programmed cell death in regulation of autoimmunity

自身免疫调节中的程序性细胞死亡

• 批准号: 8157143
• 负责人: Richard M Siegel
• 金额: $ 94.83万
• 依托单位: NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
• 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/8157143
• 关键词: Apoptosis; Autoimmunity; Cessation of life; Disease; Dominant-Negative Mutation; Family; Insulin-Dependent Diabetes Mellitus; Molecular; Process; Regulation; TNFRSF6 gene; autoimmune lymphoproliferative syndrome

Programmed cell death has been shown to be an essential feature of negative selection of autoreactive lymphocytes and regulation of both physiological and pathological immune responses. Fas, a member of the TNF-receptor superfamily also known as CD95, has been shown to be important in apoptosis of activated T and B lymphocytes initiated by signaling through their antigen receptors. Humans and mice with germ line dominant-negative mutations in Fas accumulate abnormal lymphocytes and develop systemic autoimmunity similar to patients with Systemic Lupus Erythematosus. While most patients with non-familial autoimmune disease do not carry Fas mutations, there is evidence that Fas-mediated apoptosis may be impaired in the milieu of chronic inflammation. We are investigating what signals regulate Fas-mediated apoptosis in T cells, with the eventual aim of harnessing these discoveries to modulate Fas-induced apoptosis for therapeutic goals in human disease. In activated CD4+ T cells, TCR restimulation triggers apoptosis that depends in large part on interactions between the death receptor Fas and its ligand FasL. This process, termed restimulation-induced cell death (RICD), is a mechanism of peripheral immune tolerance. TCR signaling sensitizes activated T cells to Fas-mediated apoptosis, but what pathways mediate this process are not known. Using a variety of approaches, we are investigating molecular and cellular mechanisms regulating the TCR and Fas-induced apoptosis pathways. We have found considerable heterogeneity in the ability of various T cell subsets to undergo Fas-mediated apoptosis and are investigating the molecular mechanisms underlying this heterogeneity. The goal in understanding these mechanisms is to design specific therapies to sensitize autoreactive lymphocytes to Fas-mediated apoptosis, which could constitute a long-acting and potentially permanent treatment for various autoimmune diseases such as Systemic Lupus, Multiple Sclerosis, Rheumatoid Arthritis, Type-I diabetes, and others in which autoreactive lymphocytes play a role. Through collaborations with investigators at NIH studying patients with the Autoimmune LymphoProliferative Syndrome (ALPS), a rare disorder associated with dominant-interfering Fas mutations, and the more common polygenic autoimmune disease Systemic Lupus Erythematosus (SLE), we are investigating translational implications of these findings. We are also investigating the cell biological control of Fas Ligand (FasL), the TNF-family cytokine ligand for Fas. In addition to trafficking to the plasma membrane as a type II transmembrane protein, FasL is known to be sorted into secretory lysosomes, where it can be secreted in vesicles and cleaved by metalloproteases. We are investigating which forms of FasL particpate in restimulation-induced cell death,and what molecules and motifs within the FasL cytoplasmic N-terminal domain direct its trafficking to secretory lysosomes. In a collaboration with Raif Geha's laboratory at Childrens Hospital in Boston, we are investigating the mechanisms by which mutations in TACI, a TNF-family receptor important for regulating B cell survival and class-switching, cause familial cases of common variable immunodeficiency.

程序性细胞死亡已被证明是自动反应性淋巴细胞的负选择以及生理和病理免疫反应的调节的重要特征。 FAS是TNF受体超家族的成员，也称为CD95，已被证明在通过其通过其抗原受体信号传导引发的活化T和B淋巴细胞的凋亡中很重要。在FAS中具有生殖系显性阴性突变的人类和小鼠会积累异常的淋巴细胞，并发展出类似于全身性红斑狼疮患者的全身自身免疫性。尽管大多数非家庭自身免疫性疾病的患者不带FAS突变，但有证据表明，在慢性炎症环境中，FAS介导的凋亡可能会受到损害。 我们正在研究哪些信号调节T细胞中FAS介导的细胞凋亡，最终目的是利用这些发现来调节FAS诱导的细胞凋亡，以实现人类疾病的治疗目标。在活化的CD4+ T细胞中，TCR重新刺激会触发凋亡，这在很大程度上取决于死亡受体FAS与其配体FASL之间的相互作用。该过程称为恢复诱导的细胞死亡（RICD），是外周免疫耐受性的机制。 TCR信号传导使活化的T细胞对FAS介导的细胞凋亡敏感，但是介导该过程的途径尚不清楚。使用多种方法，我们正在研究调节TCR和FAS诱导的凋亡途径的分子和细胞机制。我们发现，各种T细胞子集经历FAS介导的细胞凋亡的能力的异质性很大，并且正在研究这种异质性的分子机制。理解这些机制的目的是设计特定的疗法，以使自动反应性淋巴细胞对FAS介导的凋亡敏感，这可能构成长期效果，并可能永久性地治疗各种自身免疫性疾病，例如全身性狼疮，诸如全身性硬化症，多发性硬化症，类风湿性关节炎，类型-I型糖尿病和其他自身的疾病，并在其他疾病中进行了自身。 通过与NIH研究人员的合作，研究了患有自身免疫性淋巴结增生性综合征（ALP）的患者，这是一种与占主导地位的FAS突变相关的罕见疾病，以及更常见的多基因自身免疫性全身性狼疮性狼疮（SLE），我们正在研究这些发现的翻译含义。 我们还正在研究FAS配体的细胞生物学对照（FASL），FAS的TNF家庭细胞因子配体。 除了运输到质膜作为II型跨膜蛋白外，已知FASL被分类为分泌的溶酶体，可以在囊泡中分泌并被金属蛋白酶裂解。我们正在研究哪种形式的FASL颗粒物在重新刺激诱导的细胞死亡中，以及FASL细胞质N末端结构域中的分子和基序将其运输转移到分泌溶酶体。 在与波士顿儿童医院的Raif Geha的实验室合作的过程中，我们正在研究Taci中突变的机制，Taci（一种对调节B细胞存活和类别的TNF家庭受体很重要的受体，都会引起常见可变免疫缺陷的家庭病例。