REGULATION OF CELLULAR INFLAMMATORY RESPONSES

在发炎的人类牙龈中存在的浸润性白细胞中， 单核细胞/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（FcalphaR）和IgG的Fc部分的受体 （Fc γ R）。 然而，生理和病理意义的 由FcalphaR转导的信号还不完全清楚， 特别是与Fc γ R介导的炎症过程相比。 伊加，包括针对牙周病原体的伊加抗体，是由 浆细胞在发炎的牙龈，并具有抗炎 关于抑制补体激活的性质。 相反，用伊加刺激嗜酸性粒细胞可诱导脱颗粒 这可能导致组织损伤。 研究中心的这一组成部分 口腔生物学，与其他中心项目和核心合作， 建议检查假设，人类伊加抗体调节 炎症过程由浸润性白细胞介导， 人类牙周病 FaclphaR的存在和调节 将通过以下方法检查发炎牙龈组织中的白细胞 免疫荧光和流式细胞术。 牙龈白细胞 来自循环池，FcalphaR的上调， 外周血单核细胞、中性粒细胞和嗜酸性粒细胞以及模型 前单核细胞和前髓细胞系通过暴露于各种 分子形式、亚类、免疫复合物和片段（生成 通过人伊加的细菌伊加蛋白酶），以及通过相关细胞因子（IL- 单核细胞和中性粒细胞的IL-1、IL-6和TNF-α; 将在体外研究CSF中的嗜酸性粒细胞。 这些技术将 包括用于FcalphaR表面表达流式细胞术和FcalphaR的分析， FcalphaR-mRNA转录。 刺激这些细胞的后果 通过FcalphaR，与IgG和/或 补充，将审查方面：（一）产生 单核细胞的炎性细胞因子（IL-1、IL-6和TNF-α）， 嗜中性粒细胞和TGF-α的嗜酸性粒细胞;（ii）释放 蛋白酶的单核细胞和嗜中性粒细胞;和（iii）释放 嗜酸性粒细胞的细胞毒性颗粒蛋白。 的潜力 炎症性牙龈组织损伤由伊加释放的因子引起， 刺激的白细胞将通过确定以下来评估：（i）存在 炎症牙龈组织中释放的嗜酸性粒细胞颗粒蛋白;（ii） IgA刺激的白细胞及其产物对口腔粘膜的细胞毒性 粘膜成纤维细胞;和（iii）组织破坏性的发展 培养的口腔黏膜基质金属蛋白酶的诱导作用 暴露于IgA刺激的嗜酸性粒细胞的粘膜成纤维细胞及其 产品. 这些研究试图解决的基本问题是， 伊加是否与IgG拮抗或协同作用， 炎性病变 答案不仅有助于阐明 人类牙周病免疫发病机制研究进展 人类伊加的生理学知识及其在调节 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.