REGULATION OF PERSISTENT AB RESPONSE BY FC RECEPTORS

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Long-term persistence of antigen-specific antibody and the generation of high affinity memory B cells are well-recognized features of the humoral immune response. Recent findings have supported the concept that the specialized microenvironment of the germinal center (GC) is key to these pathways, in particular the ability of the follicular dendritic cell (FDC) network to retain immunogenic antigen in the form of immune complexes for long periods, triggering B cells to proliferate and selecting cells with antigen receptors of increasing affinities. Central to this model is the requirement that B cells and their accessory cells recognize immune complexes and respond appropriately. Two receptor classes are involved in immune complex binding: the Fc and the complement receptor families. These two receptor systems differ in respect to cellular distribution and signalling capacity. We propose to determine the contributions of the Fc receptor system to the generation and maintenance of the GC reaction. Preliminary studies have indicated that specific Fc receptors are involved in the retention of immunogenic antigen, as well as in the regulation of B cell stimulation. Mice deficient in the common gamma chain of the stimulatory IgG FcRs (FcRI and III) have precocious germinal center reactions and increased binding of immune complexes. In contrast, mice deficient in FcRII, an inhibitory receptor, are unable to mediate feedback regulation and have significantly elevated levels of serum immunoglobulin in response to antigenic stimulation. Experiments are proposed to determine: 1) the mechanism and consequences of increased FDC binding of immune complexes in gamma chain mutants on the persistent antibody response, affinity maturation and anamnestic responses: 2) the role of FcRII on the GC reaction, immune complex persistence on FDCs, and feedback inhibition and 3) the contribution of B cell FcRII as compared to macrophage and FDC FcRII expression in mediating feedback inhibition and GC reactions. These studies will provide a molecular description of the role of immune complexes and their receptors in regulating the synthesis of antibody in vivo. Perturbations of these pathways may account for some of the pathological manifestations of autoimmune disease and the lack of immune responsiveness seen in the senescence of the immune response during aging.