Fc receptors and feedback enhancement of antibody responses

Abstract: Antibodies are important for the defence against microorganisms, but are also involved inpathological reactions such as allergy or autoimmunity. The exact mechanisms involved inregulation of antibody responses is still largely unknown. In this thesis, immune regulationby antibodies and the receptors they bind to (FcR), were investigated.IgG and IgE antibodies are known to enhance antibody responses to soluble antigens,such as bovine serum albumin (BSA), when given to mice as an immune complex. While IgE-mediated enhancement is mediated via the low affinity receptor for IgE, FcεRII (CD23), the receptors involved in IgG-mediated enhancement has not been clearly defined.To assess the role of FcRs for the enhancing effect by IgG, mice deficient of different FcRs were immunized with BSA alone or BSA/IgG complexes and actively produced BSA-specific IgG in serum was analyzed. We found that IgG-mediated enhancement was abrogated in mice deficient of the common γ-chain (lacking functional FcγRI, FcγRIII), wheras it was normal in mice selectively lacking FcγRIII. This suggests that expression of a functional FcγRI for the ability of IgG to enhance. Furthermore, the response to BSA/IsG in mice lacking the inhibitory FcγRIIB was several-fold higher, induced earlier, and was more long-lived than in wild type mice. These findings suggest that FcγRIIB prevents "over-production" of antibodies rather than inhibiting the initiation of a response.Immunization of mice with BSA and IgE triggered an early increase in the number ofIgG producing specific B cells, thus resembling a secondary response. Cell transferexperiments with CD23 deficient mice demonstrated that CD23 expression on B cells, butnot on follicular dendritic cells, was required and sufficient for the stimulatory ability ofIgE. These findings are compatible with the idea that IgE antibodies acts by increasing theability of B cells to take up antigens via CD23 and present them to T cells, which could bea stimulatory feedback mechanism involved in the perpetuation of allergic disease.