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Dengue represents a growing public health burden worldwide, accounting for approximately 100 million symptomatic cases and tens of thousands of fatalities yearly. Prior infection with one serotype of dengue virus (DENV) is the greatest known risk factor for severe disease upon secondary infection with a heterologous serotype, a risk which increases as serotypes co-circulate in endemic regions. This disease risk is thought to be mediated by IgG-isotype antibodies raised during a primary infection, which poorly neutralize heterologous DENV serotypes and instead opsonize virions for uptake by FcγR-bearing cells. This antibody-dependent enhancement (ADE) of infection leads to a larger proportion of susceptible cells infected, higher viremia and greater immunopathology. We have previously characterized the induction of a serum IgA response, along with the typical IgM and IgG responses, during dengue infection, and have shown that DENV-reactive IgA can neutralize DENV and competitively antagonize IgG-mediated ADE. Here, we evaluate the potential for IgA itself to cause ADE. We show that IgG, but not IgA, mediated ADE of infection in cells expressing both FcαR and FcγRs. IgG-mediated ADE stimulated significantly higher pro-inflammatory cytokine production by primary human macrophages, while IgA did not affect, or slightly suppressed, this production. Mechanistically, we show that DENV/IgG immune complexes bind susceptible cells significantly more efficiently than DENV/IgA complexes or virus alone. Finally, we show that over the course of primary dengue infection, the expression of FcγRI (CD64) increases during the period of acute viremia, while FcγRIIa (CD32) and FcαR (CD89) expression decreases, thereby further limiting the ability of IgA to facilitate ADE in the presence of DENV. Overall, these data illustrate the distinct protective role of IgA during ADE of dengue infection and highlight the potential therapeutic and prognostic value of DENV-specific IgA.

登革热（Dengue）已成为全球日益加重的公共卫生负担，每年约造成1亿例有症状病例及数万例死亡病例。既往感染过某一血清型登革病毒（DENV），是异型血清型二次感染时引发重症的已知最大风险因素，该风险会随不同血清型在流行区域共同循环传播而升高。这种疾病风险被认为由初次感染过程中产生的IgG型抗体介导，这类抗体无法有效中和异型登革病毒血清型，反而会将病毒粒子调理素化，使其被表达Fcγ受体（FcγR）的细胞摄取。抗体依赖增强（Antibody-dependent enhancement, ADE）会使更多易感细胞被感染，引发更高的病毒血症与更严重的免疫病理损伤。我们此前已阐明登革热感染过程中血清IgA应答与典型IgM、IgG应答的诱导特征，并证实登革病毒反应性IgA能够中和登革病毒，并竞争性拮抗IgG介导的ADE。本研究旨在评估IgA自身引发ADE的可能性。我们发现，在同时表达Fcα受体（FcαR）与Fcγ受体（FcγRs）的细胞中，IgG可介导感染的ADE，而IgA则无此效应。IgG介导的ADE可刺激原代人巨噬细胞产生显著更高水平的促炎细胞因子，而IgA则不会影响该细胞因子产生，甚至会产生轻度抑制。从机制层面而言，我们证实登革病毒/IgG免疫复合物结合易感细胞的效率显著高于登革病毒/IgA复合物或单纯病毒。最后，我们发现在初次登革热感染过程中，FcγRI（CD64）的表达在急性病毒血症期升高，而FcγRIIa（CD32）与FcαR（CD89）的表达则下降，从而进一步限制了IgA在登革病毒存在时介导ADE的能力。综上，本研究数据阐明了IgA在登革热感染ADE过程中独特的保护作用，并凸显了登革病毒特异性IgA的潜在治疗与预后价值。