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      The Chosen Few: Only a Subset of Memory B Cells Responds to Secondary Dengue Virus Infections

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      * ,
      EBioMedicine
      Elsevier
      Dengue virus, Memory B cells

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          Abstract

          Dengue virus (DENV) is a mosquito-borne flavivirus that infects an estimated 400 million people each year, with one-third of the world's population at risk (WHO, 2009). Dengue infections can be caused by any one of four stereotypically distinct viruses: DENV1–4. A primary infection by one DENV serotype provides lifelong immunity to that serotype, but only short-term immunity to the other serotypes (Sabin, 1952). Moreover, in contrast to a primary DENV infection, secondary heterologous DENV infection increases the risk of hemorrhagic fever (Nimmannitya et al., 1969). This increased risk is thought to be due to antibody-dependent enhancement of infection and original antigenic sin. Antibody-dependent enhancement occurs when sub-neutralizing antibodies bind to surface Fc receptors that facilitate enhanced viral uptake (Halstead and O'Rourke, 1977). Original antigenic sin occurs when memory lymphocytes generated during a primary infection weakly recognize non-neutralizing epitopes yet preferentially expand during secondary infections by related but distinct viruses (Halstead et al., 1983). This leads to an antibody response that preferentially recognizes the original, rather than the secondary virus. A major challenge is thus to develop vaccines that avoid these problems and provide protection against all four DENV serotypes. For this purpose, an understanding of the epitope-specificities of responding B cells during pathogenic secondary DENV infections is needed. This information in turn may help develop epitopes for subunit vaccines that elicit neutralizing, rather than infection-enhancing antibody responses. During recall responses, memory B cells can differentiate into antibody-secreting plasmablasts and plasma cells, re-initiate germinal centers for affinity maturation towards the new pathogen, and undergo self-renewing divisions. Distinct subsets of human memory B cells prefer one of these fates vs. the others. These functional traits largely segregate with the isotype of the B cell receptor. IgM-expressing memory B cells tend to re-initiate germinal centers, while IgG isotype-switched memory B cells yield plasmablasts and plasma cells (Seifert et al., 2015). Yet in the context of secondary DENV infections in humans, it is unclear how pre-existing memory B cells behave. Are all Dengue-specific memory B cells recruited into the response? Or do only certain subsets respond? In this issue, Appanna et al. demonstrate that IgG memory B cell-derived plasmablasts formed during the acute phase of secondary infection have a non-overlapping clonal repertoire compared with that of memory B cells at convalescence (Appanna et al., 2016). These data agree with and extend upon similar studies by other groups (Priyamvada et al., 2016). Antibodies following DENV infection can be directed at envelope (E), pre-membrane (prM), and capsid proteins, and non-structural proteins 1, 3, and 5. Appanna and colleagues show that antibodies derived from plasmablasts are almost exclusively specific to the E protein whereas antibodies derived from DENV-specific memory B cells can recognize E, prM or non-structural proteins. A few plasmablast clones were specific for the primary, rather than the secondary virus, indicative of original antigenic sin. Yet the overwhelming majority of these plasmablasts were cross-reactive across multiple different DENV serotypes. Though numbers were somewhat limited, monoclonal antibodies from plasmablasts tended to be more potent neutralizers relative to antibodies derived from memory B cells. In addition to differences in antigen specificity between the plasmablasts and memory B cells, Appanna et al. also found minimal immunoglobulin gene overlap through repertoire sequencing. Thus, it appears that not all DENV-specific memory B cells respond to generate circulating plasmablasts during secondary infections. This suggests that there are at least two “types” of memory B cells: a subset that is predisposed to becoming plasmablasts during secondary DENV infections, and another subset that either fails to respond or is biased towards maintaining memory B cell identity. The observation that B cell subsets possess different antigen specificities following subunit vaccination or flavivirus infection is not new (Lavinder et al., 2014, Purtha et al., 2011), but given the issues of antibody-dependent enhancement and original antigenic sin, human responses to DENV warrant deeper exploration. Appanna et al. thus address an important aspect in DENV immunity: how can effective and efficient antibody responses be evaluated? The authors' data suggest that analysis of plasmablasts and their antibodies is likely insufficient as a correlate of one component of long-term immunity against DENV: diversity of the memory B cell compartment. The extent to which these antibodies may instead continue to be produced by bone marrow-resident long-lived plasma cells or enhance infections remains unknown. It also remains unknown why only a subset of memory B cells is recruited into the circulating plasmablast pool. Are the pre-existing antibody affinities of memory B cells different between E vs. prM or non-structural proteins? Or are other subsets of plasmablasts in fact formed but retained in secondary lymphoid organs? How can the desired specificities of memory B cells be preferentially recruited into the response by vaccination? These questions will be important to address as the basic biology of responses to DENV infections continues to instruct future vaccine design. Disclosure The authors declare no competing interests. D.B. is a New York Stem Cell Foundation-Robertson Investigator and is supported by grants from the National Institutes of Health (R01AI099108), the American Cancer Society (125091-RSG-13-252-01-LIB), and the New York Stem Cell Foundation (NYSCF-R-I14). R.W. is supported by a predoctoral fellowship from the National Science Foundation (DGE-1143954). The funding sources had no role in the writing of this manuscript or decision to submit. The authors were not paid to write this manuscript by pharmaceutical companies or any other agencies.

