Abstract
Immunoglobulin glycosylation is a pivotal mechanism that drives the diversification of antibody functions. The composition of the IgG glycome is influenced by environmental factors, genetic traits and inflammatory contexts. Differential IgG glycosylation has been shown to intricately modulate IgG effector functions and has a role in the initiation and progression of various diseases. Analysis of IgG glycosylation is therefore a promising tool for predicting disease severity. Several autoimmune and alloimmune disorders, including critical and potentially life-threatening conditions such as systemic lupus erythematosus, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis and antibody-mediated kidney graft rejection, are driven by immunoglobulin. In certain IgG-driven kidney diseases, including primary membranous nephropathy, IgA nephropathy and lupus nephritis, particular glycome characteristics can enhance in situ complement activation and the recruitment of innate immune cells, resulting in more severe kidney damage. Hypofucosylation, hypogalactosylation and hyposialylation are the most common IgG glycosylation traits identified in these diseases. Modulating IgG glycosylation could therefore be a promising therapeutic strategy for regulating the immune mechanisms that underlie IgG-driven kidney diseases and potentially reduce the burden of immunosuppressive drugs in affected patients.
Key points
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Aberrant glycosylation of IgG is influenced by antibody subclass and antigen specificity and is established during B cell differentiation and maturation within germinal centres.
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Hypogalactosylation of the fragment crystallizable (Fc) of anti-PLA2R1 is a key feature of primary membranous nephropathy.
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Hypogalactosylation and hyposialylation of the Fc portion of anti-neutrophil cytoplasmic antibodies and total IgG in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis are associated with more severe disease and disease relapse.
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Among patients with systemic lupus erythematosus, those with lupus nephritis have reduced levels of galactosylation of the Fc portion of total IgG.
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In patients with IgA nephropathy, hypogalactosylated IgA1 triggers the generation of anti-hypogalactosylated IgA1 autoantibodies, leading to the formation of immune complexes.
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Aberrant hyposialylation and hypofucosylation of donor-specific antibodies are associated with antibody-mediated rejection of kidney grafts.
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Beyze, A., Larroque, C. & Le Quintrec, M. The role of antibody glycosylation in autoimmune and alloimmune kidney diseases. Nat Rev Nephrol (2024). https://doi.org/10.1038/s41581-024-00850-0
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DOI: https://doi.org/10.1038/s41581-024-00850-0
