Loss of immune homeostasis in patients with idiopathic pulmonary arterial hypertension.
Peter Heukels,Odilia B. J. Corneth,Denise van Uden,Jennifer A C van Hulst,Leon M. van den Toorn,Annemien E. van den Bosch,Marlies S. Wijsenbeek,K. A. Boomars,Mirjam Kool,Rudi W. Hendriks +9 more
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In this paper, the authors showed that pulmonary injury in combination with enhanced B-cell activation is sufficient to induce pulmonary arterial hypertension (IPAH) symptoms in mice, and that immune homeostasis in patients with IPAH is compromised, as evidenced by increased BCR signalling and cTfh17 polarisation.Abstract:
Introduction Autoreactivity against pulmonary vascular structures is thought to be involved in idiopathic pulmonary arterial hypertension (IPAH), but the underlying mechanisms remain poorly understood. We hypothesised that aberrant B-cell activation contributes to IPAH aetiology. Methods Mice with enhanced B-cell activation due to B-cell-specific overexpression of the B-cell receptor (BCR) signalling molecule Bruton’s tyrosine kinase (BTK) were subjected to lung injury and examined for several pulmonary hypertension (PH) indices. Peripheral blood lymphocytes from patients with IPAH (n=13), connective tissue disease-associated PAH (CTD-PAH, n=9), congenital heart disease PAH (n=7), interstitial lung disease associated PH (n=17) and healthy controls (n=19) were characterised by 14-colour flow cytometry. Results Following pulmonary injury, BTK-overexpressing mice showed prolonged activation of B cells and CXCR5+ follicular T-helper (Tfh) cells, as well as features of PH development. Patients with CTD-PAH and CHD-PAH displayed reduced proportions of circulating non-switched-memory B cells (p=0.03, p=0.02, respectively). Interestingly, we observed increased BTK protein expression in naive (p=0.007) and memory B-cell subsets of patients with IPAH and CTD-PAH. BTK was particularly high in patients with IPAH with circulating autoantibodies (p=0.045). IPAH patients had low frequencies of circulating CXCR5+ Tfh cells (p=0.005). Hereby, the increased BTK protein expression in B cells was associated with high proportions of Tfh17 (p=0.018) and Tfh17.1 (p=0.007) cells within the circulating Tfh population. Conclusions Our study shows that pulmonary injury in combination with enhanced B-cell activation is sufficient to induce PH symptoms in mice. In parallel, immune homeostasis in patients with IPAH is compromised, as evidenced by increased BCR signalling and cTfh17 polarisation, indicating that adaptive immune activation contributes to IPAH disease induction or progression.read more
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Iron Metabolism and Idiopathic Pulmonary Arterial Hypertension: New Insights from Bioinformatic Analysis
Hua-Xi Zou,Bai-Quan Qiu,Songqing Lai,Xue-liang Zhou,Cheng-Wu Gong,Lijun Wang,Ming-Ming Yuan,An-Di He,Jichun Liu,Huang Huang +9 more
TL;DR: Zhang et al. as discussed by the authors explored the regulatory mechanisms of iron metabolism in IPH by bioinformatic analysis and identified 7 key genes (BCL2, GCLM, MSMO1, SLC7A11, SRXN1, TSPAN5, and TXNRD1).
Journal ArticleDOI
Autoimmunity in Pulmonary Arterial Hypertension: Evidence for Local Immunoglobulin Production.
Ting Shu,Yanjiang Xing,Jing Wang +2 more
TL;DR: In this article, the authors discuss specific cell types involved in the lung in situ immune response, the potential auto-antigens, and the contribution of local immunoglobulin production in PAH development, providing a theoretical basis for drug development and precise treatment in patients with PAH.
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Prevalence of Micronutrient Deficiencies and Relationship with Clinical and Patient-Related Outcomes in Pulmonary Hypertension Types I and IV
Paulien Vinke,Thomas Koudstaal,Femke Muskens,Annemien E. van den Bosch,Michiel G.J. Balvers,Mieke Poland,Renger F. Witkamp,Klaske van Norren,K. A. Boomars +8 more
TL;DR: In this article, the prevalence of micronutrient deficiencies in pulmonary arterial hypertension (PAH) and chronic thrombo-embolic pulmonary hypertension (CTEPH) patients was determined.