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          • Record: found
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          Research on dengue during World War II.

          A SABIN (1952)
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            Functional capacities of human IgM memory B cells in early inflammatory responses and secondary germinal center reactions.

            The generation and functions of human peripheral blood (PB) IgM(+)IgD(+)CD27(+) B lymphocytes with somatically mutated IgV genes are controversially discussed. We determined their differential gene expression to naive B cells and to IgM-only and IgG(+) memory B cells. This analysis revealed a high similarity of IgM(+)(IgD(+))CD27(+) and IgG(+) memory B cells but also pointed at distinct functional capacities of both subsets. In vitro analyses revealed a tendency of activated IgM(+)IgD(+)CD27(+) B cells to migrate to B-cell follicles and undergo germinal center (GC) B-cell differentiation, whereas activated IgG(+) memory B cells preferentially showed a plasma cell (PC) fate. This observation was supported by reverse regulation of B-cell lymphoma 6 and PR domain containing 1 and differential BTB and CNC homology 1, basic leucine zipper transcription factor 2 expression. Moreover, IgM(+)IgD(+)CD27(+) B lymphocytes preferentially responded to neutrophil-derived cytokines. Costimulation with catecholamines, carcinoembryonic antigen cell adhesion molecule 8 (CEACAM8), and IFN-γ caused differentiation of IgM(+)IgD(+)CD27(+) B cells into PCs, induced class switching to IgG2, and was reproducible in cocultures with neutrophils. In conclusion, this study substantiates memory B-cell characteristics of human IgM(+)IgD(+)CD27(+) B cells in that they share typical memory B-cell transcription patterns with IgG(+) post-GC B cells and show a faster and more vigorous restimulation potential, a hallmark of immune memory. Moreover, this work reveals a functional plasticity of human IgM memory B cells by showing their propensity to undergo secondary GC reactions upon reactivation, but also by their special role in early inflammation via interaction with immunomodulatory neutrophils.
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              Identification and characterization of the constituent human serum antibodies elicited by vaccination.

              Most vaccines confer protection via the elicitation of serum antibodies, yet more than 100 y after the discovery of antibodies, the molecular composition of the human serum antibody repertoire to an antigen remains unknown. Using high-resolution liquid chromatography tandem MS proteomic analyses of serum antibodies coupled with next-generation sequencing of the V gene repertoire in peripheral B cells, we have delineated the human serum IgG and B-cell receptor repertoires following tetanus toxoid (TT) booster vaccination. We show that the TT(+) serum IgG repertoire comprises ∼100 antibody clonotypes, with three clonotypes accounting for >40% of the response. All 13 recombinant IgGs examined bound to vaccine antigen with Kd ∼ 10(-8)-10(-10) M. Five of 13 IgGs recognized the same linear epitope on TT, occluding the binding site used by the toxin for cell entry, suggesting a possible explanation for the mechanism of protection conferred by the vaccine. Importantly, only a small fraction (<5%) of peripheral blood plasmablast clonotypes (CD3(-)CD14(-)CD19(+)CD27(++)CD38(++)CD20(-)TT(+)) at the peak of the response (day 7), and an even smaller fraction of memory B cells, were found to encode antibodies that could be detected in the serological memory response 9 mo postvaccination. This suggests that only a small fraction of responding peripheral B cells give rise to the bone marrow long-lived plasma cells responsible for the production of biologically relevant amounts of vaccine-specific antibodies (near or above the Kd). Collectively, our results reveal the nature and dynamics of the serological response to vaccination with direct implications for vaccine design and evaluation.
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                Author and article information

                Contributors
                Journal
                EBioMedicine
                EBioMedicine
                EBioMedicine
                Elsevier
                2352-3964
                11 October 2016
                October 2016
                11 October 2016
                : 12
                : 12-13
                Affiliations
                Department of Pathology and Immunology, Washington University in Saint Louis School of Medicine, Saint Louis, MO 63110, United States
                Author notes
                [* ]Corresponding author. deeptab@ 123456wustl.edu
                Article
                S2352-3964(16)30455-8
                10.1016/j.ebiom.2016.09.032
                5078616
                27743902
                4831130e-b483-4fda-881f-54c98a0c0022
                © 2016 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 30 September 2016
                : 30 September 2016
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                dengue virus,memory b cells
                dengue virus, memory b cells

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