GLYCOLIPIDS AND EXPERIMENTAL NEUROPATHY

描述(申请人提供)：本申请的目的是阐明抗鞘糖脂(GSL)抗体在周围神经疾病和相关神经疾病中的免疫致病作用，并为这些疾病开发有效的治疗方法。近年来，越来越多的证据表明抗GSL抗体参与了周围神经疾病的发病机制，如格林-巴利综合征(GBS)。潜在的抗原包括各种酸性GSLs，如神经节苷脂和硫酸糖脂，以及中性GSLs。这些GSLs在神经组织中含量最高，是这些神经系统疾病患者循环抗体和细胞毒免疫细胞的靶标。目前，关于这些抗体的来源和自身抗体的致病机制，特别是与抗体或免疫细胞从循环到神经内间隙的侵袭有关的问题仍然很多。我们对神经抗原自身抗体出现的了解仍然不完整，但这些知识将是制定预防和治疗这些周围神经疾病的策略的先决条件。由于越来越多的人意识到抗GSL抗体是先天感染的结果，我们推测抗GSL抗体可能是由多种糖结合抗原通过分子模拟机制产生的。这些糖结合物包括细菌脂多糖(LPS)，它们共享与GSLS相似的碳水化合物表位。(1)为了验证LPSs、抗GSLS与临床症状转归密切相关的假设，我们将从几种细菌中分离纯化LPSs，并对其结构和抗原性进行研究。(2)我们将验证一种假设，即脑微血管内皮细胞(BMEC)表面糖偶联物为抗体攻击和炎性白细胞附着提供了场所，导致在神经系统症状出现之前通透性改变。(3)我们将通过“中和”抗独特型自身抗体和与抗体结合的多肽“模拟表位”来开发治疗免疫介导性周围神经病的基本原理和有效的治疗方法。我们的最终目标是开发一种合理有效的治疗自身免疫性周围神经病和相关神经疾病的方法。与公共卫生的关系：感染性病原体可导致严重的外周神经病。其中一些病原体可能来自食物，例如小鸡。这项研究是为了确定这些代理人可以做到什么、为什么以及如何做到这一点。在已有知识的基础上，我们将测试一些有效治疗这些疾病的新策略。

DESCRIPTION (provided by applicant): The purpose of this application is to elucidate the immunopathogenic role of antiglycosphingolipid (GSL) antibodies in peripheral neuropathies and related neurological disorders and to develop effective therapies for these diseases. In recent years, mounting evidence implicates the involvement of anti-GSL antibodies in the pathogenesis of peripheral neuropathies, such as Guillain-Barr¿ syndrome (GBS). Potential antigens include a variety of acidic GSLs, such as gangliosides and sulfated glycolipids, and neutral GSLs. These GSLs are most abundant in nervous tissues and represent targets of circulating antibodies and cytotoxic immune cells in patients with these neurological disorders. At present, many questions remain regarding the origin of these antibodies and the pathogenic mechanisms of autoantibodies, particularly related to the invasion of antibodies or immune cells from the circulation to the endoneurial space. Our knowledge of the emergence of autoantibodies against neural antigens is still fragmentary, but such knowledge would be prerequisite in developing strategies for preventing and treating these peripheral neurological disorders. Since there is growing awareness that the anti-GSL antibodies arise as the result of antecedent infection, we hypothesize that anti-GSL antibodies may arise from a variety of glycoconjugate antigens through a molecular mimicry mechanism. These glycoconjugates include bacterial lipopolysaccharides (LPSs) that share carbohydrate epitopes similar to those of GSLs. Three specific aims will be carried out: (1) To test the hypothesis that there is strong correlation between LPSs, anti-GSLs, and the manisfestation of clinical symptoms, we will isolate pure LPSs from several bacteria and studies their structures and antigenicity. (2) We will test the hypothesis that brain microvascular endothelial-cell (BMEC) surface glycoconjugates provide sites for antibody attack and inflammatory leukocyte attachment, leading to permeability changes prior to the onset of neurological symptoms. (3) We will develop rationale and effective therapeutics for immunemediated peripheral neuropathies by "neutralizing" autoantibodies with anti-idiotypes and peptide "mimitopes" that bind to the antibodies. Our ultimate goal is to develop a rational and effective treatment of autoimmune peripheral neuropathies and related neurological disorders. RELATIONSHIP TO PUBLIC HEALTH: Infectious agents can induce severe peripheral neuropathies. Some of these agents can come from food, e.g., chicks. This research is to determine what, why, and how these agents can do it. Based on the knowledge gained, we will test a number of novel strategies for the effective treatment of these disorders.