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

Date Published: January 2, 2014

Publisher: Public Library of Science

Author(s): Dorothy H. L. Ng, John J. Skehel, George Kassiotis, Jean Langhorne, Eleanor M. Riley.

http://doi.org/10.1371/journal.ppat.1003843

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.

Partial Text

Infection or vaccination usually induces high levels of antigen-specific antibodies (Abs) in the systemic circulation and mucosal surfaces. These Abs can be maintained for long periods of time in the absence of re-infection, despite the relatively short half-life of serum immunoglobulins, which is measured in weeks [1]. For example, virus-neutralizing Abs have been detected in humans over 90 years after Influenza A virus infection [2] and in mice over 250 days after lymphocytic choriomeningitis virus (LCMV) infection [3]. The establishment of these long-term Ab responses relies on the maintenance of antigen-specific memory B cells (MBCs) and long-lived plasma cells (LLPCs). MBCs and LLPCs occupy distinct anatomical locations in the spleen and bone marrow, respectively, which are thought to be of finite size and under homeostatic control [4]. One consequence of such regulation is that new antigenic challenges, particularly with complex pathogens that generate large populations of MBCs and LLPCs, would affect the maintenance of Ab responses to previously encountered antigens.

We have used a mouse model to examine the requirements for maintenance of long-term humoral immunity to Influenza A virus, a virus that induces life-long humoral immunity in humans [2]. We show that serum levels of Influenza A virus-neutralizing Abs are maintained by continuous conversion of Influenza A virus-specific B cells into antibody-secreting LLPCs under steady-state conditions. A single malaria episode significantly dysregulates this maintenance of Influenza A virus-neutralizing Abs: a P. chabaudi infection, initiated after the B cell and antibody responses to Influenza A virus reach a stable plateau, results in the loss of pre-established serum Abs and plasma cells specific to Influenza A virus and in increased susceptibility to Influenza A virus re-infection. The loss of LLPC and the reduction in Abs is mediated via an FcγRIIB-dependent mechanism resulting in their apoptosis. However, continuous conversion of Influenza A virus-specific B cells into LLPCs following P. chabaudi infection eventually replenishes the LLPC pool and restores humoral immunity to Influenza A virus, highlighting that this arm of adaptive immunity can withstand considerable homeostatic disruption.

 

Source:

http://doi.org/10.1371/journal.ppat.1003843

 

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