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      Recovery of an Antiviral Antibody Response following Attrition Caused by Unrelated Infection

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          Abstract

          The homeostatic mechanisms that regulate the maintenance of immunological memory to the multiple pathogen encounters over time are unknown. We found that a single malaria episode caused significant dysregulation of pre-established Influenza A virus-specific long-lived plasma cells (LLPCs) resulting in the loss of Influenza A virus-specific Abs and increased susceptibility to Influenza A virus re-infection. This loss of LLPCs involved an FcγRIIB-dependent mechanism, leading to their apoptosis. However, given enough time following malaria, the LLPC pool and humoral immunity to Influenza A virus were eventually restored. Supporting a role for continuous conversion of Influenza A virus-specific B into LLPCs in the restoration of Influenza A virus immunity, B cell depletion experiments also demonstrated a similar requirement for the long-term maintenance of serum Influenza A virus-specific Abs in an intact LLPC compartment. These findings show that, in addition to their established role in the anamnestic response to reinfection, the B cell pool continues to be a major contributor to the maintenance of long-term humoral immunity following primary Influenza A virus infection, and to the recovery from attrition following heterologous infection. These data have implications for understanding the longevity of protective efficacy of vaccinations in countries where continuous infections are endemic.

          Author Summary

          Antibody responses to infectious pathogens are critical in host survival, recovery and protection from reinfection; they also correlate with the success of vaccination. It is currently thought that antibody serum titers are maintained at protective levels over long periods of time by specialized long-lived antibody-secreting plasma cells residing in the bone marrow. Indeed, antibodies against the original virus can still be found in survivors of the 1918 Spanish Flu, more than 90 years ago. However, it is also becoming clear that subsequent infection with heterologous pathogens may cause attrition of previously established immunological memory, in order to accommodate new lymphocyte specificities in the finite space of the host. This phenomenon is seemingly at odds with long-term maintenance of immunological memory. We also show that a single episode of malaria, caused by infection by Plasmodium chabaudi, leads to the loss of preexisting plasma cells, serum antibodies and protective immunity against Influenza A virus. However, Influenza A virus-specific immunity does eventually recover in these animals with the replenishment of plasma cells by B cells over the course of several weeks. Thus, the reported mechanism reconciles attrition of immunological memory by heterologous infection and long-term stability, and places B cells, instead of their descendant plasma cells, at the center of humoral memory.

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          Most cited references61

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          Humoral immunity due to long-lived plasma cells.

          Conventional models suggest that long-term antibody responses are maintained by the continuous differentiation of memory B cells into antibody-secreting plasma cells. This is based on the notion that plasma cells are short-lived and need to be continually replenished by memory B cells. We examined the issue of plasma cell longevity by following the persistence of LCMV-specific antibody and plasma cell numbers after in vivo depletion of memory B cells and by adoptive transfer of virus-specific plasma cells into naive mice. The results show that a substantial fraction of plasma cells can survive and continue to secrete antibody for extended periods of time (>1 year) in the absence of any detectable memory B cells. This study documents the existence of long-lived plasma cells and demonstrates a new mechanism by which humoral immunity is maintained.
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            Maintenance of serological memory by polyclonal activation of human memory B cells.

            Production of antibodies can last for a lifetime, through mechanisms that remain poorly understood. Here, we show that human memory B lymphocytes proliferate and differentiate into plasma cells in response to polyclonal stimuli, such as bystander T cell help and CpG DNA. Furthermore, plasma cells secreting antibodies to recall antigens are produced in vivo at levels proportional to the frequency of specific memory B cells, even several years after antigenic stimulation. Although antigen boosting leads to a transient increase in specific antibody levels, ongoing polyclonal activation of memory B cells offers a means to maintain serological memory for a human lifetime.
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              Cutting edge: long-term B cell memory in humans after smallpox vaccination.

              Memory B cells are a central component of humoral immunity, and yet little is known about their longevity in humans. Immune memory after smallpox vaccination (DryVax) is a valuable benchmark for understanding the longevity of B cell memory in the absence of re-exposure to Ag. In this study, we demonstrate that smallpox vaccine-specific memory B cells last for >50 years in immunized individuals. Virus-specific memory B cells initially declined postimmunization, but then reached a plateau approximately 10-fold lower than peak and were stably maintained for >50 years after vaccination at a frequency of approximately 0.1% of total circulating IgG(+) B cells. These persisting memory B cells were functional and able to mount a robust anamnestic Ab response upon revaccination. Additionally, virus-specific CD4(+) T cells were detected decades after vaccination. These data show that immunological memory to DryVax vaccine is long-lived and may contribute to protection against smallpox.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Pathog
                PLoS Pathog
                plos
                plospath
                PLoS Pathogens
                Public Library of Science (San Francisco, USA )
                1553-7366
                1553-7374
                January 2014
                January 2014
                2 January 2014
                : 10
                : 1
                : e1003843
                Affiliations
                [1 ]Division of Immunoregulation, MRC National Institute for Medical Research, London, United Kingdom
                [2 ]Division of Parasitology, MRC National Institute for Medical Research, London, United Kingdom
                [3 ]Division of Virology, MRC National Institute for Medical Research, London, United Kingdom
                London School of Hygiene and Tropical Medicine, United Kingdom
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: GK JL. Performed the experiments: DHLN GK. Analyzed the data: DHLN GK JL. Contributed reagents/materials/analysis tools: JJS. Wrote the paper: DHLN GK JL JJS.

                Article
                PPATHOGENS-D-13-00712
                10.1371/journal.ppat.1003843
                3879355
                ae9661a4-ae89-41e9-b707-4207c5ae2037
                Copyright @ 2014

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 15 March 2013
                : 5 November 2013
                Page count
                Pages: 15
                Funding
                This work was supported by the UK Medical Research Council (U117581330 and U117584248). DHLN is a recipient of an A*STAR MBBS-PhD National Science Scholarship (A*STAR, Singapore). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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