Patho-physiological analysis of collagen vascular disease development results from dysfunction of the membrane microdomain, lipid rafts

FcgRIIB是一种典型的负调节性免疫受体，在跨膜伸展处具有与系统性狼疮相关的常见结构多态性，并且这种多态性导致功能降低的受体，首次证明了负调节受体家族在免疫系统中的关键作用，监测以及以前低估的跨膜结构域在免疫受体中的功能意义。本研究旨在阐明免疫受体与多价抗原、免疫复合物和刺激性抗体发生寡聚化后形成的跨膜界面的结构，并进一步了解免疫受体信号传导的起始机制。在该基金支持的研究期间，我们首次揭示了FcgRIIA，FcgRIIB的对应物，具有正调控功能，特别是在N末端彼此自缔合（外表面）的跨膜拉伸，并且这种关联实际上是生产性的事件：借助于位于N-末端的二硫键诱变剂的受体的二聚化增强了林恩活化，Btk活化和磷脂酶C γ活化，而不进一步连接受体。该模型实验清楚地表明，在免疫受体跨膜结构域中存在特异性的、生产性的界面，并提示该界面作为解离功能界面的药物的新的治疗靶点。

The findings that FcgRIIB, a prototypical negative regulatory immune receptor, has a common structural polymorphism associated with systemic lupus erythematodes at the transmembrane stretch, and that this polymorphism results in a reduction-of-function receptor, have for the first time prevailed the pivotal role of the negative regulatory receptor family in the immuno-surveillance in humans as well as previously underestimated functional significance of transmembrane domain in immune receptors. This study has been aimed at the structural elucidation of the transmembrane interface developed after the productive oligomerization of immune receptors with polyvalent antigens, immune complexes and stimulatory antibodies, and at the further knowledge of the initiation mechanisms of immune receptor signaling. During the study interval supported by the grant, we have for the first time unveiled that FcgRIIA, a counterpart of FcgRIIB with positive regulatory functions, specifically self associate with one another at the N terminus (outer surface) of the transmembrane stretch, and that this association is in fact productive event: dimerization of the receptor with the aid of disulfide bond mutageneis located at the N-terminus augments Lyn activation, Btk activation and Phospholipase C gamma activation without further ligation of the receotir. This model experiments clearly show that there is a specific, productive interface in immune receotor transmembrane domain, and suggest that the interface serves as a novel therapeutic target for the medicines dissociating the functional interface.