Mechanisms of Antigen Trafficking in Autoimmunity

提供了 系统性红斑狼疮（SLE）是一种自身免疫性疾病，其特征在于存在 一组选定的细胞内蛋白质的自身抗体，最值得注意的是，核小体上的决定簇， RNA-蛋白质复合物。人类SLE和小鼠模型中的自身免疫应答需要 自身抗原的加工和呈递导致T细胞的活化。CD 4 T细胞有助于 自身反应性B细胞，均导致自身抗体产生和病理学。两组中B细胞的耗竭 小鼠SLE和利妥昔单抗治疗的患者改善疾病。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，呈递自身抗原，并激活自身反应性T细胞 从正常的淋巴细胞库。事实上，这可能是利妥昔单抗治疗的一种机制， 对人SLE有效。我们最近的体内研究表明， 呈递细胞（APC）在免疫发展的不同时间点激活T细胞。特别是， B细胞是免疫后早期T细胞应答中的主要ARC。后来在自身免疫性疾病中 当树突状细胞（DCs）逐渐获得APC时，B细胞失去呈递抗原的能力 在T细胞活化中起作用。我们的研究表明，DC（和其他APC）可以获得抗原， B细胞通过一种不确定的转移机制。该提案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，并确定这种机制是否具有 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T抗原之间的相互作用。 活体显微镜观察活小鼠淋巴结内的细胞。特别是，我们将确定 体内抗原转移的动力学、定位和机制。总的来说，我们的研究旨在了解 狼疮自身免疫小鼠模型中自身抗原的加工和呈递。

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.