SPECIFICITY OF HUMAN AUTOANTIBODIES TO PROTEOGLYCANS

性状（改编自申请人摘要）：硫酸蛋白乙酰肝素 (PHS)蛋白聚糖（PG）的内皮细胞表面和血管 基底膜在血管通透性中起重要作用 屏障 硫酸肝素（HS）贡献了大部分阴离子电荷 血管电荷屏障 PHS蛋白核心起着结构性作用 在血管屏障中通过其多个层粘连蛋白IV型结合位点 胶原蛋白和其他分子。 动物模型已经证明， 结合HS的阳离子分子和PHS蛋白核心的抗体， 血管损伤 研究人员和其他人已经证明，血清 自身免疫性血管疾病患者的血液中有PHS自身抗体。 研究人员假设，对PHS的自身免疫引起血管 人类自身免疫性疾病中的损伤。 研究人员建议， 对PHS组分（HS和蛋白质核心）的体液和细胞自身免疫 肽）通过经典机制引起血管损伤，包括 激活补体，启动炎症级联反应，和 内皮细胞毒性 研究人员还提出了假设 关于蛋白多糖自身免疫的免疫化学。 首先，虽然 与阴离子分子广泛交叉反应的自身抗体已经被 研究人员已经证明， 糖胺聚糖（GAGS）是高度特异性的。 调查人员 提出这些高度特异性的自身抗体对HS具有高亲和力 并且比广泛交叉反应性、低亲和力 自身抗体激活补体和引发炎症。 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意义， 恶心。 其次，PG在器官特异性中起作用。 的 蛋白聚糖的器官特异性主要由蛋白聚糖的性质决定， 蛋白质核心 研究人员提出，特定的PHS蛋白质核心 表位是器官特异性自身免疫性疾病的免疫靶点。 最后，研究人员提出，细胞介导的免疫导致 通过T细胞识别PHS部位的血管损伤， 自身抗体识别的PHS表位。

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.