Regulatory T cells protect against hypoxia-induced pulmonary arterial hypertension in mice

Pulmonary arterial hypertension (PAH) is a chronic, incurable condition characterized by pulmonary vascular remodeling, perivascular inflammation, and right heart failure. Regulatory T cells (Tregs) stave off autoimmunity, and there is increasing evidence for their compromised activity in the inflammatory milieu of PAH. Abnormal Treg function is strongly correlated with a predisposition to PAH in animals and patients. Athymic Treg-depleted rats treated with SU5416, an agent causing pulmonary vascular injury, develop PAH, which is prevented by infusing missing CD4+CD25highFOXP3+ Tregs. Abnormal Treg activity may also explain why PAH disproportionately affects women more than men. This mini review focuses on the role of Tregs in PAH with a special view to sexual dimorphism and the future promise of Treg therapy.

Download Full-text

Absence of T Cells Confers Increased Pulmonary Arterial Hypertension and Vascular Remodeling

American Journal of Respiratory and Critical Care Medicine ◽

10.1164/rccm.200608-1189oc ◽

2007 ◽

Vol 175 (12) ◽

pp. 1280-1289 ◽

Cited By ~ 117

Author(s):

Laimute Taraseviciene-Stewart ◽

Mark R. Nicolls ◽

Donatas Kraskauskas ◽

Robertas Scerbavicius ◽

Nana Burns ◽

...

Keyword(s):

T Cells ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Vascular Remodeling ◽

Pulmonary Arterial

Download Full-text

Alterations in circulating helper T-cells in idiopathic pulmonary arterial hypertension

10.1183/13993003.congress-2019.pa5051 ◽

2019 ◽

Author(s):

Denise van Uden ◽

Menno Van Nimwegen ◽

Thomas Koudstaal ◽

Peter Heukels ◽

Jennifer Van Hulst ◽

...

Keyword(s):

T Cells ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Idiopathic Pulmonary Arterial Hypertension ◽

Helper T Cells ◽

Pulmonary Arterial

Download Full-text

An upregulation of CD8+CD25+Foxp3+ T cells with suppressive function through interleukin 2 pathway in pulmonary arterial hypertension

Experimental Cell Research ◽

10.1016/j.yexcr.2017.06.017 ◽

2017 ◽

Vol 358 (2) ◽

pp. 182-187 ◽

Cited By ~ 3

Author(s):

Rong Zhu ◽

Liang Chen ◽

Yaqiong Xiong ◽

Nana Wang ◽

Xiaochen Xie ◽

...

Keyword(s):

T Cells ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Interleukin 2 ◽

Suppressive Function ◽

Pulmonary Arterial

Download Full-text

Overexpression of PD-1 on Peripheral Blood Lymphocytes in Patients with Idiopathic Pulmonary Arterial Hypertension and Its Association with High Viral Loads of Epstein-Barr Virus and Poor Clinical Parameters

Journal of Clinical Medicine ◽

10.3390/jcm9061966 ◽

2020 ◽

Vol 9 (6) ◽

pp. 1966 ◽

Cited By ~ 1

Author(s):

Michał Tomaszewski ◽

Ewelina Grywalska ◽

Andrzej Tomaszewski ◽

Piotr Błaszczak ◽

Marcin Kurzyna ◽

...

Keyword(s):

T Cells ◽

Immune System ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Epstein Barr Virus ◽

Idiopathic Pulmonary Arterial Hypertension ◽

Barr Virus ◽

Ebv Infection ◽

Pulmonary Arterial ◽

Epstein Barr

Idiopathic pulmonary arterial hypertension (IPAH) is a rare but severe disease with the elevated blood pressure in the pulmonary arteries without a known trigger of vascular remodelling. It leads to the right heart failure with reduced survival. Changes in the immunological landscape of the lungs and the periphery are common in IPAH patients, suggesting an immune system dysfunction. A cohort of 25 IPAH patients was enrolled in our study to investigate a link between the patient’s clinical status, immune parameters of the blood, and the Epstein–Barr virus (EBV) infection. We found significant alterations of the patients’ peripheral blood parameters. Therein, T lymphocytes and NK cell counts were decreased in the IPAH patients’ blood, while the proportion of regulatory T cells was increased. Additionally, levels of proinflammatory cytokines interleukin-6 (IL-6), IL-2, and interferon-gamma (IFN-γ) were elevated. We identified a weak correlation between EBV loads and IPAH patients’ clinical state (r = 0.54) and between EBV loads and overexpression of PD-1 on helper T cells (r = 0.56). We speculate that a significant dysregulation of the immune system homeostasis observed in IPAH patients may contribute to increased susceptibility of those patients to EBV infection, yet further longitudinal studies are required to characterize this relation in detail.

