Fossati Gianluca, Moots Robert J, Bucknall Roger C, Edwards Steven W
University of Liverpool, Liverpool, UK.
Arthritis Rheum. 2002 May;46(5):1351-61. doi: 10.1002/art.10230.
To determine the roles played by the neutrophil Fcgamma receptor type II (FcgammaRII) (CD32) and FcgammaRIIIb (CD16) in phagocytosis, bacterial killing, and activation by immune complexes (ICs) and to test the hypothesis that inhibition of pathologic effector neutrophil function is possible without compromising host defense.
Receptor function was probed by enzymic removal of FcgammaRIIIb from the cell surface and by use of Fab/F(ab')(2) fragments of monoclonal antibodies to block receptor-ligand binding. Cells were challenged with (a) serum-opsonized Staphylococcus aureus, (b) serum- and IgG-opsonized latex particles, and (c) synthetic soluble and insoluble ICs to mimic bacterial and inflammatory stimuli.
Phosphatidylinositol-phospholipase C treatment removed >97% of surface FcgammaRIIIb from neutrophils previously treated with tumor necrosis factor alpha to mobilize intracellular stores of receptor. This treatment profoundly inhibited activation of primed neutrophils by soluble ICs of the type found in diseased rheumatoid joints, but had no effect on phagocytosis and killing of serum-opsonized S aureus.
FcgammaRIIIb plays a major role in the secretion of toxic products in response to ICs, but little or no role in the phagocytosis and killing of serum-opsonized bacteria. The selective suppression of effector neutrophil function is therefore possible. FcgammaRIIIb, or its intracellular signaling pathway, is a potential therapeutic target in inflammatory diseases such as rheumatoid arthritis, because disruption of its function should decrease inflammatory tissue damage, but not jeopardize host protection against infection.
确定中性粒细胞II型Fcγ受体（FcγRII）（CD32）和IIIb型Fcγ受体（FcγRIIIb）（CD16）在吞噬作用、细菌杀伤以及免疫复合物（IC）激活过程中所起的作用，并验证在不损害宿主防御功能的情况下抑制病理性效应中性粒细胞功能是否可行。
通过酶促去除细胞表面的FcγRIIIb以及使用单克隆抗体的Fab/F(ab')₂片段阻断受体-配体结合来探究受体功能。用以下物质刺激细胞：（a）血清调理的金黄色葡萄球菌，（b）血清和IgG调理的乳胶颗粒，以及（c）合成的可溶性和不溶性IC，以模拟细菌和炎症刺激。
磷脂酰肌醇-磷脂酶C处理可从先前用肿瘤坏死因子α处理以动员细胞内受体储存的中性粒细胞中去除>97%的表面FcγRIIIb。这种处理显著抑制了类风湿性关节疾病中发现的那种可溶性IC对已致敏中性粒细胞的激活，但对血清调理的金黄色葡萄球菌的吞噬和杀伤没有影响。
FcγRIIIb在对IC作出反应时分泌有毒产物方面起主要作用，但在血清调理细菌的吞噬和杀伤中作用很小或没有作用。因此，选择性抑制效应中性粒细胞功能是可行的。FcγRIIIb或其细胞内信号通路是类风湿性关节炎等炎症性疾病的潜在治疗靶点，因为其功能的破坏应会减少炎症组织损伤，但不会危及宿主对感染的防护。
