Anti-platelet factor 4/polyanion antibodies mediate a new mechanism of autoimmunity

Thi-Huong Nguyen (), Nikolay Medvedev, Mihaela Delcea and Andreas Greinacher ()
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Thi-Huong Nguyen: Institute for Immunology and Transfusion Medicine, University Medicine Greifswald
Nikolay Medvedev: ZIK HIKE, Center for Innovation Competence, Humoral Immune Reactions in Cardiovascular Diseases, University of Greifswald
Mihaela Delcea: Institute for Immunology and Transfusion Medicine, University Medicine Greifswald
Andreas Greinacher: Institute for Immunology and Transfusion Medicine, University Medicine Greifswald

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: Abstract Antibodies recognizing complexes of the chemokine platelet factor 4 (PF4/CXCL4) and polyanions (P) opsonize PF4-coated bacteria hereby mediating bacterial host defense. A subset of these antibodies may activate platelets after binding to PF4/heparin complexes, causing the prothrombotic adverse drug reaction heparin-induced thrombocytopenia (HIT). In autoimmune-HIT, anti-PF4/P-antibodies activate platelets in the absence of heparin. Here we show that antibodies with binding forces of approximately 60–100 pN activate platelets in the presence of polyanions, while a subset of antibodies from autoimmune-HIT patients with binding forces ≥100 pN binds to PF4 alone in the absence of polyanions. These antibodies with high binding forces cluster PF4-molecules forming antigenic complexes which allow binding of polyanion-dependent anti-PF4/P-antibodies. The resulting immunocomplexes induce massive platelet activation in the absence of heparin. Antibody-mediated changes in endogenous proteins that trigger binding of otherwise non-pathogenic (or cofactor-dependent) antibodies may also be relevant in other antibody-mediated autoimmune disorders.

Date: 2017
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DOI: 10.1038/ncomms14945

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