SPECIFICITY OF HUMAN AUTOANTIBODIES TO PROTEOGLYCANS

人类自身抗体对蛋白聚糖的特异性

基本信息

批准号：
3138139
负责人：
Howard M. Fillit
金额：
$ 18.15万
依托单位：
MOUNT SINAI SCHOOL OF MEDICINE OF CUNY
依托单位国家：
美国
项目类别：
财政年份：
1990
资助国家：
美国
起止时间：
1990-01-01 至 1993-12-31
项目状态：
已结题

项目摘要

DESCRIPTION (Adapted from the applicant's abstract): Proteoheparan sulfate (PHS) proteoglycan (PG) on the endothelial cell surface and vascular basement membrane plays an important role in the vascular permeability barrier. Heparin sulfate (HS) contributes the majority of anionic charges to the vascular charge barrier. PHS protein core plays a structural role in the vascular barrier by its multiple binding sites for laminin, type IV collagen and other molecules. Animal models have demonstrated that cationic molecules which bind HS, and antibodies to PHS protein core, cause vascular injury. The investigators and others have demonstrated that sera from patients with autoimmune vascular disease have autoantibodies to PHS. The investigators hypothesis is that autoimmunity to PHS causes vascular injury in human autoimmune disease. The investigators propose that both humoral and cellular autoimmunity to PHS components (HS and protein core peptides) cause vascular injury by classic mechanisms, including the activation of complement, initiation of the inflammatory cascade, and endothelial cell cytotoxicity. The investigators also propose hypotheses regarding the immunochemistry of proteoglycan autoimmunity. First, while autoantibodies which broadly cross-react with anionic molecules have been described, the investigators have demonstrated autoantibodies to glycosaminoglycans (GAGS) which are highly specific. The investigators propose that these highly specific autoantibodies have high affinity for HS and are more efficient than broadly cross-reactive, low affinity autoantibodies in activating complement, and initiating inflammation. Thus, the investigators propose that antibody affinity determines the pathologic significance of autoimmunity to anionic molecules such as the GAGS. Secondly, PGs play a role in organ-specificity. The organ-specificity of proteoglycans is determined primarily by the nature of the protein core. The investigators propose that specific PHS protein core epitopes are immunologic targets in organ specific autoimmune disease. Finally, the investigators propose that cell-mediated immunity causes vascular injury via T-cell recognition of PHS sites which may differ from PHS epitopes recognized by autoantibody.

描述（改编自申请人的摘要）：硫酸盐蛋白酶（pHS）内皮细胞表面和血管上的蛋白聚糖（PG）地下膜在血管通透性中起重要作用障碍。硫酸肝素（HS）贡献大部分阴离子电荷到血管电荷屏障。 pHS蛋白质核心起着结构性的作用在血管屏障中，其多种结合位点用于层粘连蛋白，IV型胶原蛋白和其他分子。动物模型表明结合HS的阳离子分子，抗体与pHS蛋白核的抗体引起血管损伤。调查人员和其他人证明了血清自身免疫性血管疾病患者的自身抗体对PHS具有自身抗体。研究者的假设是自身免疫引起了血管人类自身免疫性疾病的损伤。调查人员建议 pHS成分的体液和细胞自身免疫（HS和蛋白质核心肽）通过经典机制造成血管损伤，包括补体的激活，炎症级联的启动和内皮细胞细胞毒性。调查人员还提出了假设关于蛋白聚糖自身免疫的免疫化学。首先，而与阴离子分子广泛反应的自身抗体已经描述的是，调查人员已经证明了自身抗体高度特异性的糖胺聚糖（插科打）。调查人员提出这些高度特定的自身抗体对HS具有很高的亲和力并且比广泛的交叉反应性，低亲和力更有效激活补体和引发炎症的自身抗体。因此，研究人员提出抗体亲和力决定了自身免疫对阴离子分子的病理学意义，例如插科打。其次，PGS在器官特异性中起作用。这蛋白聚糖的器官特异性主要取决于蛋白质核心。研究人员提出特定的pHS蛋白核心表位是器官特异性自身免疫性疾病中的免疫靶标。最后，研究人员提出细胞介导的免疫力原因通过T细胞识别pHS位点的血管损伤可能与可能不同自身抗体识别的pHS表位。