Plasmablasts During Acute Dengue Infection Represent a Small Subset of a Broader Virus-specific Memory B Cell Pool.
Plasmablasts During Acute Dengue Infection Represent a Small Subset of a Broader Virus-specific Memory B Cell Pool.
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DOI：
10.1016/j.ebiom.2016.09.003
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发表时间：
2016-10
期刊：
影响因子：
11.1
通讯作者：
Fink, Katja
中科院分区：
文献类型：
--
作者：
Appanna, Ramapraba;Srinivasan, K. G.;Xu, Mei Hui;Toh, Ying-Xiu;Velumani, Sumathy;Carbajo, Daniel;Lee, Chia Yin;Zuest, Roland;Balakrishnan, Thavamalar;Xu, Weili;Lee, Bernett;Poidinger, Michael;Zolezzi, Francesca;Leo, Yee Sin;Thein, Tun Linn;Wang, Cheng-, I;Fink, Katja
登革热在全球热带国家流行，四种登革热病毒血清型常共同传播。感染一种血清型会导致浆母细胞产生高滴度的交叉反应抗体，暂时对所有血清型都有保护作用，但会削弱后续感染中的保护性免疫。为了解这些浆母细胞的发育情况，我们分析了急性疾病期间和恢复期患者的病毒特异性B细胞特性。浆母细胞与早期恢复期间在血液中扩增的经典记忆细胞无关。我们提出，在再次感染期间，只有一小部分记忆B细胞被激活为浆母细胞，并且浆母细胞反应不能代表登革热感染后记忆B细胞的全部。
对登革热患者的纵向急性和恢复期样本中的抗体序列和功能进行了分析
浆母细胞抗体对病毒糖蛋白具有特异性，而记忆B细胞衍生的抗体能结合更多的病毒蛋白
浆母细胞似乎仅由一小部分记忆B细胞激活
抗体介导的免疫记忆由多种B细胞类型协调，这些B细胞类型在感染后的不同阶段都很重要。再次感染几天后，活化的特异性记忆B细胞会产生抗体分泌细胞，即所谓的浆母细胞。然而，对于这些浆母细胞产生的抗体是否对人类的保护有重要作用，以及母体记忆B细胞是否在记忆库中进一步维持（可能是原始克隆的亲和力成熟版本），人们知之甚少。这在疫苗接种方面很重要，因为单个B细胞亚群的组成可以作为评估疫苗效力和长期保护的生物标志物。此外，“保护性”B细胞亚群的产生可能受到疫苗设计和佐剂使用的影响。
我们研究了登革热患者纵向血液样本中浆母细胞和记忆B细胞的关系。登革热病毒（DENV）有四种血清型，预先存在的抗体可能具有交叉保护作用，也可能在异源感染后通过Fc -γ受体介导的病毒 - 抗体复合物摄取而加重疾病。因此，B细胞记忆可能既有益又有害。在这里，我们通过评估抗体序列和单克隆抗体，研究了浆母细胞和登革热病毒特异性记忆B细胞及其关系和保护潜力。我们发现这两种细胞群都主要产生血清型交叉中和抗体，而更多的浆母细胞抗体具有中和作用。在记忆库中只能发现少数浆母细胞克隆，这表明在急性疾病期间只有一部分记忆B细胞被激活，并且有一组单独的细胞作为长期记忆被保留。在这项研究中，我们开始剖析登革热感染中B细胞免疫记忆的复杂性，这一发现可以为进一步研究异源感染后哪些免疫细胞亚群会加重疾病提供信息。
Dengue is endemic in tropical countries worldwide and the four dengue virus serotypes often co-circulate. Infection with one serotype results in high titers of cross-reactive antibodies produced by plasmablasts, protecting temporarily against all serotypes, but impairing protective immunity in subsequent infections. To understand the development of these plasmablasts, we analyzed virus-specific B cell properties in patients during acute disease and at convalescence. Plasmablasts were unrelated to classical memory cells expanding in the blood during early recovery. We propose that only a small subset of memory B cells is activated as plasmablasts during repeat infection and that plasmablast responses are not representative of the memory B cell repertoire after dengue infection. Antibody sequences and functions were analyzed in longitudinal acute and convalescent samples from dengue patients Plasmablast antibodies were virus glycoprotein-specific whereas memory B cell-derived antibodies bound to more viral proteins plasmablasts seem to be activated from only a small subset of memory B cells Antibody-mediated immune memory is orchestrated by various B cell types that are relevant during different phases after an infection. Antibody-secreting cells or so-called plasmablasts are generated from activated specific memory B cell a few days after re-infection. However, little in known whether the antibodies produced by these plasmablasts are relevant for protection in humans and whether the parent memory B cells are further maintained in the memory pool, possibly as affinity-matured versions of the original clones. This is important in the context of vaccination since the repertoires of individual B cell subsets could represent biomarkers to assess efficacy and long-term protection. In addition, the generation of “protective” B cell subsets could potentially be influenced by vaccine design and by the use of adjuvants. We studied the relationship of plasmablasts and memory B cells in longitudinal blood samples from dengue patients. Dengue virus (DENV) has four serotypes and pre-existing antibodies can be cross-protective or can enhance disease after a heterologous infection via Fc-gamma-receptor-mediated uptake of virus-antibody complexes. B cell memory can therefore be both beneficial and detrimental. Here we studied plasmablasts and DENV-specific memory B cells and their relationship and protective potential by assessing antibody sequences and monoclonal antibodies. We found that both populations produced largely serotype cross-neutralizing antibodies, whereas more plasmablast antibodies were neutralizing. Few plasmablast clones could be found in the memory pool, suggesting that only a subset of memory B cells is activated during acute disease and that a separate repertoire of cells is retained as longer-term memory. In this study we started to dissect the complexity of B cell immune memory to dengue infection and the finding can inform further investigations into which immune cell subsets are disease-enhancing after a heterologous infection.
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影响因子：
11.1
作者：
Fibriansah, Guntur;Tan, Joanne L.;Smith, Scott A.;de Alwis, Adamberage R.;Thiam-Seng Ng;Kostyuchenko, Victor A.;Ibarra, Kristie D.;Wang, Jiaqi;Harris, Eva;de Silva, Aravinda;Crowe, James E., Jr.;Lok, Shee-Mei
通讯作者：
Lok, Shee-Mei
影响因子：
17.1
作者：
Jiang N;He J;Weinstein JA;Penland L;Sasaki S;He XS;Dekker CL;Zheng NY;Huang M;Sullivan M;Wilson PC;Greenberg HB;Davis MM;Fisher DS;Quake SR
通讯作者：
Quake SR
影响因子：
3.8
作者：
Lin HE;Tsai WY;Liu IJ;Li PC;Liao MY;Tsai JJ;Wu YC;Lai CY;Lu CH;Huang JH;Chang GJ;Wu HC;Wang WK
通讯作者：
Wang WK
DOI：
10.1126/science.1201730
发表时间：
2011-03-04
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Pape KA;Taylor JJ;Maul RW;Gearhart PJ;Jenkins MK
通讯作者：
Jenkins MK
影响因子：
30.3
作者：
Beltramello M;Williams KL;Simmons CP;Macagno A;Simonelli L;Quyen NT;Sukupolvi-Petty S;Navarro-Sanchez E;Young PR;de Silva AM;Rey FA;Varani L;Whitehead SS;Diamond MS;Harris E;Lanzavecchia A;Sallusto F
通讯作者：
Sallusto F