Download Full-text

POS0335 THE POTENTIAL ROLE OF IL13 IN VASCULOPATHY IN SYSTEMIC SCLEROSIS PATIENTS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.3534 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 395.1-395

Author(s):

A. Schumann ◽

H. Grasshoff ◽

S. Comduehr ◽

G. Riemekasten

Keyword(s):

T Cells ◽

Systemic Sclerosis ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Cd8 T Cells ◽

Receptor Type ◽

Type I ◽

Healthy Controls ◽

Pulmonary Arterial ◽

Acral Ulcers

Background:Systemic sclerosis (SSc) is a heterogeneous disease characterized by fibrosis, vasculopathy and autoimmunity. Dysfunctions causing disease pathology are characterized by the activation and recruitment of immune cells, as well as the formation of autoantibodies and cytokines. Profibrotic cytokines, such as interleukin-(IL)13, IL4 or IL6 play a crucial role in collagen production and fibrosis development [1]. Preliminary data reveal IL13 as a main driver for obliterative vasculopathy characterized by severe Raynaud phenomenon, acral ulcers and pulmonary arterial hypertension (PAH). Particularly acral ulcerations lead to a severe impairment in functional capacity in everyday life. In addition, pulmonary arterial hypertension is one of the main causes of the high mortality rate in SSc [2].Objectives:To prove the impact of IL13 in the pathogenesis of systemic sclerosis and thus provide the rationale for the identification of a potential new therapeutic target, we investigated IL13 expression in CD4 and CD8 T cells in patients suffering from systemic sclerosis compared to healthy controls.Methods:Peripheral blood mononuclear cells (PBMC) obtained from systemic sclerosis (SSc, n=31) patients and healthy controls (HC, n=13) were cultured without or in the presence of phorbol myristate acetate and ionomycin to activate T cells for cytokine production. Brefeldin A was used as an inhibitor of cytokine secretion. The intracellular IL13 and IL4 expression of CD4 and CD8 positive T cells were measured by flow cytometry and were compared between the investigated subgroups.To identify a disease phenotype mediated by IL13, the expression levels in the SSc group were correlated to clinical, laboratory and apparative parameters assessing organ dysfunction.Results:While there were no significant differences in IL4 expression between healthy and diseased individuals, analyses of IL13 positive CD4 and CD8 T cells showed significant differences compared to HC (CD8+IL13 p=0.048; CD4+IL13 p=0.0046) revealing the functional differences though high structural homology of the two interleukins. The increased expression of IL13 in T cells from patients with systemic sclerosis further supports the assumption of an interleukin mediated pathomechanism. Considering the IL13-mediated clinical phenotype, high levels were detected in patients showing signs for vasculopathy, correlation with sPAP (CD8+IL13 p=0.0392), NTproBNP (CD4+IL13 p=0.0461), creatinine (CD4+IL13 p=0.0227), angiotensin II receptor type I and endothelin receptor type A antibodies (CD4+IL13 p=0.0105, p=0.0042) was demonstrated. In addition, patients in the fourth quartile of CD4+IL13 expression showed a higher incidence of acral ulcers and pits than patients with low interleukin levels. Moreover, this group of patients had an increased cardiovascular comorbidity including atherosclerosis, coronary heart disease and arterial hypertension.Conclusion:Increased IL13 levels could be detected in patients with SSc, especially in patients with the phenotype of an obliterative vasculopathy. This indicates preliminary evidence for the use of IL13 blockers as a new therapeutic approach in systemic sclerosis.References:[1]Furue M, Mitoma C, Mitoma H, Tsuji G, Chiba T, Nakahara T, Uchi H, Kadono T. Pathogenesis of systemic sclerosis-current concept and emerging treatments. Immunol Res. 2017 Aug;65(4):790-797. doi: 10.1007/s12026-017-8926-y.[2]Tyndall AJ, Bannert B, Vonk M, et alCauses and risk factors for death in systemic sclerosis: a study from the EULAR Scleroderma Trials and Research (EUSTAR) database Annals of the Rheumatic Diseases 2010;69:1809-1815. doi: 10.1136/ard.2009.114264Disclosure of Interests:None declared

Download Full-text

Circulating CD4+T/methylation signatures of network-oriented SOCS3, ITGAL, NFIC, NCOR2, PGK1 genes associate with hemodynamics in pulmonary arterial hypertension patients

European Heart Journal ◽

10.1093/eurheartj/ehab724.1952 ◽

2021 ◽

Vol 42 (Supplement_1) ◽

Author(s):

G Benincasa ◽

B A Maron ◽

O Affinito ◽

M D'Alto ◽

M Franzese ◽

...

