Therefore the events that govern early B-cell activation following influenza virus infection are crucial for ameliorating disease outcome. The mechanisms underlying early B-cell activation, however, are incompletely understood. Rapid Ab

production originates from extrafollicular foci developing at the edges of the T- and B-cell zones in secondary lymphoid tissues following antigen exposure. These responses are thought to generate primarily short-lived plasma cells 9. Rapid Ab production at extrafollicular sites is attributed to T cell-independent as well as T-dependent responses 10, 11. Saracatinib manufacturer In contrast, the slower intrafollicular germinal center reactions require cognate CD4 T-cell–B-cell interactions 12, 13. They are regarded as the birthplace of long-lived humoral immunity, providing both memory B cells and long-lived plasma cells 11, 13. Both extra and intra-follicular responses develop strongly in the regional

LN following selleck chemicals influenza virus infection 14. The selection events that underlie the establishment of extrafollicular versus germinal center B-cell responses are important events in the initiation of the adaptive immune response. They coordinate the formation of crucial rapidly protective responses, while ensuring long-term protection from re-infection 11. There is evidence that rapid (antiviral) Ab production can be provided by distinct B-cell subsets 1, 11, 15–19. Marginal zone (MZ) B cells are one such subset. They can respond to blood-borne antigens through rapid production of Ab at extrafollicular sites 17, 18. In the mouse these B cells are only found in the spleen, however, and not in LN 20, 21. Thus, MZ B cells are unlikely to play a role in the response to influenza virus infections, as respiratory tract draining MedLN are the main sites of the initial influenza virus-induced B-cell response 14. Whether there are other subsets in the LN that act as functional equivalents to splenic MZ B cells is currently unknown. Recently, BCR affinity-guided selection events have been implicated as a factor that could determine the B-cell fate following protein immunization 22. Paus et al.22 used an elegant

adoptive cell transfer approach with transgenic hen egg lysozyme-specific B cells to provide evidence that BCR affinity thresholds exist that steer B cells toward the a particular response. In that study high-affinity B cell–antigen interactions resulted in predominantly extrafollicular foci responses, whereas hen egg lysozyme-specific B cells binding antigen with weaker overall affinities were predominately selected into the germinal center response. These data are consistent with a study on vesicular stomatitis virus infection-induced B-cell responses, in which Roost et al. observed no improvement on the overall Ab-affinity during the course of vesicular stomatitis virus infection and showed that early induced virus-specific Ab are of relatively high affinities 23.