Journal ArticleDOI
Immune Cells in Pulmonary Arterial Hypertension
TL;DR: In this paper , a review mainly focusses on the roles of different immune cells in pulmonary arterial hypertension (PAH) and discusses the underlying mechanisms, including dysregulated immunity and inflammation.
Journal ArticleDOI
Peripheral Blood T Cells of Patients with IPAH Have a Reduced Cytokine-Producing Capacity
Denise van Uden,Thomas Koudstaal,Jennifer A C van Hulst,M. Vink,Menno van Nimwegen,Leon M. van den Toorn,P. P. Chandoesing,Annemien E. van den Bosch,Mirjam Kool,Rudi W. Hendriks,Karin A. Boomars +10 more
TL;DR: Flow cytometry and principal component analysis point to involvement of adaptive immune responses in IPAH, which may have an implication for the development of therapeutic interventions.
References
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2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT).
Nazzareno Galiè,Marc Humbert,Jean-Luc Vachiery,Simon Gibbs,Irene Lang,Adam Torbicki,Gérald Simonneau,Andrew Peacock,Anton Vonk Noordegraaf,Maurice Beghetti,Ardeschir Ghofrani,Miguel Angel Gomez Sanchez,Georg Hansmann,Walter Klepetko,Patrizio Lancellotti,Marco Matucci,Theresa McDonagh,Luc Pierard,Pedro T. Trindade,Maurizio Zompatori,Marius M. Hoeper +20 more
TL;DR: In this paper, the authors defined the following terms: ALAT, alanine aminotransferase, ASAT, aspartate AMINOTE, and APAH, associated pulmonary arterial hypertension.
Journal ArticleDOI
Haemodynamic definitions and updated clinical classification of pulmonary hypertension.
Gérald Simonneau,Gérald Simonneau,David Montani,David Montani,David S. Celermajer,Christopher P. Denton,Michael A. Gatzoulis,Michael J. Krowka,Paul G. Williams,Rogério Souza +9 more
TL;DR: The 6th WSPH Task Force proposed to include pulmonary vascular resistance ≥3 Wood Units in the definition of all forms of pre-capillary PH associated with mPAP >20 mmHg, and included in group 1 of a subgroup “pulmonary arterial hypertension (PAH) long-term responders to calcium channel blockers”.
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Human Blood CXCR5+CD4+ T Cells Are Counterparts of T Follicular Cells and Contain Specific Subsets that Differentially Support Antibody Secretion
Rimpei Morita,Nathalie Schmitt,Salah Eddine Bentebibel,Rajaram Ranganathan,Laure Bourdery,Gerard Zurawski,Gerard Zurawski,Emile Foucat,Melissa Dullaers,Sangkon Oh,Sangkon Oh,Natalie Sabzghabaei,Elizabeth M. Lavecchio,Marilynn Punaro,Marilynn Punaro,Virginia Pascual,Virginia Pascual,Jacques Banchereau,Jacques Banchereau,Jacques Banchereau,Hideki Ueno,Hideki Ueno +21 more
TL;DR: In this article, human blood CXCR5(+)CD4(+) T cells share functional properties with T follicular helper (Tfh) cells and appear to represent their circulating memory compartment.
Journal ArticleDOI
Targeting IL-17 and TH17 cells in chronic inflammation.
Pierre Miossec,Jay K. Kolls +1 more
TL;DR: This Review focuses on the current knowledge of the IL-17–TH17 cell pathway to better understand the positive as well as potential negative consequences of targeting them.
Journal ArticleDOI
Follicular Helper T Cells
TL;DR: The realization that follicular T cells are heterogeneous, comprising helper and regulatory subsets, has raised questions regarding a possible division of labor in germinal center B cell selection and elimination.