Mechanisms of Antigen Trafficking in Autoimmunity

自身免疫中抗原贩运的机制

• 批准号: 7352535
• 负责人: Mark J Mamula
• 金额: $ 4.13万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-17 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7352535
• 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

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.

全身性红斑狼疮（SLE）是一种自身免疫性疾病，其特征是存在 自身抗体对一组细胞内蛋白，最值得注意的是，核小体和决定因素 RNA蛋白质复合物。人SLE和鼠模型中的自身免疫反应需要 自抗原的加工和表现导致T细胞的激活。 CD4 T细胞为 自动反应性B细胞，都导致自身抗体产生和病理。 B细胞在两者中的耗竭 鼠SLE和利妥昔单抗治疗的患者可以改善疾病。我们以前的研究表明 自动反应性B细胞可以逃脱外周耐受性，呈现自身抗原并激活自动反应性T细胞 从正常的淋巴细胞曲目。确实，这可能是利妥昔单抗治疗的一种机制 在人类SLE中有效。我们最近的体内工作表明，抗原的独特子集 呈现细胞（APC）在免疫发育中在不同时间点激活T细胞。尤其， B细胞是免疫后早期T细胞反应中的主要弧。后来在自身免疫性 反应，B细胞失去了抗原的能力，而树突状细胞（DC）逐渐获得APC 在T细胞激活中的功能。我们的研究表明，DC（和其他APC）可以从 B细胞通过不确定的转移机制。该提议的主要目标是直接遵循 将抗原从抗原特异性B细胞转移到其他APC，并确定该机制是否具有 自身免疫发作的生物学意义。我们工作的成功将取决于使用 体内成像核心设施。我们的研究将检查B细胞，树突状细胞和抗原T的相互作用 通过浸润显微镜在活小鼠的淋巴结内的细胞。特别是，我们将确定 体内抗原转移的动力学，位置和机制。总体而言，我们的研究旨在了解 狼疮自身免疫模型中自动抗原的加工和呈现。