单B细胞抗体技术是近年来发展起来的一种高效获取全人源抗体基因的方法。但在非感染性疾病的治疗性抗体开发中，目标靶点多为自体蛋白，由于自身免疫耐受，获取抗原特异性B细胞十分困难，限制了单B细胞技术在此领域中的应用。我们在前期研究工作中，建立了将免疫原性氨基酸引入自体蛋白中突破自身免疫耐受的方法，为解决抗原特异性B细胞来源问题提供了有效的方法。由于免疫原性氨基酸突破自身免疫耐受的机理尚不清楚，如何利用免疫原性氨基酸设计自体抗原并体外诱导B细胞分化形成抗原特异性B细胞还缺乏有效的理论指导。本项目拟对免疫原性氨基酸突破自身免疫耐受的信号途径进行深入研究,以此为基础建立基于免疫原性氨基酸诱导的B细胞体外分化和单B细胞分选体系，以肿瘤相关抗原HER2为靶点，筛选获得抗HER2全人源抗体，将单B细胞抗体技术应用于针对自身蛋白的全人源抗体药物开发，为非感染性疾病的治疗性抗体药物开发提供理论指导和方法学基础。

Single B cell technology is a high-efficient strategy for acquiring human antibody genes developed in recent years. The application of this technology, however, meets restrictions when the target antigen is autologous protein, in which the acquisition of antigen-specific B cell is very difficult because of self tolerance. In our previous work, we build a strategy for broking self tolerance by incorporating immunogenic amino acid into autologus proteins, which provides an efficient reliable source of antigen-specific B cell. However, the mechanism of immunogenic amino acid breaking immune tolerance remains unknown. As a result, designing the self antigen with immunogenic amino acid is lack of effective theory guidance. Moreover, inducing B cells differentiate in vitro using self antigen containing immunogenic amino acid need the understanding of the mechanism of immunogenic amino acid breaking self tolerance. The project intends to further research into the signal pathways of immunogenic amino acid breaking immune tolerance and provide the basis of theory and methodology for developing human antibody durgs targeting autologous proteins.