Long-term antibody production is sustained by antibody-secreting cells in the bone marrow following acute viral infection

Abstract

Acute viral infection of humans induces virus-specific serum antibody production that often persists for decades. To better understand the nature of this long-term antiviral antibody response, we studied antiviral antibody production of mice acutely infected with lymphocytic choriomeningitis virus (LCMV). Although this viral infection is resolved within 2 weeks, virus-specific serum antibody levels were maintained for > 300 days postinfection. The anatomic site of long-term antibody production was identified using an ELISPOT assay to quantitate LCMV-specific antibody-secreting cells (ASC). The initial antiviral ASC response in the spleen peaked at 8 days postinfection and then declined sharply, with less than 10% of the day 8 ASC population remaining after 60 days. Although no LCMV specific ASC were detected in the bone marrow at day 8, virus-specific ASC began accumulating in the bone marrow by 15 days postinfection. By day 60, approximately 10-fold more antiviral ASC were present in the bone marrow than in the spleen, and the bone marrow remained the major site of antibody production for > 10 months postinfection. To further characterize the LCMV-specific antibody response, the relative percentage of each IgG subclass (IgG1, IgG2a, IgG2b, and IgG3) was determined. IgG2a was the predominant IgG subclass produced during LCMV infection, and the IgG subclass profile of virus-specific ASC in the spleen and bone marrow matched the IgG subclass profile of virus-specific IgG in the serum. Following a secondary infection with LCMV, splenic ASC numbers increased rapidly with a peak at 5 days after secondary infection. This was followed by a sharp decline in ASC numbers by day 15. In contrast, virus-specific ASC numbers in bone marrow remained essentially unchanged during the acute phase of the secondary infection but increased approximately twofold at day 15, corresponding to a twofold increase in virus-specific serum antibody levels. These results indicate that following a primary viral infection or upon reexposure to a virus, the initial antibody response occurs in the spleen, but long-term antiviral antibody production is maintained in the bone marrow.