HUMAN NEUTROPHIL RC-RECEPTOR-MEDIATED PHAGOCYTOSIS

类风湿患者滑液中中性粒细胞(PMN)的聚集 关节炎和促进关节破坏的释放 炎症介质和细胞内酶对结合的反应 将含免疫球蛋白的免疫复合物与PMN Fc受体结合。跨膜的 触发这些复合体、溶酶体酶摄取的信号 炎症介质的释放和/或产生情况不佳 明白了。PMN Fc受体是一种低亲和力受体，结合 免疫复合体，在抗原性和功能上与 高亲和力Fc受体在单核细胞上表达，与两者强烈结合 单体和聚合物免疫球蛋白。Fc受体介导的PMN，而不是单核细胞 低分子可促进摄取和溶酶体酶的释放 来自人单核细胞培养上清液的重量细胞因子 和类风湿性滑液。这种细胞因子的作用被抑制。 一种既不识别PMN Fc受体的单抗(1C2) 也不包括细胞因子结合部位。某些试剂(脂肪醇、 两性霉素B、促进肿瘤的佛波醇酯和趋化肽) 它们改变了PMN Fc受体的微环境，模拟了 细胞因子刺激，可作为探测PMN Fc受体的模型 功能。该项目建议研究这些制剂的效果，并 细胞因子在Fc受体介导的摄取中的作用：1)测定 中性粒细胞Fc受体的内在变化和聚集状态 有效地转导吞噬信号；2)测定 细胞骨架关联有助于有效地转导 吞噬信号；以及3)细胞激活机制的确定 从而导致影响Fc受体融化的膜脂变化 摄取。对中性粒细胞进行上述吞噬修饰 评估的药物和下列参数：Fc受体聚集和 亲和力；配体依赖和非配体依赖的Fc受体内化； Fc受体与1C2抗原的细胞骨架结合；膜流动性； 蛋白激酶C的活化和肌醇磷脂的水解。 这些实验将提供有关神经元功能调节的信息。 炎症时聚集的中性粒细胞表达低亲和力Fc受体 并调节免疫复合体的清除和破坏。

Neutrophils (PMN) collect in the synovial fluid of patients with rheumatoid arthritis and contribute to joint destruction by the release of inflammatory mediators and intracellular enzymes in response to the binding of IgG containing immune complexes to PMN Fc receptors. The transmembrane signals that trigger ingestion of these complexes, lysosomal enzyme release, and/or production of inflammatory mediators are not well understood. The PMN Fc receptor is a low avidity receptor which binds immune complexes and is antigenically and functionally distinct from the high avidity Fc receptor expressed on monocytes which avidly binds both monomeric and polymeric IgG. PMN, but not monocyte, Fc-receptor-mediated ingestion and lysosomal enzyme release can be enhanced by a low molecular weight cytokine derived from human mononuclear cell culture supernatants and rheumatoid synovial fluid. The action of this cytokine is inhibited by a monoclonal antibody (1C2) which recognizes neither the PMN Fc receptor nor the cytokine binding site. Certain agents (aliphatic alcohols, amphotericin B, tumor-promoting phorbol esters, and chemotactic peptides) which modify the microenvironment of the PMN Fc receptor mimic aspects of cytokine stimulation and can be used as models to probe PMN Fc receptor function. This project proposes to study the effect of these agents and cytokine on Fc-receptor-mediated ingestion by: 1) Determination of intrinsic changes in, and aggregation state of, PMN Fc receptors which efficiently transduce a phagocytic signal; 2) Determination of the cytoskeletal associations which contribute to the efficient transduction of a phagocytic signal; and 3) Determination of the cell activation mechanisms which result in membrane lipid changes affecting Fc-receptor-meldiated ingestion. PMN will be treated with the above phagocytosis modifying agents and the following paramaters assessed: Fc receptor aggregation and avidity; ligand-dependent and - independent Fc receptor internalization; cytoskeleton attachment of Fc receptors and 1C2 antigen; membrane fluidity; and protein kinase C activation and inositol phospholipid hydrolysis. These experiments will provide information on the functional modulation of the low avidity Fc receptor expressed on PMN which collect at inflammatory sites and which mediate clearance and destruction of immune complexes.