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性疾病（如类风湿性关节炎）具有许多共同特征，包括产生自身抗体、主要产生IgG的浆细胞浸润病变和IgG连接聚糖的异常糖基化。特别引人注目的是IgG分子上的N-连接聚糖侧链中半乳糖（Gal）的缺乏。聚糖对免疫球蛋白（IG）的生物学活性具有深远的影响。Gal残基的缺乏使这些分子致病，这是由于通常被Gal覆盖的末端N-乙酰葡糖胺残基暴露并被普遍存在的甘露糖结合凝集素识别，导致补体激活，所有炎症后果导致组织损伤。基于大量的文献报道和我们的初步数据，我们建议检验这一假设，即在PD的单核细胞浸润中大量发现的产生Ig的细胞分泌具有异常糖基化模式的IG分子。这又改变了这种IG分子的生物学特性，即它们激活补体和与在炎症病变中的吞噬细胞上表达的Fc受体相互作用的能力。IG的糖基化减少可能是由于炎性病变中发现的几种细胞类型局部产生的细胞因子的作用。因此，我们提出以下具体目标：1）通过与对组分单糖高度特异性的凝集素的反应性和通过直接碳水化合物分析来表征PD患者中IG分子的糖基化异常模式。2)通过比较血清和病变中IG的糖基化模式，确定异常糖基化IG分子的来源，以确定炎性病变中是否局部产生糖基化改变的IG分子。3)确定异常糖基化Ig是否对选定的PD相关细菌抗原具有特异性。4)研究PD患者半乳糖缺乏型IG合成的可能机制以及聚糖改变的IG分子的生物学活性。这些研究的结果将产生有关以前未探索的参与PD发展的炎症途径的信息。

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.