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Defining new BCR-antigen trafficking pathways

定义新的 BCR 抗原运输途径

基本信息

批准号：
MR/W025868/1
负责人：
Dessi Malinova
金额：
$ 51.61万
依托单位：
Queen's University Belfast
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2023
资助国家：
英国
起止时间：
2023 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FW025868%2F1
关键词：
Defining new BCR antigen trafficking

项目摘要

Infectious diseases claim over 6 million lives a year worldwide. Our immune system responds to infections through the coordinated action of many specialised cells. B cells are one critical component of this response, producing antibodies to neutralise infectious agents. The cellular processes which activate B cells to respond to infection can result in autoimmunity or cancer if triggered inappropriately. B cell leukaemia is one of the most prevalent malignancies in children with increasing incidence in developed countries. How these cellular processes are regulated remains unclear. Understanding how B cells are activated can help us to design more efficient vaccines, control B cell autoimmunity and identify new therapies for B cell cancers. Upon infection, B cells recognise and take up foreign agents (antigen) through a receptor on their surface (BCR). Binding of antigen to the BCR induces signalling and uptake of the antigen-BCR complex into the B cell. This internalised antigen is transported to specific compartments within the B cells, where it is processed and loaded onto receptors recognised by other immune cells. These are exported back to the B cell surface, where they are recognised by T cells, another crucial immune cell type. T cell signals instruct the B cells to divide and differentiate into either antibody-producing cells or memory B cells. These steps are essential for antibody-mediated protection and long-term immunity to the infectious agent. The amount of antigen taken up by the B cell, and its trafficking through the cell, determine the quantity and quality of T cell help provided. The mechanisms of antigen uptake and trafficking from the B cell surface to processing compartments are unclear. My previous research has identified a network of proteins involved in antigen uptake, most of which are unknown in B cells. One of these proteins, SORLA, is known to regulate intracellular trafficking of proteins in cells outside the immune system. Its role in B cells has not been defined though it is overexpressed in B cell lymphomas. Our preliminary work suggests SORLA is recruited to the internalised BCR-antigen molecules and SORLA depletion significantly reduces BCR uptake. Further, deletion of SORLA in animal models reduced their response to immunisation, highlighting an important and physiologically relevant role for SORLA in the immune response following infection or vaccination. Here, I propose to investigate the mechanisms behind this novel BCR trafficking regulation. We will delete SORL1, the gene encoding SORLA, and measure the effect on B cell signalling and antigen trafficking through the cell. We will investigate possible interactions between SORLA and known BCR uptake or activation components to understand the coordination between these pathways. We will quantify the amount and variety of antigens presented on the B cell surface, to understand how SORLA affects B cell competition for T cell help. Further, since the BCR is important during the development of B cells, we will investigate how disrupted BCR trafficking affects the number of mature B cells in an organism. Finally, to understand how this new regulator of antigen uptake is involved in the B cell response to immunisation, we will analyse B cell growth and differentiation into antibody-producing or memory B cells and production of highly specific antibodies. Together, these studies will provide a more complete understanding of B cell antigen uptake and its regulation. This could allow us to engineer antigens that promote uptake and presentation by B cells, which has important implications for vaccine innovation. It will also further our knowledge of antigen uptake and presentation in malignant B cells - a process with untapped potential for discovery of new B cell cancer therapies.

传染病每年在全世界夺去600多万人的生命。我们的免疫系统通过许多专门细胞的协调行动对感染做出反应。B细胞是这种反应的一个关键组成部分，产生抗体来中和感染因子。激活B细胞以响应感染的细胞过程如果被不适当地触发，可能导致自身免疫或癌症。B细胞白血病是儿童中最常见的恶性肿瘤之一，在发达国家发病率不断增加。这些细胞过程是如何调节的仍不清楚。了解B细胞是如何被激活的可以帮助我们设计更有效的疫苗，控制B细胞自身免疫，并确定B细胞癌症的新疗法。一旦感染，B细胞通过其表面上的受体（BCR）识别并吸收外来因子（抗原）。抗原与BCR的结合诱导信号传导和抗原-BCR复合物进入B细胞的摄取。这种内化的抗原被转运到B细胞内的特定区室，在那里它被加工并加载到被其他免疫细胞识别的受体上。它们被输出回B细胞表面，在那里它们被另一种重要的免疫细胞类型T细胞识别。T细胞信号指示B细胞分裂并分化为抗体产生细胞或记忆B细胞。这些步骤对于抗体介导的保护和对感染因子的长期免疫是必不可少的。由B细胞吸收的抗原量及其通过细胞的运输决定了所提供的T细胞帮助的数量和质量。抗原从B细胞表面摄取和运输到加工区室的机制尚不清楚。我之前的研究已经确定了一个参与抗原摄取的蛋白质网络，其中大部分在B细胞中是未知的。已知这些蛋白质之一SORLA调节免疫系统外细胞中蛋白质的细胞内运输。尽管它在B细胞淋巴瘤中过表达，但其在B细胞中的作用尚未确定。我们的初步工作表明，SORLA被募集到内化的BCR抗原分子中，SORLA消耗显著降低BCR摄取。此外，动物模型中SORLA的缺失降低了它们对免疫的反应，突出了SORLA在感染或疫苗接种后的免疫反应中的重要和生理相关作用。在这里，我建议调查这种新的BCR贩运调节背后的机制。我们将删除SORL 1（编码SORL A的基因），并测量对B细胞信号传导和抗原通过细胞运输的影响。我们将研究SORLA和已知的BCR摄取或激活成分之间可能的相互作用，以了解这些途径之间的协调。我们将量化B细胞表面呈递的抗原的数量和种类，以了解SORLA如何影响B细胞对T细胞帮助的竞争。此外，由于BCR在B细胞的发育过程中很重要，我们将研究破坏的BCR运输如何影响生物体中成熟B细胞的数量。最后，为了了解这种新的抗原摄取调节剂如何参与B细胞对免疫的应答，我们将分析B细胞生长和分化为抗体产生或记忆B细胞以及高度特异性抗体的产生。总之，这些研究将提供一个更完整的理解B细胞抗原摄取及其调节。这可以让我们设计抗原，促进B细胞的吸收和呈递，这对疫苗创新具有重要意义。它也将进一步我们的恶性B细胞中的抗原摄取和呈递的知识-一个具有发现新的B细胞癌症疗法的未开发潜力的过程。