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

Anti-HLA antibodies with complementary and synergistic interaction geometries promote classical complement activation on platelets.
Haematologica. 2018 Sep 27;:
Authors: Rijkers M, Schmidt D, Lu N, Kramer CSM, Heidt S, Mulder A, Porcelijn L, Claas FHJ, Leebeek FWG, Jansen AJG, Jongerius I, Zeerleder SS, Vidarsson G, Voorberg J, de Haas M
Abstract
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 e...

Source: Haematologica - September 27, 2018 Category: Hematology Authors: Rijkers M, Schmidt D, Lu N, Kramer CSM, Heidt S, Mulder A, Porcelijn L, Claas FHJ, Leebeek FWG, Jansen AJG, Jongerius I, Zeerleder SS, Vidarsson G, Voorberg J, de Haas M Tags: Haematologica Source Type: research