Laboratory of Immunology, Virginia-Maryland Regional College of Veterinary Medicine, and Maryland Pathogen Research Institute, University of Maryland, College Park, MD 20742, USA.
Proc Natl Acad Sci U S A. 2011 Nov 8;108(45):18406-11. doi: 10.1073/pnas.1115348108. Epub 2011 Oct 31.
IgG was traditionally thought to neutralize virions by blocking their attachment to or penetration into mucosal epithelial cells, a common site of exposure to viruses. However, we describe an intracellular neutralizing action for an influenza hemagglutinin-specific monoclonal antibody, Y8-10C2 (Y8), which has neutralizing activity only at an acidic pH. When Y8 was applied to the basolateral surface of Madin-Darby canine kidney cells expressing the rat neonatal Fc receptor for IgG (FcRn), it significantly reduced viral replication following apical exposure of the cell monolayer to influenza virus. Virus neutralization by Y8 mAb was dependent on FcRn expression and its transport of IgG. As both FcRn and Y8 mAb bind their partners only at acidic pH, the Y8 mAb is proposed to carry out its antiviral activity intracellularly. Furthermore, the virus, Y8 mAb, and FcRn colocalized within endosomes, possibly inhibiting the fusion of viral envelopes with endosomal membranes during primary uncoating, and preventing the accumulation of the neutralized viral nucleoprotein antigen in the nucleus. Prophylactic administration of Y8 mAb before viral challenge in WT mice, but not FcRn-KO mice, conferred protection from lethality, prevented weight loss, resulted in a significant reduction in pulmonary virus titers, and largely reduced virus-induced lung pathology. Thus, this study reveals an intracellular mechanism for viral neutralization in polarized epithelial cells that is dependent on FcRn-mediated transport of neutralizing IgG.
IgG 传统上被认为通过阻止病毒附着或穿透黏膜上皮细胞（病毒常见的暴露部位）来中和病毒。然而，我们描述了一种针对流感血凝素特异性单克隆抗体 Y8-10C2（Y8）的细胞内中和作用，该抗体仅在酸性 pH 值下具有中和活性。当 Y8 被应用于表达大鼠新生 Fc 受体（FcRn）的 Madin-Darby 犬肾细胞的基底外侧表面时，它可显著减少细胞单层顶端暴露于流感病毒后病毒的复制。Y8 mAb 对病毒的中和作用依赖于 FcRn 的表达及其对 IgG 的转运。由于 FcRn 和 Y8 mAb 仅在酸性 pH 值下结合其配体，因此推测 Y8 mAb 在细胞内发挥其抗病毒活性。此外，病毒、Y8 mAb 和 FcRn 在内体中聚集，可能在初次脱壳过程中抑制病毒包膜与内体膜融合，并防止中和的病毒核蛋白抗原在核内积累。在 WT 小鼠而不是 FcRn-KO 小鼠中，在病毒攻击前预防性给予 Y8 mAb 可提供对致死性的保护、防止体重减轻、导致肺部病毒滴度显著降低，并在很大程度上减少病毒引起的肺病理学变化。因此，这项研究揭示了极化上皮细胞中依赖于 FcRn 介导的中和性 IgG 转运的病毒中和的细胞内机制。
