Increased PTPN22 Expression and Defective CREB Activation Impair Regulatory T-Cell Differentiation in Non-ST-Segment Elevation Acute Coronary Syndromes

Flego, Davide; Severino, Anna; Trotta, Francesco; Previtero, Marco; Ucci, Sarassunta; Zara, Chiara; Massaro, Gianluca; Pedicino, Daniela; Biasucci, Luigi M.; Liuzzo, Giovanna; Crea, Filippo

doi:10.1016/j.jacc.2015.01.027

Cited by 35 publications

(35 citation statements)

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“…CD4 + T-cells from ACS patients show an enhanced response to TCR stimulation (34–36) and have a lower setting of the T-cell activation threshold, attributable to enhanced amplification of proximal TCR-mediated signals. CD4 + T-cells show increased accumulation of CD3 complexes and zeta-chain-associated protein kinase of 70 kD (Zap70) in the immunological synapse, higher early tyrosine phosphorylation after TCR stimulation, and defective deactivation of the lymphocyte-specific protein tyrosine kinase (LCK) (34–36).…”

Section: Tcr Signaling Alterations In Acsmentioning

confidence: 99%

“…CD4 + T-cells show increased accumulation of CD3 complexes and zeta-chain-associated protein kinase of 70 kD (Zap70) in the immunological synapse, higher early tyrosine phosphorylation after TCR stimulation, and defective deactivation of the lymphocyte-specific protein tyrosine kinase (LCK) (34–36). These abnormalities involving the upstream TCR signaling pathway strongly contribute to the higher cytotoxic ability of helper T-cells in ACS patients; indeed, CD4 + T-cells from ACS patients are able to kill endothelial and vascular smooth muscle cells in vitro (15,34).…”

Section: Tcr Signaling Alterations In Acsmentioning

confidence: 99%

“…Indeed, CD4 + T-cells from ACS patients exhibit reduced phosphorylation of Zap70 at its inhibitory residue Tyr-292 (36). This residue is implicated in TCR/CD3 complex internalization, immunological synapse formation, and down-modulation of the proximal events in TCR signaling.…”

Section: Tcr Signaling Alterations In Acsmentioning

confidence: 99%

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Adaptive Immunity Dysregulation in Acute Coronary Syndromes

Flego

Liuzzo

Weyand

et al. 2016

Journal of the American College of Cardiology

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Although the early outcome of acute coronary syndrome (ACS) has considerably improved in the last decade, cardiovascular diseases still represent the main cause of morbidity and mortality worldwide. This is mainly due to the fact that recurrence of ACS eventually leads to the pandemics of heart failure and sudden cardiac death, thus calling for a reappraisal of the mechanisms responsible for coronary instability. In this review, we will discuss recent advances in our understanding of how adaptive immunity contributes to the pathogenesis of ACS, as well as the clinical implications that arise from these new pathogenic concepts.

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Section: Tcr Signaling Alterations In Acsmentioning

confidence: 99%

Section: Tcr Signaling Alterations In Acsmentioning

confidence: 99%

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Adaptive Immunity Dysregulation in Acute Coronary Syndromes

Flego

Liuzzo

Weyand

et al. 2016

Journal of the American College of Cardiology

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“…These regulatory T-cells are involved in the control of autoimmunity [4]. Accordingly, a lower number or a decreased function of these cells has been found in patients suffering from lupus erythematous, type-1 diabetes, rheumatoid arthritis, and multiple sclerosis [5], as well as in patients with ACS [6, 7]. Moreover, in ACS the production of pro-inflammatory cytokines is not adequately counterbalanced by anti-inflammatory cytokines, such as IL-10; these alterations have been related to a worse short- and long-term prognosis [8, 9].…”

Section: Introductionmentioning

confidence: 99%

Atorvastatin inhibits the immediate-early response gene EGR1 and improves the functional profile of CD4⁺T-lymphocytes in acute coronary syndromes

et al. 2017

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Background- Adaptive immune-response is associated with a worse outcome in acute coronary syndromes. Statins have anti-inflammatory activity beyond lowering lipid levels. We investigated the effects of ex-vivo and in-vivo atorvastatin treatment in acute coronary syndromes on CD4+T-cells, and the underlying molecular mechanisms.Approach and results- Blood samples were collected from 50 statin-naïve acute coronary syndrome patients. We assessed CD4+T-cell activation by flow-cytometry, the expression of 84 T-helper transcription-factors and 84 T-cell related genes by RT-qPCR, and protein expression by Western-blot, before and after 24-hours incubation with increasing doses of atorvastatin: 3-10-26 g/ml (corresponding to blood levels achieved with doses of 10-40-80 mg, respectively). After incubation, we found a significant decrease in interferon-?-producing CD4+CD28nullT-cells (P = 0.009) and a significant increase in interleukin-10-producing CD4+CD25highT-cells (P < 0.001). Atorvastatin increased the expression of 2 genes and decreased the expression of 12 genes (in particular, EGR1, FOS,CCR2 and toll like receptor-4; >3-fold changes).The in-vivo effects of atorvastatin were analyzed in 10 statin-free acute coronary syndrome patients at baseline, and after 24h and 48h of atorvastatin therapy (80 mg/daily): EGR1-gene expression decreased at 24h (P = 0.01) and 48h (P = 0.005); EGR1-protein levels decreased at 48h (P = 0.03).Conclusions-In acute coronary syndromes, the effects of atorvastatin on immune system might be partially related to the inhibition of the master regulator gene EGR1. Our finding might offer a causal explanation on why statins improve the early outcome in acute coronary syndromes.

