CD32a antibodies induce thrombocytopenia and type II hypersensitivity reactions in FCGR2A mice

Meyer, Todd; Robles‐Carrillo, Liza; Dávila, Mónica; Brodie, Meghan; Desai, Hina; Rivera-Amaya, Mildred; Francis, John L.; Amirkhosravi, Ali

doi:10.1182/blood-2015-04-638684

Cited by 10 publications

(8 citation statements)

References 32 publications

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“…Anti-FcgRIIA mAbs (clone IV.3, 60 mg per mouse) were injected twice intravenously (24 and 4 hours) before challenge. Note that, unlike in FcgRIIA tg mice, 30 IV.3 administration did not induce hypothermia or symptoms of anaphylaxis or platelet depletion. Three hundred micrograms per mouse of anti-Gr-1 (RB6-8C5), 300 mg per mouse anti-Ly-6G (NIMP-R14), 30 mg or 60 mg per mouse anti-CD200R3 (Ba103), mAbs, or corresponding rat IgG 2b isotype control mAbs were injected intravenously 24 hours before challenge.…”

Section: In Vivo Blocking and Depletionmentioning

confidence: 82%

Mechanisms of anaphylaxis in human low-affinity IgG receptor locus knock-in mice

Gillis

Jönsson

Mancardi

et al. 2017

Journal of Allergy and Clinical Immunology

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Section: In Vivo Blocking and Depletionmentioning

confidence: 82%

Mechanisms of anaphylaxis in human low-affinity IgG receptor locus knock-in mice

Gillis

Jönsson

Mancardi

et al. 2017

Journal of Allergy and Clinical Immunology

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“…Platelets Are Critical During the Systemic Response. ICs injected into FcγRIIA TGN mice trigger systemic shock (22)(23)(24). Although thrombosis in the lungs and thrombocytopenia accompany systemic shock in these mice (22,(25)(26)(27), the platelet contribution to IC-induced shock has never been formally assessed.…”

Section: Resultsmentioning

confidence: 99%

“…Temperature was measured using a rectal probe thermometer at indicated time points. Signs of apparent shock were assessed as described previously (24, 77) using a score from 0 to 3 (24,77). A score of 3 represents completely immobilized and unconscious mice (mice collapse and do not react to sound or touch), a score of 2 represents mice with impaired mobility and irregular respiration, a score of 1 corresponds to mice with slow motions and shallow respiration, and a score of 0 describes normal mice.…”

Section: Methodsmentioning

confidence: 99%

“…To more accurately model FcγRIIA reactions in mice, transgenic FcγRIIA (FcγRIIA TGN ) mice that display FcγRIIA expression on platelets and certain leukocytes, including monocytes and neutrophils as in humans, were developed (12,20). Notably, stimulation of FcγRIIA in transgenic mice induces a shock response that is reminiscent of anaphylaxis in humans, with a strong reliance on neutrophil activity and implicating release of plateletactivating factor (PAF) (14,(21)(22)(23)(24).…”

Section: Significancementioning

confidence: 99%

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Platelets release pathogenic serotonin and return to circulation after immune complex-mediated sequestration

Cloutier

Allaeys

Marcoux

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

170

163

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There is a growing appreciation for the contribution of platelets to immunity; however, our knowledge mostly relies on platelet functions associated with vascular injury and the prevention of bleeding. Circulating immune complexes (ICs) contribute to both chronic and acute inflammation in a multitude of clinical conditions. Herein, we scrutinized platelet responses to systemic ICs in the absence of tissue and endothelial wall injury. Platelet activation by circulating ICs through a mechanism requiring expression of platelet Fcγ receptor IIA resulted in the induction of systemic shock. IC-driven shock was dependent on release of serotonin from platelet-dense granules secondary to platelet outside-in signaling by αIIbβ3 and its ligand fibrinogen. While activated platelets sequestered in the lungs and leaky vasculature of the blood-brain barrier, platelets also sequestered in the absence of shock in mice lacking peripheral serotonin. Unexpectedly, platelets returned to the blood circulation with emptied granules and were thereby ineffective at promoting subsequent systemic shock, although they still underwent sequestration. We propose that in response to circulating ICs, platelets are a crucial mediator of the inflammatory response highly relevant to sepsis, viremia, and anaphylaxis. In addition, platelets recirculate after degranulation and sequestration, demonstrating that in adaptive immunity implicating antibody responses, activated platelets are longer lived than anticipated and may explain platelet count fluctuations in IC-driven diseases.

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“…FcγRs are critical in the development of thrombocytopenia and thrombosis induced by IgG/PF4/H complexes, with FcγRIIA the most important contributor to HIT pathophysiology (▶ Figure 2). The FcγRIIA pathway is therefore a potential target for new treatments of HIT, which could be based on the use of either therapeutic monoclonal antibodies (77) or inhibitors specific to Src kinases, such as dasatinib (78), or to Syk, such as R406 and PRT-060318 (79,80). 12-LOX has also been proposed as a potential target for HIT treatment (35), but further studies will be necessary to evaluate these new approaches.…”

Section: Resultsmentioning

confidence: 99%

Risk factors for heparin-induced thrombocytopenia: Focus on Fcγ receptors

Rollin¹,

Pouplard²,

Gruel

2016

Thromb Haemost

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SummaryFcγ receptors have critical roles in the pathophysiology of heparin-induced thrombocytopenia (HIT), a severe immune-mediated complication of heparin treatment. Activation of platelets, monocytes and neutrophils by platelet-activating anti-PF4/heparin IgG antibodies results in thrombocytopenia, hypercoagulability and thrombosis in susceptible patients, effects that depend on FcγRIIA. In addition, FcγRIIIA receptors probably contribute to clearance of platelets sensitised by HIT immune complexes. FcγRI has also been reported to be involved in monocyte activation by HIT IgG antibodies and synthesis of tissue factor. This review focuses on the role of these FcγRs in HIT pathophysiology, including the potential influence of several gene variations associated with variable risk of HIT and related thrombosis. In particular, the 276P and 326Q alleles of CD148, a protein tyrosine phosphatase that regulates FcγRIIA signalling, are associated with a lower risk of HIT, and platelets from healthy donors expressing these alleles are hyporesponsive to anti-PF4/H antibodies. It was also recently demonstrated that the risk of thrombosis is higher in HIT patients expressing the R isoform of the FcγRIIA H131R polymorphism, with HIT antibodies shown to activate RR platelets more efficiently, mainly explained by an inhibitory effect of normal IgG2, which bound to the FcγRIIA 131H isoform more efficiently. Environmental risk factors probably interact with these gene polymorphisms affecting FcγRs, thereby increasing thrombosis risk in HIT.

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CD32a antibodies induce thrombocytopenia and type II hypersensitivity reactions in FCGR2A mice

Abstract: Key Points CD32a antibodies induce thrombocytopenia and hypersensitivity reactions in FCGR2A mice. Effector-deficient CD32a antibodies prevent IgG-induced thrombosis and shock in FCGR2A mice.

Cited by 10 publications

References 32 publications

Mechanisms of anaphylaxis in human low-affinity IgG receptor locus knock-in mice

Mechanisms of anaphylaxis in human low-affinity IgG receptor locus knock-in mice

Platelets release pathogenic serotonin and return to circulation after immune complex-mediated sequestration

Risk factors for heparin-induced thrombocytopenia: Focus on Fcγ receptors

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