Table_1_Monomeric IgA Antagonizes IgG-Mediated Enhancement of DENV Infection.docx

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 Fc 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 Fc gamma receptor-positive K562 cells. Furthermore, we show that IgA potently antagonizes the ADE activity of IgG. These results suggest that levels of DENV-reactive IgA induced by DENV infection might regulate the overall IgG mediated ADE activity of DENV-immune plasma in vivo, and may serve as a predictor of disease risk.

登革热病毒（DENV）是一种常见的人体病原体，每年感染约4亿人，导致约1亿人出现症状性疾病。登革热的一个显著特征是，某些先前对DENV具有特异性免疫的人群患严重疾病的风险增加。这一现象的一个假设机制为抗体依赖性增强（ADE），其中先前感染产生的低效中和性IgG抗体将DENV调理，从而增加带有Fcγ受体细胞的感染。尽管IgM和IgG是最常研究的DENV反应性抗体亚型，但我们的研究小组以及其他研究团队已描述了在登革热期间诱导DENV特异性血清IgA反应。我们假设单体IgA能够中和DENV，而不会引发ADE。为了验证这一假设，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，亚型转换不影响这两种单克隆抗体的抗原结合和中和特性。我们展示，DENV反应性IgG，而非IgA，在Fcγ受体阳性的K562细胞中介导ADE。此外，我们显示IgA能够有效地拮抗IgG的ADE活性。这些结果表明，由DENV感染诱导的DENV反应性IgA水平可能会调节体内DENV免疫血浆中由IgG介导的ADE活动的总体水平，并可能作为疾病风险的预测指标。