REGULATION OF CELLULAR INFLAMMATORY RESPONSES

在发炎的人牙龈中存在的浸润性白细胞中， 单核/巨噬细胞、中性粒细胞和嗜酸性粒细胞表达表面 免疫球蛋白(Ig)A的Fc部分(FcalphaR)和免疫球蛋白G的受体 (FcGammaR)。然而，其生理和病理意义 不完全理解由FcalphaR传递的信号， 尤其是与FcGammaR介导的炎症过程相比。 免疫球蛋白，包括对牙周病原体的IgA抗体，是由 炎症牙龈中的浆细胞，并具有抗炎作用 关于抑制补体激活的特性。 相反，用IgA刺激嗜酸性粒细胞会导致脱颗粒。 这可能会导致组织损伤。研究中心的这个组件 对于口腔生物学，与其他中心项目和核心合作， 建议检验人类免疫球蛋白A抗体调节 炎性细胞介导的炎症过程与 人类牙周病。FaclphaR的存在及其调控 发炎的牙龈组织中的白细胞将通过 免疫荧光和流式细胞术。因为牙龈中的白细胞 源于循环池，FcalphaR上调 外周血单核细胞、中性粒细胞和嗜酸性粒细胞及模型 前单核细胞和早幼粒细胞系暴露于不同的 分子形式、亚类、免疫复合体和片段(生成 细菌免疫球蛋白A蛋白)，以及相关的细胞因子(IL- 单核细胞和中性粒细胞的IL-6、TNF-α；IL-3、IL-5、GM- 用于嗜酸性粒细胞的脑脊液)将在体外进行研究。这些技术将会 包括流式细胞术检测FcalphaR表面表达和分析 FcalphaR-mRNA转录。刺激这些细胞的后果 通过FcalphaR与Ig G和/或受体的比较 补充，将从以下方面进行审查：(I)生成 炎性细胞因子(IL-1、IL-6和TNF-α)通过单核细胞和 嗜酸性粒细胞和转化生长因子-α的释放； 单核细胞和中性粒细胞的蛋白水解酶；以及(Iii)释放 嗜酸性粒细胞的细胞毒性颗粒蛋白。潜在的 由IgA释放的因子引起的牙龈组织炎性损伤 刺激的白细胞将通过确定：(I)存在 炎症牙龈组织中释放的嗜酸性粒细胞蛋白；(Ii) 免疫球蛋白A刺激的白细胞及其产物对口腔的细胞毒作用 粘膜成纤维细胞；和(Iii)组织破坏性的发展 口腔培养物的特性(基质金属蛋白酶的诱导) 黏膜成纤维细胞暴露于IgA刺激的嗜酸性粒细胞及其功能 产品。这些研究试图解决的根本问题是 是免疫球蛋白A与免疫球蛋白G拮抗还是协同作用 炎症性病变。答案不仅有助于阐明 人类牙周病的免疫发病机制研究进展 人类免疫球蛋白A的生理学知识及其调节作用 炎症过程。

Among the infiltrating leukocytes present in inflamed human gingiva, monocytes/macrophages, neutrophils, and eosinophils express surface receptors for the Fc part of immunoglobulin (Ig) A (FcalphaR) and of IgG (FcgammaR). However, the physiological and pathological significance of the signals transduced by FcalphaR are incompletely understood, especially in comparison with FcgammaR-mediated inflammatory processes. IgA, including IgA antibodies to periodontal pathogens, is produced by plasma cells in inflamed gingiva, and possesses anti-inflammatory properties with respect to inhibition of complement activation. Conversely, stimulation of eosinophils with IgA induces degranulation which may lead to tissue damage. This component of the Research Center for Oral Biology, in collaboration with other Center Projects and Cores, proposes to examine the hypothesis that human IgA antibodies modulate inflammatory processes mediated by infiltrating leukocytes relevant to human periodontal disease. The presence and regulation of FaclphaR on leukocytes in inflamed gingival tissue will be examined by immunofluorescence and flow cytometry. As gingival leukocytes are derived from the circulating pool, the up-regulation of FcalphaR on peripheral blood monocytes, neutrophils, and eosinophils, and model promonocytic and promyelocytic cell lines by exposure to various molecular forms, subclasses, immune complexes, and fragments (generated by bacterial IgA proteases) of human IgA, and by relevant cytokines (IL- 1, IL-6, and TNF-alpha for monocytes and neutrophils; IL-3, IL-5, and GM- CSF for eosinophils) will be investigated in vitro. The techniques will include flow cytometry for FcalphaR surface expression and analysis of FcalphaR-mRNA transcription. the consequences of stimulating these cells through he FcalphaR, in comparison with receptors for IgG and/or complement, will be examined with respect to: (i) the generation of inflammatory cytokines (IL-1, IL-6, and TNF-alpha) by monocytes and neutrophils, and of TGF-alpha by eosinophils; (ii) the release of proteases by monocytes and neutrophils; and (iii) the release of cytotoxic granule proteins by eosinophils. The potential for inflammatory gingival tissue damage caused by factors released from IgA- stimulated leukocytes will be assessed by determining: (i) the presence of released eosinophil granule proteins in inflamed gingival tissue; (ii) cytotoxicity of IgA-stimulated leukocytes and their products towards oral mucosal fibroblasts; and (iii) the development of tissue-destructive properties (induction of matrix metalloproteinases) in cultured oral mucosal fibroblasts exposed to IgA-stimulated eosinophils and their products. The fundamental question that these studies seek to address is whether IgA acts antagonistically to or synergistically with IgG in inflammatory lesions. The answer will not only help to elucidate the immunopathogenesis of human periodontal disease, but also advance knowledge of the physiology of human IgA and its role in modulating inflammatory processes.