自免疫疾病易感HLA-DR异常增强CD4介导TCR抗原识别的力学调控机制研究

CD4介导的T细胞受体（TCR）通过异常识别二类MHC分子所呈递的自身抗原，引发免疫系统攻击自身组织器官，导致自身免疫性疾病，严重影响人类生命健康。研究表明，人源二类MHC（HLA-DR）的基因多态性与自免疫疾病密切相关，HLA-DR易感基因可能是诱发自免疫疾病的高危因素，但其分子机制尚不清楚。申请人前期研究工作发现了生物拉力可以诱导HLA-DR构象变化，产生HLA-DR与CD4的新互作面，增强它们相互作用。因此，申请人提出了该项目核心猜想：自免疫疾病易感HLA-DR可能异常响应生物拉力，变构增强CD4介导的TCR抗原识别和T细胞活化。申请人将融合单分子力谱、分子动力学模拟、免疫学等技术，聚焦研究自免疫疾病易感HLA-DR如何异常激活CD4介导的TCR抗原识别，旨在揭示其力学-化学耦合调控的分子机制，为理解自免疫疾病易感HLA-DR的致病机理以及其治疗策略提供全新的科学理论基础。

T cell receptor (TCR) cooperating with CD4 abnormally recognizes self-antigens presented by Major Histocompatibility Complex Class II (MHC-II), which triggers the immune system to attack its own tissues and organs, results in autoimmune diseases, and seriously affects human health. Previous studies have shown that HLA-DR (one type of MHC-II) polymorphism is closely related to autoimmune diseases, which may be a high risk to induce autoimmune diseases. However, the molecular mechanism remains unclear. Our previous studies have found that mechanical force can induce the conformational change of HLA-DR, generate a new interaction between HLA-DR and CD4, and finally enhance their interaction. Therefore, we propose that HLA-DR associated with susceptibility to autoimmune disease might abnormally respond to mechanical force, which enhances CD4-mediated TCR antigen recognition and T cell activation. We will integrate single-molecule force spectroscopy, molecular dynamics simulation and immunological methods to study how HLA-DR associated with susceptibility to autoimmune disease abnormally activates CD4-mediated TCR antigen recognition, revealing the molecular mechanism of the mechanical-chemical coupling regulation. It will provide a novel knowledge to understand the pathogenic mechanism of HLA-DR associated with susceptibility to autoimmune disease.