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）是活化T细胞的关键效应分子，是B细胞产生同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 细胞和 B 细胞的异常 CD40L 表达被认为会导致多种人类免疫和炎症疾病，其中系统性红斑狼疮（狼疮、SLE）和类风湿性关节炎最为突出。因此，有必要鉴定调节 CD40L 的因素，以更好地了解这些疾病的病因并可能开发新的治疗策略。申请人现在的研究表明，相关转录因子TFE3和TFEB是T细胞中CD40L基因表达的生理学和直接激活剂。小鼠 T 细胞中 TFE3 和 TFEB 同时失活会导致类似于由 CD40L 缺陷引起的人类高 IgM 综合征的免疫缺陷，其特征是对胸腺 (T) 依赖性抗原的体液免疫反应缺陷、生发中心形成不良，但 T 独立体液反应正常。来自此类小鼠的 T 细胞表现出受损的 CD40L 表达。这一发现是通过表达转显性阴性 (TON) 抑制蛋白而实现的，该蛋白通过转基因同时阻断 T 细胞中的 TFE3 和 TFEB 活性。这是必要的，因为遗传性 TFEB 缺陷会导致早期胚胎死亡，并且 TFE3 和 TFEB 相对于 CD40L 来说在功能上是多余的。拟议研究的目的是进一步明确 TFE3 和 TFEB 如何通过其在控制淋巴细胞中 CD40L 表达的作用来促进免疫功能和自身免疫性疾病 SLE。目标 1 中的实验将从分子角度定义 TFE3 和 TFEB 控制 CD40L 表达以响应小鼠和人类 T 细胞中 T 细胞刺激的条件和方法。在目标 2 中，我们将评估 TFE3 和 TFEB 依赖性 CD40L 表达对狼疮倾向 MRL/lpr 小鼠自身免疫性疾病发展的贡献。在目标 3 中，与运行 SUNY-Downstate 狼疮队列的 E. Ginzler 博士合作研究，将评估 TFE3 和 TFEB 对 SLE 患者淋巴细胞异常 CD40L 表达的状态和贡献。这些信息对于充分了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识别新的预后标志物非常重要。