Long-lived antigen-induced IgM plasma cells demonstrate somatic mutations and contribute to long-term protection

Abstract

Long-lived plasma cells are critical to humoral immunity as a lifelong source of protective antibodies. Antigen-activated B cells—with T-cell help—undergo affinity maturation within germinal centres and persist as long-lived IgG plasma cells in the bone marrow. Here we show that antigen-specific, induced IgM plasma cells also persist for a lifetime. Unlike long-lived IgG plasma cells, which develop in germinal centres and then home to the bone marrow, IgM plasma cells are primarily retained within the spleen and can develop even in the absence of germinal centres. Interestingly, their expressed IgV loci exhibit somatic mutations introduced by the activation-induced cytidine deaminase (AID). However, these IgM plasma cells are probably not antigen-selected, as replacement mutations are spread through the variable segment and not enriched within the CDRs. Finally, antibodies from long-lived IgM plasma cells provide protective host immunity against a lethal virus challenge.

Memory B cell heterogeneity: Remembrance of things past

“…We are currently examining how polymerization enhances the functionality of these antibodies. Interestingly, somatically mutated IgM + LLPCs that preferentially localize to the spleen have been described that provide protective immunity against influenza challenge, yet these appear to be generated in a GC‐independent manner, whereas Plasmodium ‐specific IgM LLPCs do not . Therefore, to truly determine the unique roles of these various types of IgM + B cells and their antibodies in protective immune responses, it will be essential to study these antigen‐specific IgM + B memory cells in both mice and humans in response to specific infections.…”

Extrafollicular activities: perspectives on HIV infection, germinal center-independent maturation pathways, and KSHV-mediated lymphoproliferation

“…al. demonstrated long-term protective immunity against influenza virus arising from a GC-independent IgM response [11]. Interestingly, this response was maintained in the absence of T cell help, and the authors postulate that the extrafollicular IgM response could serve as an auxiliary pathway for humoral immunity to persist in the presence of serious defects in the T cell compartment, such as those that exist during HIV infection.…”

Here, There, and Anywhere? Arguments for and against the Physical Plasma Cell Survival Niche

“…Perhaps because many plasma cells home swiftly to the BM soon after their generation (12, 13), it is generally thought that plasma cells must integrate into specialized BM microenvironments, or niches, where they must remain indefinitely to survive (6, 14). However plasma cells exhibiting hallmarks of long-lived cells have also been captured in the spleen of mice and people (6, 15–17) and the lungs of influenza-infected mice (18), and recent data indicate that IgA-secreting plasma cells in the gut are also long-lived (19). What then if anything is unique about these tissues?…”

“…Indeed, such events might cause mature BM plasma cells to relocate to the spleen or other sites. As mentioned above mature plasma cells can be readily captured in the spleen at steady state (6, 15–17), with decay rates that mirror their counterparts in the BM (6, 15–17), and drug-induced blockade of bone remodeling has been shown to divert plasma cell (and megakaryocyte) homing from the BM to the spleen without impairing serum antibody responses (76). Given that CXCL12-expressing stromal cells are also found in the splenic red pulp (62), it is tempting to predict that early in terminal B cell differentiation, cohorts of newly formed plasma cells lodge in CXCL12-rich regions of the spleen where they may remain for extended periods as long-lived cells.…”