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, FcγRIIa, in initiating platelet activation is well understood, the role of the major platelet adhesion receptor, integrin αIIbβ3, 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 FcγRIIa and αIIbβ3, 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 FcγRIIa was sufficient for platelet adhesion and initial signal transduction events, platelet spreading and thrombus formation over IgG-coated surfaces showed an absolute requirement for αIIbβ3 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 FcγRIIa, Lyn, and αIIbβ3 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-αIIbβ3-directed therapeutics.
Highlights
IgG immune complexes contribute to the etiology and pathogenesis of a number of autoimmune disorders, including heparin-induced thrombocytopenia [1], systemic lupus erythematosus [2,3], and collagen-induced/rheumatoid arthritis [4]
Both FcγRIIa immune receptor tyrosine-based activation motifs (ITAMs) phosphorylation and Syk recruitment were suppressed by abciximab (Fig 1C), consistent with the known amplification of platelet activation responses via ligand binding-induced outside-in signaling through αIIbβ3 [24,25]
Consistent with the premise that αIIbβ3 requires fibrinogen to support cell spreading on immobilized IgG, Chinese Hamster Ovary (CHO) cells stably expressing both FcγRIIa and αIIbβ3 failed to spread on IgG-coated glass slides unless soluble fibrinogen was present (S3 Fig)
Summary
IgG immune complexes contribute to the etiology and pathogenesis of a number of autoimmune disorders, including heparin-induced thrombocytopenia [1], systemic lupus erythematosus [2,3], and collagen-induced/rheumatoid arthritis [4]. Patients with immune complexrelated disorders are known to be hypercoagulable [5], and susceptible to both thrombocytopenia [6,7] and thrombosis [8,9] These disorders are thought to be precipitated, at least in part, by platelets that have become activated via their interaction with autoimmune antibody/antigen complexes—an event that was shown almost 50 years ago to induce secretion of platelet granule constituents [10], and that is known to be mediated by the binding of the Fc region of IgG-containing immune complexes to the platelet cell surface Fc receptor, FcγRIIa. FcγRIIa is a member of the immunoglobulin gene superfamily comprised of an extracellular domain that binds the Fc region of IgG, a single pass transmembrane domain, and a cytoplasmic tail that contains two YxxL immune receptor tyrosine-based activation motifs (ITAMs) [11,12]. Activation of Syk, in turn, promotes an intracellular signaling cascade that eventually leads to phosphorylation and activation of phospholipase C (PLC) γ2 [16], resulting in calcium mobilization, granule secretion, integrin activation, platelet aggregation, and thrombus formation
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