IMMUNOBIOLOGY OF AUTOIMMUNITY TO HEPARAN SULFATE

硫酸乙酰肝素自身免疫的免疫生物学

• 批准号: 3726997
• 负责人: HOWARD FILLIT
• 金额: --
• 依托单位: MOUNT SINAI SCHOOL OF MEDICINE OF CUNY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3726997
• 关键词: B lymphocyte; antiidiotype antibody; autoantibody; autoantigens; autoimmune disorder; autoimmunity; cardiovascular disorder; cross immunity; gene mutation; genetic library; heparan sulfate; human genetic material tag; human subject; immunogenetics; immunoglobulin idiotypes; immunoglobulin structure; injury; laboratory mouse; laboratory rabbit; monoclonal antibody; passive immunization; vascular endothelium

Vascular heparan sulfate proteoglycan (HSPG) plays an important structural and functional role in the vascular permeability barrier. HSPG is comprised of two major components: heparan sulfate (HS) (a glycosaminoglycan (GAG)), and a protein core. In animal models, antibodies to HSPG protein core cause vascular injury. In humans and in animal models of systemic lupus erythematosus (SLE), investigators have demonstrated serum antibodies and deposited antibodies in glomeruli which are broadly cross-reactive with both DNA and HS GAG. In humans, we demonstrated autoantibodies to intact HSPG. We further demonstrated immunospecific autoantibodies to HS GAG in patients with vascular disease. Preliminary data from our laboratory also indicate the presence of autoantibodies to HSPG protein core in human SLE sera. The hypothesis of this proposal is that autoimmunity to vascular HSPG causes vascular injury in autoimmune disease. Our hypothesis has significance for understanding the specificity and significance of polyspecific autoantibodies reactive with anionic molecules in autoimmune disease. The pathologic origin and significance of anti-DNA and anti- phospholipid antibodies in autoimmune disease is unknown. We propose that HS is the immunospecific epitope of high affinity with which anti-DNA and anti-phospholipid antibodies are reactive. High affinity autoantibodies to HS are pathologically significant because they are more efficient than broadly cross-reactive, low affinity autoantibodies in activating complement, and initiating inflammation. PG protein core epitopes also play a role in organ-specificity. A corollary hypothesis proposes that organ-specific (vascular-specific) HSPG protein core epitopes are immunologic targets in organ-specific autoimmune disease. Careful immunochemical studies are required to investigate this hypothesis. Hybridoma technology will be employed to study the immunochemistry of monoclonal anti-HSPG autoantibodies from humans and mice with autoimmune vascular disease. We will also determine this immunodominant sites of HSPG protein core recognized by murine SLE T cell clones. Finally, we will explore mechanisms of autoimmune vascular injury by investigations of complement activation and endothelial cell cytotoxicity employing monoclonal autoantibodies to HSPG from patients and mice with autoimmune vascular disease.

血管硫酸乙酰肝素蛋白多糖(HSPG)起着重要的结构作用 以及在血管通透性屏障中的作用。HSPG是 由两个主要成分组成：硫酸乙酰肝素(a 糖胺多聚糖(GAG)和一个蛋白质核心。在动物模型中，抗体 对HSPG蛋白核心造成血管损伤。在人类和动物模型中 研究人员证实，系统性红斑狼疮(SLE) 血清抗体和肾小球沉积抗体广泛存在 与DNA和HS Gag发生交叉反应。在人类身上，我们展示了 针对完整HSPG的自身抗体。我们进一步证明了免疫特异性 血管疾病患者抗HS-GAG自身抗体的研究初步 我们实验室的数据也表明存在自身抗体 人系统性红斑狼疮血清中HSPG蛋白核心。 这一建议的假设是对血管HSPG的自身免疫 在自身免疫性疾病中导致血管损伤。我们的假设已经 对理解的特殊性和意义的意义 自身免疫中与阴离子分子反应的多特异性自身抗体 疾病。抗DNA抗体和抗-DNA抗体的病理来源及意义 磷脂抗体在自身免疫性疾病中的作用尚不清楚。我们建议 HS是一种高亲和力的免疫特异性表位，与抗DNA和 抗磷脂抗体是反应性的。高亲和力自身抗体 HS具有重要的病理意义，因为它们比 广泛的交叉反应，低亲和力的自身抗体激活 补充，并引发炎症。 PG蛋白核心表位也在器官特异性中发挥作用。一个 推论认为，器官特异性(血管特异性)HSPG 蛋白质核心表位是器官特异性自身免疫的免疫靶点 疾病。 需要仔细的免疫化学研究来研究这一假说。 杂交瘤技术将用于研究肿瘤的免疫化学 来自自身免疫性人和小鼠的抗HSPG单抗 血管疾病。我们还将确定HSPG的免疫优势部位 小鼠SLE T细胞克隆识别的蛋白质核心。 最后，我们将探讨自身免疫性血管损伤的机制。 补体活化与血管内皮细胞毒性的研究 使用抗HSPG的患者和小鼠的单克隆自身抗体 自身免疫性血管疾病。