par Bharadwaj, Pranay;Shrestha, Sweta;Pongracz, Tamas;Concetta, Catalano;Sharma, Shilpee 
;Le Moine, Alain;de Haan, Noortje;Murakami, Naoka;Riella, Leonardo LV;Holovska, Vanda;Wuhrer, Manfred;Marchant, Arnaud ;Ackerman, Margaret M.E.
Référence Cell reports. Medicine, 3, 11, page (100818)
Publication Publié, 2022-11-01
;Le Moine, Alain;de Haan, Noortje;Murakami, Naoka;Riella, Leonardo LV;Holovska, Vanda;Wuhrer, Manfred;Marchant, Arnaud ;Ackerman, Margaret M.E.Référence Cell reports. Medicine, 3, 11, page (100818)
Publication Publié, 2022-11-01
Article révisé par les pairs
| Résumé : | Antibody-mediated rejection (AMR) is the leading cause of graft failure. While donor-specific antibodies (DSAs) are associated with a higher risk of AMR, not all patients with DSAs develop rejection, suggesting that the characteristics of alloantibodies determining their pathogenicity remain undefined. Using human leukocyte antigen (HLA)-A2-specific antibodies as a model, we apply systems serology tools to investigate qualitative features of immunoglobulin G (IgG) alloantibodies including Fc-glycosylation patterns and FcγR-binding properties. Levels of afucosylated anti-A2 antibodies are elevated in seropositive patients, especially those with AMR, suggesting potential cytotoxicity via FcγRIII-mediated mechanisms. Afucosylation of both glycoengineered monoclonal and naturally glycovariant polyclonal serum IgG specific to HLA-A2 drives potentiated binding to, slower dissociation from, and enhanced signaling through FcγRIII, a receptor widely expressed on innate effector cells, and greater cytotoxicity against HLA-A2+ cells mediated by natural killer (NK) cells. Collectively, these results suggest that afucosylated DSA may be a biomarker of AMR and contribute to pathogenesis. |
