Ben Mkaddem Sanae, Aloulou Meryem, Benhamou Marc, Monteiro Renato C
Inserm, U1149, Centre de Recherche sur l'Inflammation, Paris, France.
J Clin Immunol. 2014 Jul;34 Suppl 1:S46-50. doi: 10.1007/s10875-014-0031-6. Epub 2014 Apr 13.
The mechanism for anti-inflammatory action of intravenous immunoglobulin (IVIg) in the treatment of autoimmune and inflammatory diseases involves IgG Fc receptors (FcγR). Although the inhibitory FcγRIIB plays an important role in IVIg action, FcγRIIIA has recently been identified as another major anti-inflammatory actor. Interaction of FcγRIIIA with uncomplexed IgG1 or IVIg, or with bivalent anti-FcγRIII F(ab')2 dampened calcium responses, ROS production, endocytosis and phagocytosis, induced by heterologous activating receptors. This inhibitory action required the inhibitory configuration of the ITAM motif (ITAMi) present within the FcγRIII-associated FcRγ subunit. This allowed SHP-1 recruitment and formation of intracellular inhibisome clusters containing FcγRIII and the targeted activating receptor. Therefore, IVIg functionally interact with FcγRIIIA inducing ITAMi signaling which can prevent development of autoimmune and inflammatory disorders independently of FcγRIIB. This new mechanism of action for IVIg reveals a therapeutic potential for FcγRIIIA targeting in inflammatory diseases.
静脉注射免疫球蛋白（IVIg）在治疗自身免疫性和炎性疾病中的抗炎作用机制涉及IgG Fc受体（FcγR）。虽然抑制性FcγRIIB在IVIg作用中起重要作用，但FcγRIIIA最近已被确定为另一个主要的抗炎因子。FcγRIIIA与未复合的IgG1或IVIg，或与二价抗FcγRIII F(ab')2相互作用，可减弱由异源激活受体诱导的钙反应、活性氧生成、内吞作用和吞噬作用。这种抑制作用需要FcγRIII相关FcRγ亚基中存在的免疫受体酪氨酸激活基序（ITAM）的抑制性构型（ITAMi）。这使得SHP-1募集并形成包含FcγRIII和靶向激活受体的细胞内抑制体簇。因此，IVIg与FcγRIIIA功能性相互作用，诱导ITAMi信号传导，从而可独立于FcγRIIB预防自身免疫性和炎性疾病的发展。IVIg这种新的作用机制揭示了靶向FcγRIIIA在炎性疾病中的治疗潜力。
