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

• Published in: Nature communications 2017-05, Vol.8 (1), p.14945-14945, Article 14945
• Main Authors: Nguyen, Thi-Huong, Medvedev, Nikolay, Delcea, Mihaela, Greinacher, Andreas
• Format: Article
• Language: English
• Subjects: 631/250/1933; 631/250/2152/2153/1291; 631/250/38; 631/45/612/1221; Antibodies; Antibodies - isolation & purification; Antibodies - pharmacology; Antigens; Autoimmunity - drug effects; Bacteria; Bacterial infections; Biological activity; Blood Platelets - drug effects; Blood Platelets - metabolism; Blood Platelets - ultrastructure; Chemokines; Gram-positive bacteria; Heparin - metabolism; Humanities and Social Sciences; Humans; multidisciplinary; Platelet Aggregation - drug effects; Platelet Factor 4 - antagonists & inhibitors; Polymers - pharmacology; Protein Binding - drug effects; Science; Signal transduction; Thrombocytopenia; Thrombosis
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms14945

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. Antibodies against the platelet factor 4 (PF4) support bacterial host defence but in some cases may lead to heparin-induced thrombocytopenia (HIT). Nguyen et al. show that in autoimmune HIT a subset of antibodies binds strongly to PF4 causing its conformational change that leads to association of non-pathogenic PF4 antibodies and thrombotic platelet activation.