Fc galactosylation of anti-platelet human IgG1 alloantibodies enhances complement activation on platelets

Thijs L.J. van Osch, Janita J. Oosterhoff, Arthur E.H. Bentlage, Jan Nouta, Carolien A.M. Koeleman, Dionne M. Geerdes, Juk Yee Mok, Sebastiaan Heidt, Arend Mulder, Wim J.E. van Esch, Rick Kapur, Leendert Porcelijn, C. Ellen van der Schoot, Masja de Haas, Manfred Wuhrer, Jan Voorberg, Gestur Vidarsson*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

18 Citations (Scopus)

Abstract

Approximately 20% of patients receiving multiple platelet transfusions develop platelet alloantibodies, which can be directed against human leukocyte antigens (HLA) and, to a lesser extent, against human platelet antigens (HPA). These antibodies can lead to the rapid clearance of donor platelets, presumably through IgG-Fc receptor (FcγR)-mediated phagocytosis or via complement activation, resulting in platelet refractoriness. Strikingly, not all patients with anti-HLA or -HPA antibodies develop platelet refractoriness upon unmatched platelet transfusions. Previously, we found that IgG Fc glycosylation of anti-HLA antibodies was highly variable between patients with platelet refractoriness, especially with respect to galactosylation and sialylation of the Fc-bound sugar moiety. Here, we produced recombinant glycoengineered anti-HLA and anti-HPA-1a monoclonal antibodies with varying Fc galactosylation and sialylation levels and studied their ability to activate the classical complement pathway. We observed that anti-HLA monoclonal antibodies with different specificities, binding simultaneously to the same HLA-molecules, or anti-HLA in combination with anti-HPA-1a monoclonal antibodies interacted synergistically with C1q, the first component of the classical pathway. Elevated Fc galactosylation and, to a lesser extent, sialylation significantly increased the complement-activating properties of anti-HLA and anti-HPA-1a monoclonal antibodies. We propose that both the breadth of the polyclonal immune response, with recognition of different HLA epitopes and in some cases HPA antigens, and the type of Fc glycosylation can provide an optimal stoichiometry for C1q binding and subsequent complement activation. These factors can shift the effect of a platelet alloimmune response to a clinically relevant response, leading to complement-mediated clearance of donor platelets, as observed in platelet refractoriness.

Original languageEnglish
Pages (from-to)2432-2444
Number of pages13
JournalHaematologica
Volume107
Issue number10
DOIs
Publication statusPublished - Oct 2022
Externally publishedYes

Bibliographical note

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© 2022 Ferrata Storti Foundation Published under a CC BY-NC license.

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