Rapid and Massive Virus-Specific Plasmablast Responses during Acute Dengue Virus Infection in Humans

Abstract

h Humoral immune responses are thought to play a major role in dengue virus-induced immunopathology; however, little is known about the plasmablasts producing these antibodies during an ongoing infection. Herein we present an analysis of plasmablast responses in patients with acute dengue virus infection. We found very potent plasmablast responses that often increased more than 1,000-fold over the baseline levels in healthy volunteers. In many patients, these responses made up as much 30% of the peripheral lymphocyte population. These responses were largely dengue virus specific and almost entirely made up of IgG-secreting cells, and plasmablasts reached very high numbers at a time after fever onset that generally coincided with the window where the most serious dengue virus-induced pathology is observed. The presence of these large, rapid, and virus-specific plasmablast responses raises the question as to whether these cells might have a role in dengue immunopathology during the ongoing infection. These findings clearly illustrate the need for a detailed understanding of the repertoire and specificity of the antibodies that these plasmablasts produce. Dengue virus causes an infection with symptoms ranging from a mild fever to severe hemorrhagic fever with vascular leakage that ranges in severity from minor subcutaneous bleeding to severe gastrointestinal bleeding (5,28,34). A striking epidemiological and immunological characteristic of dengue fever (DF) is that the severe immunopathology is more likely to occur in individuals who have previously been infected with a heterologous dengue virus serotype (8,29,32). While the exact mechanism of this phenomenon remains to be fully elucidated, several hypotheses have been developed over the last few decades to explain the reason for the exacerbated pathology observed in these patients. One of the main hypotheses revolves around a mechanism referred to as antibody-dependent enhancement (ADE) (14). This hypothesis suggests that during a secondary infection, cross-reactive yet poorly cross-neutralizing antibodies produced against a previously encountered serotype will mediate an increased infectivity, in addition to altering the host range of target cells. This mechanism has been extensively studied in vitro (6,17,20), and its importance in vivo is beginning to be elucidated (2, 10, 27). Another proposed hypothesis (22,23) suggests that an enhanced infection together with a potent T cell-mediated recall response produces massive amounts of effector mediators (4, 11-13, 15, 16, 25), a so-called cytokine storm, that is responsible for the observed immunopathology. These two mechanisms are not mutually exclusive and may in fact work in concert to cause the immunopathology of dengue disease.While human T cell responses during acute dengue virus infection have been studied in some detail, much less is known about the B cell responses. Early studies in dengue patients showed that increases in immunoglobulin-containing cells could be observed during infection and that these cel...

Tissue Distribution and Dependence of Responsiveness of Human Antigen-Specific Memory B Cells

“…Previous observations by our group (28,40) and others (51)(52)(53)(54) found that secondary immune responses show a characteristic appearance of Ag-specific plasmablasts in the PB between days 6 and 7, in contrast to the appearance of such cells after day 10 in response to primary immunization (55). Consistent with the characteristics of a secondary response, we detected an increased anti-TT IgG titer together with TT + PC and TT + mBC expansion at day 7 and found TT + PC declined by day 14, comparably between HD, splenectomized, and tonsillectomized individuals.…”

Impaired Antibody-mediated Protection and Defective IgA B-Cell Memory in Experimental Infection of Adults with Respiratory Syncytial Virus

“…Similarly, using B-cell ELISpots, antigen-specific ASCs against RSV were shown to arise after Day 17 and peak around Day 110 ( Figure 3A). Peak virus-specific ASC frequencies ranged from 5% to 50% of total ASCs, comparable with that after influenza or yellow fever vaccination ( Figure 3B) (30)(31)(32)(33). Thus, the virus-specific acute ASC responses to RSV infection appeared quantitatively intact.…”

Plasmablasts Generated during Repeated Dengue Infection Are Virus Glycoprotein–Specific and Bind to Multiple Virus Serotypes

“…During secondary infection, large numbers of PBs are observed 6-7 d after the onset of fever (6,17); yet, the specificity of these PBs and their origin from either naive or MBCs has not been studied. PBs (CD20…”