Mechanisms of Antigen Trafficking in Autoimmunity

自身免疫中抗原贩运的机制

• 批准号: 7680476
• 负责人: Mark J Mamula
• 金额: $ 5.22万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7680476
• 关键词: Antigen-Presenting Cells; Antigens; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmune Responses; Autoimmunity; B-Lymphocytes; Biological; CD4 Positive T Lymphocytes; Cell physiology; Complex; Core Facility; Data; Dendritic Cells; Development; Disease; Goals; Human; Image; Immune response; Immunity; Immunization; Kinetics; Label; Laser Microscopy; Life; Location; Lupus; Lupus Erythematosus; Lymphocyte; Modeling; Monitor; Mus; Nucleosomes; Pathology; Patients; Peripheral; Process; Production; Proteins; Research Design; Systemic Lupus Erythematosus; T-Cell Activation; T-Lymphocyte; Time; Work; autoreactive B cell; autoreactive T cell; in vivo; intravital microscopy; lymph nodes; macrophage; response; rituximab; success; trafficking; two-photon

PROVIDED. Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the presence of autoantibodies to a select group of intracellular proteins, most notably, determinants on nucleosomes and RNA-protein complexes. Autoimmune responses in human SLE and in murine models require the processing and presentation of self antigen leading to the activation of T cells. CD4 T cells provide help to autoreactive B cells, all leading to autoantibody production and pathology. The depletion of B cells in both murine SLE and in Rituximab-treated patients ameliorates disease. Our previous studies have shown that autoreactive B cells can escape peripheral tolerance, present autoantigens, and activate autoreactive T cells from the normal repertoire of lymphocytes. Indeed, this may be one mechanism by which Rituximab therapy is efficacious in human SLE. Our recent in vivo work demonstrates that unique subsets of antigen presenting cells (APCs) activate T cells at different time points in the development of immunity. In particular, B cells are the primary ARC in the early T cell responses post-immunization. Later in the autoimmune response, B cells lose the ability to present antigen while dendritic cells (DCs) gradually acquire APC function in T cell activation. Our studies demonstrate that DCs (and other APCs) can acquire antigen from the B cells by an undetermined transfer mechanism. The major goal of this proposal is to directly follow the transfer of antigen from antigen-specific B cells to other APCs and to determine if this mechanism has biological significance to the onset of autoimmunity. The success of our work will depend on the use of the In Vivo Imaging core facility. Our studies will examine the interaction of B cells, dendritic cells, and antigen T cells within the lymph node of a living mouse by intravital microscopy. In particular, we will identify the kinetics, location and mechanism of antigen transfer in vivo. Overall, our studies are designed to understand the processing and presentation of presentation of autoantigens in murine models of lupus autoimmunity.

但前提是。 系统性红斑狼疮是一种自身免疫性疾病，其特征是 针对选定的一组细胞内蛋白的自身抗体，最值得注意的是核小体和 RNA-蛋白质复合体。在人类SLE和小鼠模型中的自身免疫反应需要 自身抗原的加工和提呈，导致T细胞的激活。CD4T细胞提供帮助 自身反应性B细胞，所有这些都会导致自身抗体的产生和病理。两组患者B细胞的耗竭 在小鼠系统性红斑狼疮和利妥昔单抗治疗的患者中，可以改善疾病。我们之前的研究表明， 自身反应性B细胞可以逃避外周耐受，提供自身抗原，并激活自身反应性T细胞 从正常的淋巴细胞中分离出来。事实上，这可能是利妥昔单抗疗法的一种机制 对人类系统性红斑狼疮有效。我们最近在体内的研究表明，独特的抗原亚群 提呈细胞(APC)在免疫发育的不同时间点激活T细胞。特别是， B细胞是免疫后早期T细胞应答的主要ARC。在后来的自身免疫中 B细胞失去提呈抗原的能力，而树突状细胞(DC)逐渐获得APC 在T细胞活化中的作用。我们的研究表明，DC(和其他APC)可以从 B细胞通过一种未知的转移机制。这项提案的主要目标是直接遵循 将抗原从抗原特异的B细胞转移到其他APC，并确定这一机制是否具有 自身免疫发病的生物学意义。我们工作的成功将取决于如何利用 在Vivo成像核心设施中。我们的研究将检验B细胞、树突状细胞和T抗原之间的相互作用 活体显微镜观察活体小鼠淋巴结内的细胞。特别是，我们将标识 体内抗原转移的动力学、定位和机制。总体而言，我们的研究旨在了解 狼疮自身免疫小鼠模型中自身抗原提呈的处理和呈递。