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

Nature Communications
Thi-Huong NguyenA Greinacher

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.

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Citations

Aug 14, 2018·Journal of Thrombosis and Haemostasis : JTH·T E Warkentin
Dec 7, 2018·Hematology·Tamam Bakchoul, Irene Marini
Oct 2, 2019·Journal of Thrombosis and Haemostasis : JTH·Thi-Huong NguyenAndreas Greinacher
Jul 23, 2020·The Annals of Pharmacotherapy·John A Dougherty, Robyn Lupoli Yarsley
Oct 30, 2016·Journal of Molecular Recognition : JMR·Thi-Huong Nguyen
Jul 18, 2017·European Biophysics Journal : EBJ·Thi-Huong Nguyen, Andreas Greinacher
Apr 30, 2020·Journal of Clinical Medicine·Brigitte TardyClaire Pouplard
Mar 15, 2018·Frontiers in Medicine·Caroline SutFabrice Cognasse
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Aug 29, 2017·Journal of Thrombosis and Haemostasis : JTH·A GreinacherT E Warkentin
Apr 5, 2018·International Journal of Molecular Sciences·Van-Chien Bui, Thi-Huong Nguyen
Jun 17, 2020·International Journal of Laboratory Hematology·Beng H Chong
Apr 10, 2021·The New England Journal of Medicine·Andreas GreinacherSabine Eichinger
Apr 21, 2021·Journal of Thrombosis and Haemostasis : JTH·Johannes ThalerPaul Knöbl
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Aug 28, 2021·Biomedicines·Francesco NappiSanjeet Singh Avtaar Singh

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Methods Mentioned

BETA
enzyme-linked immunoassay
x-ray crystallography
affinity purification
isothermal titration calorimetry
dynamic light scattering
X-ray
chips
AFM
force measurements
light scattering

Software Mentioned

Origin script
Origin
JPK
SMFS
JPK NanoWizard
Zetasizer

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