Department of Cell Biology, Center for Research and Advanced Studies, The National Polytechnic Institute, Cinvestav-IPN, Av. IPN 2508, San Pedro Zacatenco, Gustavo A. Madero, 07360 Mexico City, Mexico.
Department of Molecular Biomedicine, Center for Research and Advanced Studies, The National Polytechnic Institute, Cinvestav-IPN, Av. IPN 2508, San Pedro Zacatenco, Gustavo A. Madero, 07360 Mexico City, Mexico.
J Immunol Res. 2021 Apr 26;2021:5511841. doi: 10.1155/2021/5511841. eCollection 2021.
Dengue is a worldwide expanding threat caused by dengue virus (DENV) infection. To date, no specific treatment or effective vaccine is available. Antibodies produced by plasma cells (PCs) might be involved concomitantly in protection and severe dengue immunopathology. Although a massive appearance of PCs has been reported during acute DENV infection in humans, this response has been poorly characterized. Here, we show the dynamic of PC generation in immune-competent mice cutaneously inoculated with DENV compared with two control experimental groups: mice inoculated with inactivated DENV or with PBS. We found that PC numbers increased significantly in the skin-draining lymph node (DLN), peaking at day 10 and abruptly decreasing by day 14 after DENV inoculation. Class-switched IgG PCs appeared from day 7 and dominated the response, while in contrast, the frequency of IgM PCs decreased from day 7 onwards. Even though the kinetic of the response was similar between DENV- and iDENV-inoculated mice, the intensity of the response was significantly different. Interestingly, we demonstrated a similar PC response to virus antigens (E and prM) by ELISPOT. characterization showed that PCs were distributed in the medullary cords and in close proximity to germinal centers (GCs), suggesting both an extrafollicular and a GC origin. Proliferating PCs (Ki-67) were found as early as 3-day postinoculation, and in-depth analysis showed that these PCs were in active phases of cell cycle during the kinetic. Finally, we found a progressive appearance of high-affinity neutralizing DENV-specific IgG further supporting GC involvement. Of note, these antibodies seem to be highly cross-reactive, as a large proportion recognizes Zika virus (ZIKV). The strong PC response to skin-inoculated DENV in this work resembles the findings already described in humans. We consider that this study contributes to the understanding of the biology of the humoral immune response to DENV in an immunocompetent murine model.
登革热是由登革病毒（DENV）感染引起的全球范围不断扩大的威胁。迄今为止，尚无特效治疗方法或有效的疫苗。浆细胞（PCs）产生的抗体可能同时参与保护和严重登革热免疫病理学。尽管已经报道在人类急性 DENV 感染期间大量出现 PC，但对这种反应的特征描述却很少。在这里，我们展示了与两个对照实验对照组（接种灭活 DENV 或 PBS 的小鼠）相比，免疫功能正常的小鼠经皮接种 DENV 后 PC 生成的动态。我们发现，PC 数量在皮肤引流淋巴结（DLN）中显著增加，在 DENV 接种后第 10 天达到峰值，并在第 14 天急剧下降。从第 7 天开始出现类别转换的 IgG PC，并主导了反应，而相比之下，IgM PC 的频率从第 7 天开始下降。尽管 DENV 和 iDENV 接种小鼠的反应动力学相似，但反应的强度却有很大的不同。有趣的是，我们通过 ELISPOT 证明了对病毒抗原（E 和 prM）的类似 PC 反应。 特征分析表明，PC 分布在髓质索中，并且靠近生发中心（GC），这表明既有滤泡外起源又有 GC 起源。早在接种后 3 天就发现增殖的 PC（Ki-67），深入分析表明，在动力学过程中，这些 PC 处于细胞周期的活跃阶段。最后，我们发现高亲和力中和 DENV 特异性 IgG 的逐渐出现进一步支持 GC 的参与。值得注意的是，这些抗体似乎具有高度的交叉反应性，因为很大一部分抗体识别寨卡病毒（ZIKV）。本工作中皮肤接种 DENV 引起的强烈 PC 反应与已经在人类中描述的发现相似。我们认为，这项研究有助于在免疫功能正常的小鼠模型中理解针对 DENV 的体液免疫反应的生物学。
