PERIODONTAL DISEASE:ROLE OF ABERRANT Ig GLYCOSYLATION

描述（由申请人提供）：牙周病（PD）与其他人类慢性炎症疾病（如类风湿关节炎）有许多共同特征，包括产生自身抗体，主要产生IgG的浆细胞浸润病变，以及IgG连接聚糖的异常糖基化。尤其引人注目的是在IgG分子的n链聚糖侧链中缺乏半乳糖（Gal）。聚糖对免疫球蛋白（Ig）的生物活性有深远的影响。由于通常被Gal覆盖的末端n -乙酰氨基葡萄糖残基暴露并被无处不在的甘露糖结合凝集素识别，导致补体活化，所有炎症后果导致组织损伤，因此缺乏Gal残基使这些分子具有致病性。基于大量的文献报道和我们的初步数据，我们提出验证一种假设，即在PD中浸润的单核细胞中大量发现的产igg细胞分泌的Ig分子具有异常的糖基化模式。这反过来又改变了这些Ig分子的生物学特性，即它们激活补体的能力，以及与炎症病变中吞噬细胞上表达的Fc受体相互作用的能力。Ig糖基化的降低可能是由于炎性病变中几种细胞类型局部产生的细胞因子的影响。因此，我们提出以下具体目标：1)通过对单糖成分高度特异性的凝集素的反应性和直接的碳水化合物分析来表征PD患者Ig分子糖基化异常的模式。2)通过比较血清和病变中Ig的糖基化模式来确定异常糖基化Ig分子的来源，以确定糖基化改变的Ig分子是否在炎症病变中局部产生。3)确定异常糖基化的Igs是否对与PD相关的选定细菌抗原具有特异性。4)研究PD患者缺乏gal的Ig合成可能涉及的机制以及多糖改变后Ig分子的生物学活性。这些研究的结果将提供有关参与PD发展的先前未被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.