Hooks without bait: IgG repertoire–mediated immune regulation across immune development and ageing

Abstract Background Immunoglobulin G (IgG) changes across the life course as B-cell selection, antigenic experience, inflammation, class switching, somatic diversification, and Fc glycosylation evolve. The ‘hooks without bait’ hypothesis proposes that idiotype/variable-region determinants within a polyclonal IgG repertoire can recognize complementary structures on developing or mature lymphocytes and other accessible targets, thereby modulating cellular functions even when the cognate antigen is absent. This review reassesses the evidence for this proposition in the context of immune ageing. Main body Experiments in which purified IgG was applied to thymic or peripheral immune cells reported donor-state-dependent changes in cytokine production, differentiation, homing molecules, and subset frequency across B cells, conventional and unconventional T cells, and innate lymphoid cells. Proteomic and multi-omic studies identified broad, clinically patterned IgG-binding landscapes, although most direct cell-modulation and target-mapping evidence comes from one research programme and requires independent replication. Four propositions organize the revised hypothesis: regulation may occur during immune development and in mature peripheral cells; repertoire composition changes with immune state; binding to cell-surface or accessible intracellular proteins may accompany functional changes; and the biological output depends on the aggregate repertoire and target-cell context. Integrating ageing is a critical test of this framework because ageing remodels both the antibody-producing compartment and the target-cell environment. Current evidence does not establish variable-region or idiotype exclusivity; Fc receptors, glycans, immune complexes, complement, target accessibility, and intracellular antibody sensing remain plausible contributors. Conclusions The literature justifies testing a lifespan IgG repertoire-mediated immune programming hypothesis in which maternal IgG may influence lymphocyte development and endogenous or therapeutic IgG may continue to shape mature immune function. Age-stratified donor-recipient experiments, Fab/Fc separation, direct binding validation, target perturbation, longitudinal sampling, independent replication, and in vivo confirmation are required to determine whether repertoire-mediated interactions contribute to immunosenescence, inflammageing, vaccine responsiveness, or healthy ageing.