Platelet Activation and Thrombus Formation over IgG Immune Complexes Requires Integrin ?IIb?3 and Lyn Kinase.

ABSTRACT: IgG immune complexes contribute to the etiology and pathogenesis of numerous autoimmune disorders, including heparin-induced thrombocytopenia, systemic lupus erythematosus, rheumatoid- and collagen-induced arthritis, and chronic glomerulonephritis. Patients suffering from immune complex-related disorders are known to be susceptible to platelet-mediated thrombotic events. Though the role of the Fc receptor, Fc?RIIa, in initiating platelet activation is well understood, the role of the major platelet adhesion receptor, integrin ?IIb?3, in amplifying platelet activation and mediating adhesion and aggregation downstream of encountering IgG immune complexes is poorly understood. The goal of this investigation was to gain a better understanding of the relative roles of these two receptor systems in immune complex-mediated thrombotic complications. Human platelets, and mouse platelets genetically engineered to differentially express Fc?RIIa and ?IIb?3, were allowed to interact with IgG-coated surfaces under both static and flow conditions, and their ability to spread and form thrombi evaluated in the presence and absence of clinically-used fibrinogen receptor antagonists. Although binding of IgG immune complexes to Fc?RIIa was sufficient for platelet adhesion and initial signal transduction events, platelet spreading and thrombus formation over IgG-coated surfaces showed an absolute requirement for ?IIb?3 and its ligands. Tyrosine kinases Lyn and Syk were found to play key roles in IgG-induced platelet activation events. Taken together, our data suggest a complex functional interplay between Fc?RIIa, Lyn, and ?IIb?3 in immune complex-induced platelet activation. Future studies may be warranted to determine whether patients suffering from immune complex disorders might benefit from treatment with anti-?IIb?3-directed therapeutics.

SUBMITTER: Zhi H 

PROVIDER: S-EPMC4546160 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature