Antibody Feedback Regulation From Epitope Masking to T Helper Cell Activation

Abstract: Antibodies have the ability to influence the antibody response against the very antigen they are specific for, in a process called antibody feedback regulation. Depending on the nature of the antigen, the antibody response can be either enhanced or almost completely inhibited. This thesis focuses on the underlying mechanisms of antibody feedback regulation in vivo. Antigen-specific IgG can inhibit the antibody response to a particulate antigen. Based on its ability to inhibit B cell activation, the inhibitory Fc?RIIB (low affinity receptor for IgG) has been suggested to be involved. Here we show that although Fc?RIIB is required for efficient suppression in vitro, it is not required in vivo. Therefore, even though Fc?RIIB can inhibit antibody responses, other mechanisms (such as epitope masking and enhanced antigen clearance) play a more dominant role in vivo.The antibody response to soluble antigen is greatly enhanced when it is introduced to the immune system in complex with antigen-specific IgG or IgE. We found that Fc?RIIB attenuates the magnitude of IgG-mediated enhancement. In mice lacking Fc?RIIB, IgG enhanced the antibody response much more efficiently than in normal mice.Since B cells require CD4+ T cell help in order to become antibody-producing cells, we examined the CD4+ T cell response to immune complexes in vivo. Using an adoptive transfer strategy with transgenic ovalbumin (OVA)-specific CD4+T cells, we could show that the enhanced OVA-specific IgG response to IgG2a/OVA and IgE/OVA complexes was preceded by a potent OVA-specific CD4+ T cell response. IgG2a-mediated enhancement was dependent on activating Fc? receptors, whereas IgE-mediated enhancement was dependent on CD23, the low affinity receptor for IgE. We identified CD23+ B cells as the responsible effector cells for IgE-mediated enhancement in vivo. Taken together, these results show that Fc receptor-mediated antigen presentation is a major mechanism underlying antibody feedback enhancement.