Role of IgM in the shaping of antibody responses

IgM is the first antibody produced during development and during the course of a primary immune response. Mice deficient in secreted IgM (mus-/-) are unable to mount efficient antibody responses to protein immunization unless the protein is co administered with specific IgM. To define the mechanism by which IgM exerts this adjuvant activity, the splenic localization of IgM-containing immune complexes (IgM-IC) was first analyzed. Within 30 minutes, IgM-IC are trapped by macrophages, dendritic cells, and B cells in the marginal zone (MZ). IgM-IC (but not antigen alone) are then transported by MZ B cells into the B cell follicle and deposited onto follicular dendritic cells (FDCs), a process dependent on an intact complement system. B cell receptor (BCR) engagement is not required for FDC localization, but instead alters MZ B cell migration to the T-B border. IgG-containing immune complexes (IgG-IC) also bind MZ B cells and are transported for deposition onto FDCs. In contrast to IgM-IC deposition, IgG-IC are only partially dependent on complement for FDC deposition. While IgG-IC traffic normally after IgM-IC immunization, exposure of mice to IgG-IC inhibit the subsequent deposition of IgM-IC, identifying a potential mechanism important in the cessation of the immune response. The deposition of IgM-IC on FDCs is a transient event as little IgM-IC can be detected 72 hr after injection, as opposed to IgG-IC, which are retained for long periods of time (at least 10 days). The significance of IgM-IC deposition was demonstrated in mice with disrupted FDC networks. In these mice, neither IgM-IC nor IgG-IC deposit onto FDCs. The antibody responses in these mice are impaired as evidenced by decreased IgG levels and a loss of affinity maturation. IgM-IC were shown to promote germinal center formation and promote class switching and affinity maturation. These results provide mechanistic insights into the adjuvant effect of IgM that promotes efficient primary immune responses. Additionally, IgM is identified as a major link between the innate and adaptive response through the activation of complement, which facilitates Ag deposition on FDCs necessary for the promotion of high affinity antibodies.