HUMAN NEUTROPHIL RC-RECEPTOR-MEDIATED PHAGOCYTOSIS

中性粒细胞（PMN）聚集在类风湿关节炎患者的滑液中， 关节炎，并有助于通过释放关节破坏 炎症介质和细胞内酶的结合 含有免疫复合物的IgG与PMN Fc受体的结合。 跨膜 触发摄取这些复合物的信号，溶酶体酶 炎症介质的释放和/或产生 明白 PMN Fc受体是一种低亲合力受体， 免疫复合物，并且在抗原性和功能上不同于免疫复合物。 在单核细胞上表达的高亲合力Fc受体， 单体和多聚IgG。 PMN，而非单核细胞，Fc受体介导 摄取和溶酶体酶释放可以通过低分子量的 来自人单核细胞培养物上清液的细胞因子的重量 和类风湿性滑液 这种细胞因子的作用被抑制， 单克隆抗体（1C 2），其既不识别PMN Fc受体， 也没有细胞因子结合位点。 某些试剂（脂肪醇， 两性霉素B、促肿瘤佛波酯和趋化肽） 其修饰PMNFc受体模拟物方面的微环境， 细胞因子刺激，并可用作探测PMN Fc受体的模型 功能 本项目拟研究这些药剂的作用， 细胞因子对Fc受体介导的摄取的影响，通过：1）测定 PMN Fc受体的内在变化和聚集状态， 有效地抑制吞噬细胞信号; 2）确定 细胞骨架协会，有助于有效转导 吞噬信号;和3）确定细胞活化机制 其导致影响Fc受体介导的膜脂质变化， 摄入 PMN将用上述吞噬作用修饰剂处理。 药物和评估的以下参数：Fc受体聚集和 亲合力;配体依赖性和非依赖性Fc受体内化; Fc受体和1C 2抗原的细胞骨架附着;膜流动性; 以及蛋白激酶C活化和肌醇磷脂水解。 这些实验将提供有关功能调节的信息， 中性粒细胞上表达的低亲和力Fc受体在炎症反应中聚集， 位点，并介导免疫复合物的清除和破坏。

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.