Hazenbos W L, Heijnen I A, Meyer D, Hofhuis F M, Renardel de Lavalette C R, Schmidt R E, Capel P J, van de Winkel J G, Gessner J E, van den Berg T K, Verbeek J S
Department of Immunology, University Hospital Utrecht, The Netherlands.
J Immunol. 1998 Sep 15;161(6):3026-32.
Previously, we have demonstrated that phagocytosis of IgG1-coated particles by macrophages in vitro is impaired by deletion of Fc gamma RIII in mice, suggesting that IgG1 may interact preferentially with Fc gamma RIII. In the present study, the biologic relevance of this observation was addressed by triggering various effector functions of the immune system in Fc gamma RIII(-/-) mice, using panels of mAbs of different IgG subclasses. Both binding and phagocytosis of IgG1-coated sheep or human erythrocytes by Fc gamma RIII(-/-) macrophages in vitro were strongly impaired, indicating that the impaired ingestion of complexed IgG1 by Fc gamma RIII(-/-) macrophages is due to a defect in binding. An in vivo consequence of the defective phagocytosis was observed by resistance of Fc gamma RIII-deficient mice to experimental autoimmune hemolytic anemia, as shown by a lack of IgG1-mediated erythrophagocytosis in vivo by liver macrophages. Furthermore, trapping of soluble IgG1-containing immune complexes by follicular dendritic cells in mesenteric lymph nodes from Fc gamma RIII(-/-) mice was abolished. Whole blood from Fc gamma RIII(-/-) mice was unable to induce lysis of tumor cells in the presence of IgG1 antitumor Abs. Finally, IgG1 mAbs proved unable to mount a passive cutaneous anaphylaxis in Fc gamma RIII(-/-) mice. Together, these results demonstrate that IgG1 complexes, either in particulate or in soluble form, trigger in vitro and in vivo immune effector functions in mice predominantly via Fc gamma RIII.
此前，我们已经证明，小鼠体内FcγRIII的缺失会损害巨噬细胞在体外对IgG1包被颗粒的吞噬作用，这表明IgG1可能优先与FcγRIII相互作用。在本研究中，通过使用不同IgG亚类的单克隆抗体面板触发FcγRIII(-/-)小鼠免疫系统的各种效应功能，探讨了这一观察结果的生物学相关性。FcγRIII(-/-)巨噬细胞在体外对IgG1包被的绵羊或人红细胞的结合和吞噬作用均受到严重损害，这表明FcγRIII(-/-)巨噬细胞对复合IgG1摄取受损是由于结合缺陷所致。通过FcγRIII缺陷小鼠对实验性自身免疫性溶血性贫血的抗性，观察到吞噬作用缺陷的体内后果，如肝脏巨噬细胞在体内缺乏IgG1介导的红细胞吞噬作用所示。此外，FcγRIII(-/-)小鼠肠系膜淋巴结中滤泡树突状细胞对含可溶性IgG1免疫复合物的捕获被消除。在存在IgG1抗肿瘤抗体的情况下，FcγRIII(-/-)小鼠的全血无法诱导肿瘤细胞裂解。最后，IgG1单克隆抗体在FcγRIII(-/-)小鼠中无法引发被动皮肤过敏反应。总之，这些结果表明，IgG1复合物，无论是颗粒形式还是可溶性形式，在小鼠体内外主要通过FcγRIII触发免疫效应功能。