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“…In recent years, the role of biomarkers that reflect the inflammation and the inflammatory situation in coronary artery disease has been investigated in many studies (1, 2). Acute coronary syndrome (ACS), as the name suggests, defines all clinical situations caused by myocardial ischemia as a result of the decrease in coronary artery blood flow.…”

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IRAK-4 Variants in acute coronary syndrome patients

Ergen¹

2017

Anatol J Cardiol

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On the other hand, the stent type is also crucial in case of recurrent ischemic events. In addition, DAPT duration can differ according to the first-and second-generation DES. DAPT duration can be shorter in second-generation DES than in firstgeneration DES (5). It will be beneficial to know which generation of stent was used in your case, which could have led to a better outcome of DAPT discontinuation. Author`s ReplyTo the Editor,We thank the authors for their contribution to our study that was recently published in the Anatolian Journal of Cardiology 2017; 17: 73-4 entitled "Ticagrelor-associated thrombotic thrombocytopenic purpura" (1). Initially, we used biolimus-eluting stent during primary percutaneous coronary intervention in the patient. Although DAPT duration was reduced to at least 6 months in patients with stable coronary artery disease, DAPT duration of at least 12 months is still recommended in patients with ST elevation myocardial infarction (2). Numerous studies have indicated that second-generation stents have low stent thrombosis (ST) and major adverse cardiac events. A 3-month usage of these new stents in treatment has shown to be unrelated to increased ST rate (3). Even with these findings, we could not conclude whether ticagrelor cessation at 5 weeks of therapy in our case would not have caused ST. In addition, the authors mainly emphasized a switch to thienopyridine derivatives. A switch from clopidogrel to ticlopidine and no relapse in the aforementioned case (4) could be explained by different action mechanisms leading to TTP with clopidogrel and ticlopidine. AD-AMTS-13 deficiency is common in ticlopidine-associated cases in contrast to ADAMTS-13 independence in clopidogrel-associated ones (5). Prasugrel-linked TTP cases are few, and the exact mechanism is not clearly identified. Our ticagrelor-linked TTP case was also the first one in literature, and its exact mechanism was also not established. Eventually, P2Y12 inhibition was not re-initiated, and fortunately, no ST or TTP relapse occurred. after intracoronary drug-eluting stent placement in a patient with previous clopidogrel-induced thrombotic thrombocytopenic purpura: a case report.

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Increased PTPN22 Expression and Defective CREB Activation Impair Regulatory T-Cell Differentiation in Non-ST-Segment Elevation Acute Coronary Syndromes

Abstract: The persistent overexpression of PTPN22 and the transient reduction of CREB activity, associated with impaired Treg differentiation, might play a role in ACS.

Cited by 35 publications

References 30 publications

Adaptive Immunity Dysregulation in Acute Coronary Syndromes

Adaptive Immunity Dysregulation in Acute Coronary Syndromes

Atorvastatin inhibits the immediate-early response gene EGR1 and improves the functional profile of CD4⁺T-lymphocytes in acute coronary syndromes

IRAK-4 Variants in acute coronary syndrome patients

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Increased PTPN22 Expression and Defective CREB Activation Impair Regulatory T-Cell Differentiation in Non-ST-Segment Elevation Acute Coronary Syndromes

Abstract: The persistent overexpression of PTPN22 and the transient reduction of CREB activity, associated with impaired Treg differentiation, might play a role in ACS.

Cited by 35 publications

References 30 publications

Adaptive Immunity Dysregulation in Acute Coronary Syndromes

Adaptive Immunity Dysregulation in Acute Coronary Syndromes

Atorvastatin inhibits the immediate-early response gene EGR1 and improves the functional profile of CD4+T-lymphocytes in acute coronary syndromes

IRAK-4 Variants in acute coronary syndrome patients

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Atorvastatin inhibits the immediate-early response gene EGR1 and improves the functional profile of CD4⁺T-lymphocytes in acute coronary syndromes