通过转基因同时阻断T细胞中的TFE 3和TFEB活性。这是必要的，因为遗传性TFEB缺陷导致早期胚胎死亡，并且TFE 3和TFEB相对于CD 40 L是功能冗余的。所提出的研究的目的是进一步确定TFE 3和TFEB如何主要通过其在控制淋巴细胞中的CD 40 L表达中的作用而促进免疫功能和自身免疫性疾病SLE。目的1中的实验将从分子上定义TFE 3和TFEB控制小鼠和人T细胞中响应T细胞刺激的CD 40 L表达的条件和方法。在目的2中，我们将评估TFE 3和TFEB依赖性CD 40 L表达对狼疮易感MRL/lpr小鼠中自身免疫性疾病发展的贡献。在目标3中，与E. Ginzler是SUNY-Downstate狼疮队列的负责人，他将评估TFE 3和TFEB对SLE患者淋巴细胞异常CD 40 L表达的作用和状态。这些信息对于充分理解这种免疫病理学的分子基础、设计新的治疗策略以及可能鉴定新的预后标志物是重要的。