Epitope-Specific Suppression of IgG Responses by Passively Administered Specific IgG: Evidence of Epitope Masking

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.

ABO incompatibility and RhIG immunoprophylaxis protect against non‐D alloimmunization by pregnancy

“…Although several studies have previously addressed the possible mechanisms of action of RhIG, the exact mechanism(s) remain unclear. [11][12][13]24,25 Whereas the antigen masking or steric hindrance hypothesis appears to be the prevailing mechanism in the antibody-mediated immune suppression model with sheep RBCs in mice, 26 this mechanism insufficiently explains RhIG function in humans, based on the low level of opsonization sufficient to exert suppression. [9][10][11] Furthermore, antigen masking is an antigen-specific mechanism and if this was the main explanation for RhIG function, it would not prevent development of other RBC alloantibody specificities as found in our study.…”

Mice Immunized with IgG Anti-Sheep Red Blood Cells (SRBC) Together With SRBC Have a Suppressed Anti-SRBC Antibody Response but Generate Germinal Centers and Anti-IgG Antibodies in Response to the Passively Administered IgG

“…Spleen sections for confocal microscopy were prepared as described ( 21 ). GCs were visualized by staining the sections with anti-B220-Pacific Blue (clone RA3-6B2) (BD Biosciences), anti-CD169 (MOMA)-FITC (clone MOMA-1) (Bio-Rad antibodies, Raleigh, NC, USA), and biotinylated peanut agglutinin (PNA; Vector Laboratories, Burlingame, CA, USA) for 1 h in room temperature.…”

“…Although IgG-mediated suppression of antibody responses has been studied for decades, no consensus as to the mechanism behind has been reached. Suppression works well in all tested wild-type mouse strains, including C57BL/6 ( 20 , 21 ), and in mice lacking activating FcγRs ( 15 , 20 , 22 ), the neonatal FcR, FcRn ( 15 ), the inhibitory FcγRIIB ( 14 , 15 , 22 ), as well as complement receptors 1 and 2, C1q, or C3 ( 20 ). In spite of its ability to almost completely suppress antibody responses, IgG administered with sheep red blood cells (SRBC) has little or no effect on the priming of specific CD4 + T helper cells ( 15 , 23 , 24 ).…”

“…In spite of its ability to almost completely suppress antibody responses, IgG administered with sheep red blood cells (SRBC) has little or no effect on the priming of specific CD4 + T helper cells ( 15 , 23 , 24 ). IgG-mediated suppression is dose dependent ( 13 , 15 ), and suppression affects a wide range of parameters associated with a humoral immune response: primary IgM and IgG responses ( 13 – 16 , 20 ), antigen-specific germinal center (GC) B cells ( 21 ), extra-follicular antibody-secreting cells ( 21 ), long-lived plasma cells ( 21 ), and induction of immunological memory ( 21 ). Suppression is restricted to the antigen to which the IgG antibodies bind ( 15 ) and no skewed suppression of certain IgG isotypes has been reported ( 24 ) [reviewed in Ref.…”

Role of Memory B Cells in Hemagglutinin-Specific Antibody Production Following Human Influenza A Virus Infection

“…Preexisting anti-HA Abs and anti-HA Abs generated at various stages after IAV infection are thought to play an important role in regulating the fine specificity of the anti-HA Ab response [15]. The anti-HA Abs could block B cell recognition of particular epitopes/antigenic sites by epitope masking or more generally suppress the response by facilitating HA removal through Fc-mediated mechanisms [56,57]. Epitope masking by preexisting Abs does not fit with the observation that patterns of HA-reactive Ab production early in the response to IAV infection directly reflect OAS hierarchies of HA-reactive Ab levels in the circulation prior to infection [13].…”