自身免疫疾病相关FcγRIIB-I232T抑制功能缺失的分子机制研究

项目名称： 自身免疫疾病相关FcγRIIB-I232T抑制功能缺失的分子机制研究

项目编号： No.31501140

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 生物科学

项目作者： 徐利玲

作者单位： 清华大学

项目金额： 10万元

中文摘要： B淋巴细胞的异常活化与自身免疫疾病发生发展密切相关。FcγRIIB是B细胞上唯一表达的Fcγ受体，在抗原抗体复合物介导的B细胞活化中起到关键性抑制作用。我们近期的工作发现FcγRIIB穿膜区点突变I232T与大陆人群类风湿性关节炎易感性正相关，且FcγRIIB-I232T无法阻止狼疮患者B细胞BCR微簇体在免疫突触内与CD19微簇体共定位，而导致此点突变抑制功能丧失的分子机制不完全清楚。活细胞单分子成像实验揭示FcγRIIB-I232T在细胞膜上布朗运动能力显著低于野生型，且易形成100 nm以下的纳簇体。在本计划为期一年的研究中，我们将采用结构模拟及核磁共振光谱分析穿膜区短肽的结构变化结合高精度单分子和超分辨率成像实验，研究当FcγRIIB活化时，由于FcγRIIB-I232T布朗运动能力低无法捕捉免疫复合物中的抗体Fc区，导致其丧失抑制能力的新机制。

中文关键词： FcgammaRIIB；单核苷酸多态性；穿膜区；系统性红斑狼疮；

英文摘要： Aberrant B cell activations is associated with autoimmune diseases such as systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA), however the underlying mechanism is incompletely understood. To balance immunoprotection and immunopathology, B cell activation is under strict control by BCR co-receptor FcγRIIB which is the only Fcγ receptor that expressed on B cell and play a key role in inhibiting B cell activation upon antigen-antibody complex stimulation. Our recent work found that transmembrane mutant FcγRIIB-I232T was associated with RA patients in Han Chinese population. This mutant also showed loss-of-function phenotype in departing the synaptic colocalization of BCR microclusters and CD19 microclusters in B cells from SLE patients. It’s our interest to study activation and response of the lymphocytes from autoimmune disease patients. What’s more, to investigate the loss-of-function mechanism of FcγRIIB-I232T, we combined super-resolution imaging, single molecule tracking, computer simulation and nuclear magnetic resonance (NMR) techniques. Based on the observations that slower diffusion mobility of FcγRIIB-I232T, which leaded it to form more nanoclusters smaller than 100 nM and higher phosphorylation level of ITIM in FcγRIIB-I232T cytoplasmic tail, we propose a novel model for the FcγRIIB-I232T lo

英文关键词： FcgammaRIIB；single nucleartide polymorphism；transmembrane domain；lupus；