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Loss of immune homeostasis in patients with idiopathic pulmonary arterial hypertension
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...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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BMJ Publishing Group
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8606455/ https://www.ncbi.nlm.nih.gov/pubmed/33963088 http://dx.doi.org/10.1136/thoraxjnl-2020-215460 |
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author | Heukels, Peter Corneth, Odilia B J van Uden, Denise van Hulst, Jennifer A C van den Toorn, Leon M van den Bosch, Annemien E Wijsenbeek, Marlies S Boomars, Karin A Kool, Mirjam Hendriks, Rudi W |
author_facet | Heukels, Peter Corneth, Odilia B J van Uden, Denise van Hulst, Jennifer A C van den Toorn, Leon M van den Bosch, Annemien E Wijsenbeek, Marlies S Boomars, Karin A Kool, Mirjam Hendriks, Rudi W |
author_sort | Heukels, Peter |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8606455 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | BMJ Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-86064552021-12-03 Loss of immune homeostasis in patients with idiopathic pulmonary arterial hypertension Heukels, Peter Corneth, Odilia B J van Uden, Denise van Hulst, Jennifer A C van den Toorn, Leon M van den Bosch, Annemien E Wijsenbeek, Marlies S Boomars, Karin A Kool, Mirjam Hendriks, Rudi W Thorax Pulmonary Vasculature 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. BMJ Publishing Group 2021-12 2021-05-07 /pmc/articles/PMC8606455/ /pubmed/33963088 http://dx.doi.org/10.1136/thoraxjnl-2020-215460 Text en © Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ. https://creativecommons.org/licenses/by/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Pulmonary Vasculature Heukels, Peter Corneth, Odilia B J van Uden, Denise van Hulst, Jennifer A C van den Toorn, Leon M van den Bosch, Annemien E Wijsenbeek, Marlies S Boomars, Karin A Kool, Mirjam Hendriks, Rudi W Loss of immune homeostasis in patients with idiopathic pulmonary arterial hypertension |
title | Loss of immune homeostasis in patients with idiopathic pulmonary arterial hypertension |
title_full | Loss of immune homeostasis in patients with idiopathic pulmonary arterial hypertension |
title_fullStr | Loss of immune homeostasis in patients with idiopathic pulmonary arterial hypertension |
title_full_unstemmed | Loss of immune homeostasis in patients with idiopathic pulmonary arterial hypertension |
title_short | Loss of immune homeostasis in patients with idiopathic pulmonary arterial hypertension |
title_sort | loss of immune homeostasis in patients with idiopathic pulmonary arterial hypertension |
topic | Pulmonary Vasculature |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8606455/ https://www.ncbi.nlm.nih.gov/pubmed/33963088 http://dx.doi.org/10.1136/thoraxjnl-2020-215460 |
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