Dengue Virus Activates Polyreactive, Natural IgG B Cells after Primary and Secondary Infection

Abstract

BackgroundDengue virus is transmitted by mosquitoes and has four serotypes. Cross-protection to other serotypes lasting for a few months is observed following infection with one serotype. There is evidence that low-affinity T and/or B cells from primary infections contribute to the severe syndromes often associated with secondary dengue infections. such pronounced immune-mediated enhancement suggests a dengue-specific pattern of immune cell activation. This study investigates the acute and early convalescent B cell response leading to the generation of cross-reactive and neutralizing antibodies following dengue infection.Methodology/Principal FindingsWe assayed blood samples taken from dengue patients with primary or secondary infection during acute disease and convalescence and compared them to samples from patients presenting with non-dengue related fever. Dengue induced massive early plasmablast formation, which correlated with the appearance of polyclonal, cross-reactive IgG for both primary and secondary infection. Surprisingly, the contribution of IgG to the neutralizing titer 4–7 days after fever onset was more than 50% even after primary infection.Conclusions/SignificancePoly-reactive and virus serotype cross-reactive IgG are an important component of the innate response in humans during both primary and secondary dengue infection, and “innate specificities” seem to constitute part of the adaptive response in dengue. While of potential importance for protection during secondary infection, cross-reactive B cells will also compete with highly neutralizing B cells and possibly interfere with their development.

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

“…In contrast to the memory B response, which is reportedly dominated by prM-and nonstructural protein-specific cells (6,(13)(14)(15), PBs preferentially bound to the E protein. This, in turn, implies that mature virus particles are the activating Ag that triggers B cells early during infection.…”

“…Typical dengue symptoms include high fever, vascular leakage, rashes, headache, and bone and muscle pain. Dengue patients exhibit hallmarks of severe inflammation, including increased serum cytokine concentrations (4,5), high numbers of activated T cells, B cells, enormous numbers of plasmablasts (PBs) (6)(7)(8), and high titers of circulating dengue-specific Abs. Sera from infected patients contain Abs against dengue virus (DENV) structural proteins (including prM, the E glycoprotein, and capsid protein), as well as against nonstructural proteins (primarily against NS1, which is secreted by infected cells) (9).…”

“…Moreover, cross-reactive MBCs might also be beneficial during heterologous infection, because they can lead to the production of large amounts of dengue-binding Abs, which, although not providing sterile protection, could positively influence the outcome of the disease by decreasing the virus load earlier in secondary cases compared with primary cases (11). In fact, serum from both primary and secondary patients is serotype cross-reactive in ELISA during the first weeks postinfection (6), and patients seem to be protected against all serotypes for a limited time (12), suggesting a potential protective role for the polyclonal Ab response generated during acute disease.…”

“…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…”

Human Memory B Cells in Healthy Gingiva, Gingivitis, and Periodontitis

“…Naive B cells, memory B cells, and ASCs were characterized as CD19 Differential expression between plasmablasts and plasma cells was used to investigate ASC subsets. Unlike plasmablasts and memory B cells, plasma cells express very low level of MHC class II (HLA-DR) (20)(21)(22) and also express CD138 (a well-known marker for plasma cell) (18,(23)(24)(25).…”