PERIODONTAL DISEASE:ROLE OF ABERRANT Ig GLYCOSYLATION

描述(申请人提供)：牙周病(PD)与其他人类慢性炎症性疾病(如类风湿性关节炎)有许多共同特征，包括产生自身抗体，病变中主要产生免疫球蛋白G的浆细胞渗透，以及免疫球蛋白连接的糖链的异常糖基化。尤其引人注目的是，在免疫球蛋白分子的N-连接的糖链上缺乏半乳糖。多糖对免疫球蛋白(Ig)的生物活性有深远的影响。Gal残基的缺乏使这些分子致病，这是因为通常由Gal覆盖的末端N-乙酰氨基葡萄糖残基暴露出来，并被普遍存在的甘露糖结合凝集素识别，从而激活补体，导致所有炎症后果，导致组织损伤。根据大量的文献报道和我们的初步数据，我们提出了一种假设，即PD患者的单个核细胞中发现大量产生Ig的细胞，其分泌的Ig分子的糖基化模式异常。这反过来改变了这些免疫球蛋白分子的生物学特性，即它们激活补体的能力，并与炎症病变中滞留的吞噬细胞上表达的Fc受体相互作用。Ig的糖基化减少可能是由于炎症病变中发现的几种细胞类型局部产生的细胞因子的影响。因此，我们提出了以下具体目标：1)通过与成分单糖高度特异的凝集素反应和直接碳水化合物分析来表征PD患者Ig分子的糖基化异常模式。2)通过比较血清和皮损中Ig的糖基化模式，确定糖基化异常的Ig分子的来源，以确定局部是否有糖基化改变的Ig分子在炎症病变中产生。3)确定异常糖基化的免疫球蛋白是否对与帕金森病相关的选定细菌的抗原具有特异性。4)研究PD患者Gal缺陷型Ig合成的可能机制及糖链改变对Ig分子生物学活性的影响。这些研究的结果将产生关于参与帕金森病发展的先前未探索的炎症途径的信息。

DESCRIPTION (provided by applicant): Periodontal disease (PD) shares many common features with other human chronic inflammatory disease, such as rheumatoid arthritis, including production of autoantibodies, infiltration of lesions with plasma cells producing mainly IgG, and aberrant glycosylation of IgG-linked glycans. Particularly striking is the deficiency of galactose (Gal) in N-linked glycan side-chains on IgG molecules. Glycans have a profound effect on the biological activities of immunoglobulins (Ig). Deficiency of Gal residues renders such molecules pathogenic due to the fact that terminal N-acetylglucosamine residues, normally covered by Gal, became exposed and are recognized by the ubiquitous mannose-binding lectin resulting in the activation of complement with all the inflammatory consequences resulting in tissue damage. Based on considerable literature reports and our preliminary data, we propose to test the hypothesis that Ig-producing cells found in abundance in mononuclear cell infiltrates in PD secrete Ig molecules with aberrant glycosylation pattern of their glycan moieties. This in turn alters the biological properties of such Ig molecules with respect to their ability to activate complement and to interact with Fc receptors expressed on phagocytic cells resident in the inflamed lesions. Reduced glycosylation of Ig is likely to be due to the effect of cytokines locally produced by several cell types found in inflammatory lesions. Therefore, we propose the following Specific Aims: 1) Characterize the pattern of glycosylation aberrancies of Ig molecules in PD patients by reactivity with lectins highly specific for component monosaccharides and by direct carbohydrate analyses. 2) Determine the origin of aberrantly glycosylated Ig molecules by comparing glycosylation patterns of Ig in serum and lesions to determine whether Ig molecules with altered glycosylation are produced locally in the inflammatory lesions. 3) Determine if the aberrantly glycosylated Igs are specific for antigens of selected bacteria associated with PD. 4) Study mechanisms possibly involved in synthesis of Gal-deficient Ig in PD patients and the biological activities of Ig molecules with altered glycans. Results of these studies will generate information concerning previously unexplored inflammatory pathways that participate in the development of PD.