Anti-HLA antibodies with complementary and synergistic interaction geometries promote classical complement activation on platelets.

Rijkers, Maaike; Schmidt, David; Lu, Nina; Kramer, Cynthia S M; Heidt, Sebastiaan; Mulder, Arend; Porcelijn, Leendert; Claas, Frans H J; Leebeek, Frank W G; Jansen, A J Gerard; Jongerius, Ilse; Zeerleder, Sacha S; Vidarsson, Gestur; Voorberg, Jan; de Haas, Masja (2019). Anti-HLA antibodies with complementary and synergistic interaction geometries promote classical complement activation on platelets. Haematologica - the hematology journal, 104(2), pp. 403-416. Ferrata-Storti Foundation 10.3324/haematol.2018.201665

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High titers of HLA antibodies are associated with platelet refractoriness, causing poor platelet increments after transfusions in a subset of patients with HLA antibodies. Currently, we do not know the biological mechanisms that explain the variability in clinical responses in HLA alloimmunized patients receiving platelet transfusions. Previously we showed that a subset of anti-HLA IgG-antibodies induces FcγRIIa-dependent platelet activation and enhanced phagocytosis. Here we investigated whether anti-HLA IgG can induce complement activation on platelets. We found that a subset of anti-HLA IgG induced complement activation via the classical pathway, causing C4b and C3b deposition and formation of the membrane-attack complex. This resulted in permeabilization of platelet membranes and increased calcium influx. Complement activation also caused enhanced α-granule release, as measured by CD62P surface exposure. Blocking studies revealed that platelet activation was caused by FcγRIIa-dependent signaling as well as HLA antibody induced complement activation. Synergistic complement activation employing combinations of monoclonal IgGs suggested that assembly of oligomeric IgG complexes strongly promoted complement activation through binding of IgGs to different antigenic determinants on HLA. In agreement with this, we observed that preventing anti-HLA-IgG hexamer formation using an IgG-Fc:Fc blocking peptide, completely inhibited C3b and C4b deposition. Our results show that HLA antibodies can induce complement activation on platelets including membrane attack complex formation, pore formation and calcium influx. We propose that these events can contribute to fast platelet clearance in vivo in patients refractory to platelet transfusions with HLA alloantibodies, who may benefit from functional-platelet matching and treatment with complement inhibitors.

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