Reverse engineering of a pathogenic antibody reveals the molecular mechanism of vaccine-induced immune thrombotic thrombocytopenia DOI Open Access
Daniil G. Ivanov, Nikola Ivetic, Yi Du

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Июль 1, 2023

Abstract The massive COVID-19 vaccine roll-out campaign illuminated a range of rare side effects, the most dangerous which – vaccine-induced immune thrombotic thrombocytopenia (VITT) is caused by adenoviral (Ad)-vectored vaccines. VITT occurrence had been linked to production pathogenic antibodies that recognize an endogenous chemokine, platelet factor 4 (PF4). Mass spectrometry (MS)-based evaluation ensemble anti-PF4 obtained from patient’s blood indicates its major component monoclonal antibody. Structural characterization this antibody reveals several unusual characteristics, such as presence N -glycan in Fab segment and high density acidic amino acid residues CDR regions. A recombinant version (RVT1) was generated transient expression mammalian cells based on newly determined sequence. It captures key properties antibodies, their ability activate platelets PF4-dependent fashion. Homology modeling well-defined polyanionic paratope, docking studies indicate polycationic PF4 readily accommodates two segments, cross-linking yield polymerized complexes. Their existence verified with native MS detecting assemblies large 3 (PF4) 2 , pointing out at FcγRIIa-mediated activation molecular mechanism underlying clinical manifestations. In addition affinity, RVT1 binds other targets, indicating polyreactive nature This surprising polyspecificity not only sheds light etiology, but also opens up opportunities manage pathology. Significance Statement Vaccine-induced effect adenoviral-vectored vaccines emergence autoantibodies recognizing We have engineered sequencing patient-derived causes triggers thrombosis. used characterize architecture complexes combination biophysical computational approaches, revealing VITT. results work demonstrate critical role electrostatics recognition latter. Availability will be invaluable for future aiming understanding general mechanistic features autoimmune pathologies.

Язык: Английский

Reverse engineering of a pathogenic antibody reveals the molecular mechanism of vaccine-induced immune thrombotic thrombocytopenia DOI Open Access
Daniil G. Ivanov, Nikola Ivetic, Yi Du

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Июль 1, 2023

Abstract The massive COVID-19 vaccine roll-out campaign illuminated a range of rare side effects, the most dangerous which – vaccine-induced immune thrombotic thrombocytopenia (VITT) is caused by adenoviral (Ad)-vectored vaccines. VITT occurrence had been linked to production pathogenic antibodies that recognize an endogenous chemokine, platelet factor 4 (PF4). Mass spectrometry (MS)-based evaluation ensemble anti-PF4 obtained from patient’s blood indicates its major component monoclonal antibody. Structural characterization this antibody reveals several unusual characteristics, such as presence N -glycan in Fab segment and high density acidic amino acid residues CDR regions. A recombinant version (RVT1) was generated transient expression mammalian cells based on newly determined sequence. It captures key properties antibodies, their ability activate platelets PF4-dependent fashion. Homology modeling well-defined polyanionic paratope, docking studies indicate polycationic PF4 readily accommodates two segments, cross-linking yield polymerized complexes. Their existence verified with native MS detecting assemblies large 3 (PF4) 2 , pointing out at FcγRIIa-mediated activation molecular mechanism underlying clinical manifestations. In addition affinity, RVT1 binds other targets, indicating polyreactive nature This surprising polyspecificity not only sheds light etiology, but also opens up opportunities manage pathology. Significance Statement Vaccine-induced effect adenoviral-vectored vaccines emergence autoantibodies recognizing We have engineered sequencing patient-derived causes triggers thrombosis. used characterize architecture complexes combination biophysical computational approaches, revealing VITT. results work demonstrate critical role electrostatics recognition latter. Availability will be invaluable for future aiming understanding general mechanistic features autoimmune pathologies.

Язык: Английский

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