Dengue virus (DENV) is a prevalent human pathogen, infecting approximately 400 million individuals per year and causing symptomatic disease in approximately 100 million. A distinct feature of dengue is the increased risk for severe disease in some individuals with preexisting DENV-specific immunity. One proposed mechanism for this phenomenon is antibody-dependent enhancement (ADE), in which poorly-neutralizing IgG antibodies from a prior infection opsonize DENV to increase infection of F_c gamma receptor-bearing cells. While IgM and IgG are the most commonly studied DENV-reactive antibody isotypes, our group and others have described the induction of DENV-specific serum IgA responses during dengue. We hypothesized that monomeric IgA would be able to neutralize DENV without the possibility of ADE. To test this, we synthesized IgG and IgA versions of two different DENV-reactive monoclonal antibodies. We demonstrate that isotype-switching does not affect the antigen binding and neutralization properties of the two mAbs. We show that DENV-reactive IgG, but not IgA, mediates ADE in an F_c gamma receptor-positive K562 cells. Furthermore, we show that IgA potently antagonizes the ADE activity of IgG. These results suggest that levels of serum DENV-reactive IgA induced by DENV infection might regulate the overall ADE activity of DENV-immune plasma in vivo and warrants further study as a predictor of disease risk and/or therapeutic.

中文翻译：

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单体 IgA 拮抗 IgG 介导的 DENV 感染增强

登革热病毒 (DENV) 是一种流行的人类病原体，每年感染约 4 亿人，并导致约 1 亿人出现症状。登革热的一个显着特征是某些具有 DENV 特异性免疫的个体患严重疾病的风险增加。一个提议的机制对于这种现象是抗体依赖性增强作用（ADE），其中差的中和IgG抗体从先前感染调理DENV增加的F感染_Ç携带γ受体的细胞。虽然 IgM 和 IgG 是最常研究的 DENV 反应性抗体同种型，但我们的小组和其他人已经描述了登革热期间 DENV 特异性血清 IgA 反应的诱导。我们假设单体 IgA 能够中和 DENV 而不会发生 ADE。为了测试这一点，我们合成了两种不同的 DENV 反应性单克隆抗体的 IgG 和 IgA 版本。我们证明同种型转换不会影响两种 mAb 的抗原结合和中和特性。我们表明 DENV 反应性 IgG，而不是 IgA，介导 F _{c 中的}ADEγ 受体阳性 K562 细胞。此外，我们表明 IgA 有效拮抗 IgG 的 ADE 活性。这些结果表明，DENV 感染诱导的血清 DENV 反应性 IgA 水平可能在体内调节 DENV 免疫血浆的整体 ADE 活性，值得进一步研究作为疾病风险和/或治疗的预测指标。