ROLE OF GLYCOLIPIDS IN EXPERIMENTAL NEUROPATHY

在一些多发性神经病患者中，有IgM单抗 与周围神经髓鞘结合的抗体(m蛋白)和 这可能会导致神经病。这些M蛋白结合到 由多个外围设备共享的碳水化合物决定因素 神经糖蛋白，包括髓鞘相关糖蛋白 (MAG)和周围神经中的两种糖脂。我们有 表征了这两种人马尾和马尾的糖脂 发现它们属于一类新的糖脂，称为 硫酸葡萄糖醛酸基糖脂(SGGL)。亚细胞定位 对牛周围神经的研究表明，它们是 富含轴膜成分，同时存在于髓鞘中 以及较低浓度的其他神经胶质相关膜。在……里面 此外，这些糖脂存在于牛硬脑膜和 转化大鼠雪旺细胞。在这个项目中，我们计划进一步 M蛋白结合抗原决定簇(S)的鉴定 在神经病患者身上，并开发合成类似物 抗原表位。然后可以使用这些类似物 在治疗上阻断或清除循环中的M-蛋白 改善患者的神经病变。为了更好地理解角色 这些糖脂在这种疾病的发病机制中的作用，我们计划 SGGLS免疫动物诱导实验性变态反应 神经炎(EAN)及其多克隆抗体的获得 周围神经糖脂。使用EAN建立EAN模型 结构上定义明确的糖脂抗原应该是非常 重要的是提供直接证据证明这些抗原可以 实际上导致了神经病。多克隆抗血清将是 有助于研究它们的脱髓鞘和抑制髓鞘形成 在体外和体内的活性，在开发敏感的检测 对这些抗原进行定量，并用于免疫细胞化学 这些抗原在神经中的定位。一旦这种动物 模型建立后，其致病机制 障碍可以从体液免疫和细胞免疫的角度进行研究。 调节分泌的机制以及T和B细胞的相互作用 M蛋白。因此，该项目的结果将是 不仅对了解其发病机制和 脱髓鞘神经病的病理生理学研究 IgM-蛋白和浆细胞异型，也为提供 关于其他自身免疫性疾病机制的重要信息 如多发性硬化症、格林-巴利综合征等。

In some patients with polyneuropathy there are IgM monoclonal antibodies (m-proteins) that bind to peripheral nerve myelin and that may cause the neuropathy. These M-proteins bind to carbohydrate determinants that are shared by a number of peripheral nerve glycoproteins, including the myelin-associated glycoprotein (MAG), and two glycolipids in peripheral nerve. We have characterized these two glycolipids from human cauda equina and found that they belong to a new class of glycolipids termed sulfated glucuronyl-glycolipids (SGGLs). Subcellular localization studies of bovine peripheral nerve have demonstrated that they are enriched in the axolemma-enriched fraction, while present in myelin and other glial-related membranes in lower concentrations. In addition, these glycolipids are present in bovine dura master and transformed rat Schwann cells. In this project, we plan to further characterize the antigenic determinant(s) that bind to M-proteins in patients with neuropathy and to develop synthetic analogues of the antigenic epitopes. These analogues could then be used therapeutically to block or remove circulating M-proteins in patients and improve the neuropathy. To better understand the role of these glycolipids in the pathogenesis of this disorder, we plan to immunize animals with SGGLs to induce experimental allergic neuritis (EAN) and to obtain polyclonal antibodies against these peripheral nerve glycolipids. Establishing the EAN model with structurally well-defined glycolipid antigens should be extremely important in affording a direct proof that these antigens can actually cause the neuropathy. The polyclonal antisera will be useful in studying their demyelinating and myelination-inhibiting activities in vitro and in vivo, in developing sensitive assays for quantitating these antigens, and for the immunocytochemical localization of these antigens in the nerve. Once this animal model is established, the pathogenetic mechanisms underlying this disorder can be studied in terms of humoral and cellular immune mechanisms, and T- and B-cell interactions regulating the secretion of M-proteins. The results of this project would therefore be important not only for understanding the pathogenesis and pathophysiology of the demyelinating neuropathy associated with IgM M-proteins and plasma cell dyscrasia, but also for providing vital information on the mechanisms of other autoimmune diseases such as multiple sclerosis, Guillain-Barre syndrome, etc.