Abstract
Specific IgG, passively administered together with particulate antigen, can completely prevent induction of antibody responses to this antigen. The ability of IgG to suppress antibody responses to sheep red blood cells (SRBCs) is intact in mice lacking FcγRs, complement factor 1q, C3, or complement receptors 1 and 2, suggesting that Fc-dependent effector functions are not involved. Two of the most widely discussed explanations for the suppressive effect are increased clearance of IgG–antigen complexes and/or that IgG “hides” the antigen from recognition by specific B cells, so-called epitope masking. The majority of data on how IgG induces suppression was obtained through studies of the effects on IgM-secreting single spleen cells during the first week after immunization. Here, we show that IgG also suppresses antigen-specific extrafollicular antibody-secreting cells, germinal center B-cells, long-lived plasma cells, long-term IgG responses, and induction of memory antibody responses. IgG anti-SRBC reduced the amount of SRBC in the spleens of wild-type, but not of FcγR-deficient mice. However, no correlation between suppression and the amount of SRBC in the spleen was observed, suggesting that increased clearance does not explain IgG-mediated suppression. Instead, we found compelling evidence for epitope masking because IgG anti-NP administered with NP-SRBC suppressed the IgG anti-NP, but not the IgG anti-SRBC response. Vice versa, IgG anti-SRBC administered with NP-SRBC, suppressed only the IgG anti-SRBC response. In conclusion, passively transferred IgG suppressed all measured parameters of an antigen-specific antibody/B cell response and an important mechanism of action is likely to be epitope masking.
Highlights
When antibodies are passively administered together with their specific antigen, they either down- or upregulate the antibody response against this antigen [1,2,3]
Spleens were harvested after 10 min and the amount of extracellular nitrophenyl acetyl (NP)-sheep red blood cells (SRBCs) was determined by confocal laser scanning microscopy (Figures 1A–R; enhanced images are shown in Figure S1 in Supplementary Material)
Some spleens were analyzed for NP-SRBC after 1 h and 24 h, but, as expected, very little or no antigen could be detected at these time points [Ref. [31] and data not shown]
Summary
When antibodies are passively administered together with their specific antigen, they either down- or upregulate the antibody response against this antigen [1,2,3]. IgM, IgG, and IgE enhance antibody responses and their effects depend on interactions of the immune complexes with Fc- or complement receptors, causing more efficient delivery of antigen to splenic B cell follicles and/ or causing enhanced presentation of antigen to CD4+ T cells. Since the 1960s, the suppressive capacity of IgG has been used clinically to protect rhesus D antigen (RhD)-negative women from becoming immunized against fetal RhD-positive erythrocytes entering the maternal circulation through transplacental hemorrhage [6]. It is of substantial theoretical interest to understand how small amounts of IgG can completely prevent antibody responses to the antigen they recognize. Understanding these mechanisms may aid in finding effective monoclonal IgG anti-RhD antibodies to use in RhD-prophylaxis
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