Keyword(s):

T Cells ◽

Pulmonary Arterial Hypertension ◽

Cardiac Index ◽

Arterial Hypertension ◽

Cd4 T Cells ◽

Right Atrial ◽

Potential Candidate ◽

Mrna Levels ◽

Non Invasive ◽

Pulmonary Arterial

Abstract Background CD4+ T cells are associated with pulmonary arterial hypertension (PAH) pathogenesis but mechanistic insights are limited. Purpose To identify differential CD4+ T methylation signatures in healthy controls vs PAH and evaluate a putative association with the cardiopulmonary hemodynamic profile of affected patients. Methods We used RRBS platform to profile CD4+ T DNA methylome in the CLEOPAHTRA clinical trial. Results Differentially methylated CpG sites (N=631) annotated to N=408 genes (DMGs). Most of them (65%) were hypermethylated and localized in distal intergenic (36%) and promoter regions (31%). Promoter-related network analysis established the PAH subnetwork highlighting 5 hub DMGs (SOCS3, GNAS, ITGAL, NCOR2, NFIC) and 5 non-hub DMGs (NR4A2, GRM2, PGK1, STMN1, LIMS2) as potential candidate genes (Figure 1). The Infinium Human MethylationEPIC BeadChip on CD4+ T cells from an independent study population confirmed the global RRBS-methylation trends. Both in idiopathic and Associated-PAH, each of these 10 network-oriented DMGs was strongly correlated with at least one hemodynamic parameter such as right atrial pressure (RAP), cardiac index (CI), mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance (PVR), and pulmonary capillary wedge pressure (PCWP) (Figure 2). In addition, mRNA levels of the ITGAL, NFIC, NCOR2, PGK1 genes and the IL-6-STAT3-SOCS3 signaling axis were significantly upregulated in PBMCs from patients with PAH vs controls suggesting putative drug targets. Furthermore, both SOCS3 methylation and mRNA levels were positively correlated with cardiac index (CI) in idiopathic PAH whereas both PGK1 methylation and mRNA levels were positively correlated with RAP and inversely with CI in Associated PAH suggesting putative non-invasive biomarkers. Conclusions This hypothesis-generating study shows for the first time that circulating CD4+ T methylation signatures, inclusive of SOCS3, ITGAL, NFIC, NCOR2, and PGK1 genes may yield insight into pro-inflammatory mechanisms that exacerbate vascular remodeling in PAH and suggest non-invasive biomarkers to optimize patient phenotyping and, possibly, prognostication in PAH. FUNDunding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): PRIN2017F8ZB89 from Italian Ministry of University and Research (MIUR) (PI Prof Napoli) and Ricerca Corrente (RC) 2019 from Italian Ministry of Health (PI Prof. Napoli). Figure 1 Figure 2

Download Full-text

Abstract 13535: The Synergistic Effects of Incretin-related Drugs for the Treatment of Pulmonary Arterial Hypertension

Circulation ◽

10.1161/circ.130.suppl_2.13535 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Susumu Hosokawa ◽

Go Haraguchi ◽

Yasuhiro Maejima ◽

Shozaburo Doi ◽

Mitsuaki Isobe

Keyword(s):

T Cells ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Synergistic Effects ◽

Cell Activity ◽

Mrna Levels ◽

Sprague Dawley ◽

Dipeptidyl Peptidase 4 ◽

Caveolin 1 ◽

Pulmonary Arterial

Introduction: A growing body of evidence suggests that inflammation plays a crucial role in the development of pulmonary arterial hypertension (PAH). Dipeptidyl peptidase-4 (DPP-4; also known as CD26), a protease which degrades incretin hormones such as glucagon-like peptide-1 (GLP-1), modulates inflammatory processes by regulating activity of T cells through co-stimulatory pathway. Hypothesis: Incretin-related drugs, including both DPP-4 inhibitors and GLP-1 receptor agonists, suppress the progression of PAH by attenuating inflammatory response of PA. Methods: Sprague Dawley rats were injected monocrotaline to induce PAH (N=80). After 14 days from PAH induction, these rats were treated with alogliptin, a DPP-4 inhibitor (M+A, N=20), liraglutide, a GLP-1 receptor agonist (M+L, N=20), both of these drugs (M+A+L, N=20), or vehicle (M, N=20). Results: A significant increase of survival was observed on days 30 after PAH induction both in the M+A and M+L compared to the M (M+A: 45%* vs. M+L: 60%* vs. M: 5%, * p <0.05). Both alogliptin and liraglutide markedly improved right ventricular pressure (M+A: 33±4.1mmHg* vs. M+L: 26±1.9mmHg* vs. M: 85.9±1.2mmHg, * p <0.05). mRNA levels of both CD28 and CD86, co-stimulators of T cells, significantly decreased and the level of caveolin-1 markedly increased in lung tissues of the M+A compared to those in the M. mRNA levels of both Tissue Factor (TF) and PAI-1 significantly decreased in lung tissues of the M+L than those in the M. Consistently, survival of rats in the M+A+L was the highest (65%) among all of the groups of PAH rats. Coimmunoprecipitation assays revealed that CD26 in T cells physically interacted with caveolin-1 in rat pulmonary vascular smooth muscle cells (rPASMCs). Immunoblot analyses showed that alogliptin suppressed caveolin-1 phosphorylation in rPASMCs. Furthermore, reporter gene assays demonstrated that alogliptin significantly inhibited the transcriptional activity of NF-κB. Conclusions: These results suggest that DPP-4 inhibition and stimulation of GLP-1 receptors synergistically mediate salutary effects on monocrotaline-induced PAH by modulating T cell activity and TF-associated signaling pathway. Thus, incretin-related drugs have a potential as a novel therapeutic tool for PAH.

Download Full-text