Afucosylation of HLA-specific IgG1 as a potential predictor of antibody pathogenicity in kidney transplantation

Summary Antibody-mediated rejection (AMR) is the leading cause of graft failure. While donor-specific antibodies (DSA) are associated with a higher risk of AMR, not all patients with DSA develop rejection suggesting that the characteristics of alloantibodies that determine their pathogenicity remain undefined. Using human leukocyte antigen (HLA)-A2-specific antibodies as a model, we applied systems serology tools to investigate qualitative features of immunoglobulin G (IgG) alloantibodies including Fc-glycosylation patterns and Fc γ R binding properties. The levels of afucosylation of anti-A2 antibodies were elevated in all seropositive patients and were significantly higher in AMR patients, suggesting potential cytotoxicity via Fc γ RIII-mediated mechanisms. Afucosylation of both glycoengineered monoclonal and naturally glycovariant polyclonal serum IgG specific to HLA-A2 exhibited potentiated binding to, slower dissociation from, and enhanced signaling through Fc γ RIII, a receptor widely expressed on innate effector cells. Collectively, these results suggest that afucosylated DSA may be a biomarker of AMR and could contribute to its pathogenesis. Graphical Abstract. Potential influence of HLA-A2-specific IgG1 afucosylation, FcγRIIIa binding and activation on ADCC and graft rejection. Illustration created with https://BioRender.com .