Abstract
IgM antibodies specific for a certain antigen can enhance antibody responses when administered together with this antigen, a process believed to require complement activation by IgM. However, recent data show that a knock-in mouse strain, Cμ13, which only produces IgM unable to activate complement, has normal antibody responses. Moreover, the recently discovered murine IgM Fc receptor (FcµR or TOSO/FAIM3) was shown to affect antibody responses. This prompted the re-investigation of whether complement activation by specific IgM is indeed required for enhancement of antibody responses and whether the mutation in Cµ13 IgM also caused impaired binding to FcµR. The results show that IgM from Cµ13 and wildtype mice bound equally well to the murine FcµR. In spite of this, specific Cμ13 IgM administered together with sheep red blood cells or keyhole limpet hemocyanine was a very poor enhancer of the antibody and germinal center responses as compared with wildtype IgM. Within seconds after immunization, wildtype IgM induced deposition of C3 on sheep red blood cells in the blood. IgM which efficiently enhanced the T-dependent humoral immune response had no effect on activation of specific CD4+ T cells as measured by cell numbers, cell division, blast transformation, or expression of the activation markers LFA-1 and CD44 in vivo. These observations confirm the importance of complement for the ability of specific IgM to enhance antibody responses and suggest that there is a divergence between the regulation of T- and B-cell responses by IgM.
Highlights
Antibodies, passively administered together with antigen, can dramatically alter the immune response to the antigen via antibody feedback regulation
sheep red blood cells (SRBC)-specific IgM from Cμ13 and BALB/c mice, with the same concentrations (1.74 mg/ml as determined by OD280 nm assuming that an OD of 1.5 corresponds to 1 mg/ml), were tested in hemolysis and hemagglutination assays
An interesting question is how this can be reconciled with the ability of natural IgM as well as FcμR to potentiate antibody responses [19,20,21,22], especially since the enhancement by natural IgM does not seem to require complement activation [15]
Summary
Antibodies, passively administered together with antigen, can dramatically alter the immune response to the antigen via antibody feedback regulation. IgG is able to suppress responses to large antigens such as erythrocytes, and this has been used successfully in the clinic since the 1960's to prevent hemolytic disease of the newborn [2,3]. Rhesus negative mothers carrying Rhesus positive babies can become immunized after transplacental hemorrage and produce IgG anti-RhD which will damage fetal erythrocytes. This immunization can be prevented by administration of preformed. Administration of IgM anti-RhD together with Rhesus positive erythrocytes leads to (unwanted) higher antibody responses, illustrating that IgM is able to feedback enhance the immune response to erythrocytes [2]
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