Converging Roles of Platelets and CD32a in IGG-mediated Hypersensitivity Reactions

Abstract

Background: Injection of certain IgGs into CD32A transgenic mice causes hypersensitivity reactions (HR), which are thought to be largely neutrophil-driven. The presence of CD32a on platelets in these mice fundamentally alters the nature of HR by introducing complexities involving thrombosis and spleen function. Aims: We set out to identify differential responses to anti-platelet antibodies vs. immune complexes in CD32A mice and to identify the impact of platelet depletion and splenectomy on IgG-mediated HR. Methods: HR and thrombosis were evaluated following injection of monoclonal (mAb) or polyclonal (pAb) antibodies directed against platelet or soluble antigens, including: (1) IV.3 (mAb that binds platelet CD32a), and rabbit anti-mouse-platelet pAbs; (2) thrombotic IgG immune complexes (IC) consisting of CD40L+anti-CD40L mAb or b2GPI+anti-b2GPI pAb. These were injected into mice having or lacking CD32a, in some cases following platelet depletion or splenectomy. Reactions to these IgGs were assessed by signs of HR and by measurement of core body temperature, platelet counts, and pulmonary thrombosis. Results: IV.3 caused HR but not thrombosis in CD32A mice which was markedly suppressed by platelet depletion, suggesting platelets are primary mediators of IV.3-induced HR in this model. IV.3 caused HR similarly in control or splenectomized CD32A mice, suggesting splenic involvement is not required. Rabbit anti-mouse platelet pAbs caused HR in CD32A but not WT mice, suggesting a requirement for CD32A. Finally, platelet depletion significantly blunted both IC-induced HR and thrombosis. Conclusion: These data indicate that platelets per se, and in particular platelet CD32a, play primary roles in IgG-mediated hypersensitivity reactions in CD32A transgenic mice. They also highlight the importance of including platelets in the analysis of hypersensitivity reactions in mouse models, underscoring the value of CD32a in translating mouse model results to human pathology.