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Enhanced Bruton’s tyrosine kinase in B-cells and autoreactive IgA in patients with idiopathic pulmonary fibrosis

RATIONALE: Idiopathic Pulmonary Fibrosis (IPF) is thought to be triggered by repeated alveolar epithelial cell injury. Current evidence suggests that aberrant immune activation may contribute. However, the role of B-cell activation remains unclear. We determined the phenotype and activation status o...

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Autores principales: Heukels, Peter, van Hulst, Jennifer A. C., van Nimwegen, Menno, Boorsma, Carian E., Melgert, Barbro N., von der Thusen, Jan H., van den Blink, Bernt, Hoek, Rogier A. S., Miedema, Jelle R., Neys, Stefan F. H., Corneth, Odilia B. J., Hendriks, Rudi W., Wijsenbeek, Marlies S., Kool, Mirjam
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814043/
https://www.ncbi.nlm.nih.gov/pubmed/31651327
http://dx.doi.org/10.1186/s12931-019-1195-7
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author Heukels, Peter
van Hulst, Jennifer A. C.
van Nimwegen, Menno
Boorsma, Carian E.
Melgert, Barbro N.
von der Thusen, Jan H.
van den Blink, Bernt
Hoek, Rogier A. S.
Miedema, Jelle R.
Neys, Stefan F. H.
Corneth, Odilia B. J.
Hendriks, Rudi W.
Wijsenbeek, Marlies S.
Kool, Mirjam
author_facet Heukels, Peter
van Hulst, Jennifer A. C.
van Nimwegen, Menno
Boorsma, Carian E.
Melgert, Barbro N.
von der Thusen, Jan H.
van den Blink, Bernt
Hoek, Rogier A. S.
Miedema, Jelle R.
Neys, Stefan F. H.
Corneth, Odilia B. J.
Hendriks, Rudi W.
Wijsenbeek, Marlies S.
Kool, Mirjam
author_sort Heukels, Peter
collection PubMed
description RATIONALE: Idiopathic Pulmonary Fibrosis (IPF) is thought to be triggered by repeated alveolar epithelial cell injury. Current evidence suggests that aberrant immune activation may contribute. However, the role of B-cell activation remains unclear. We determined the phenotype and activation status of B-cell subsets and evaluated the contribution of activated B-cells to the development of lung fibrosis both in humans and in mice. METHODS: B-cells in blood, mediastinal lymph node, and lung single-cell suspensions of IPF patients and healthy controls (HC) were characterized using 14-color flow cytometry. Mice were exposed to bleomycin to provoke pulmonary fibrosis. RESULTS: More IgA(+) memory B-cells and plasmablasts were found in blood (n = 27) and lungs (n = 11) of IPF patients compared to HC (n = 21) and control lungs (n = 9). IPF patients had higher levels of autoreactive IgA in plasma, which correlated with an enhanced decline of forced vital capacity (p = 0.002, r = − 0.50). Bruton’s tyrosine kinase expression was higher in circulating IPF B-cells compared to HC, indicating enhanced B-cell activation. Bleomycin-exposed mice had increased pulmonary IgA(+) germinal center and plasma cell proportions compared to control mice. The degree of lung fibrosis correlated with pulmonary germinal center B-cell proportions (p = 0.010, r = 0.88). CONCLUSION: Our study demonstrates that IPF patients have more circulating activated B-cells and autoreactive IgA, which correlate with disease progression. These B-cell alterations were also observed in the widely used mouse model of experimental pulmonary fibrosis. Autoreactive IgA could be useful as a biomarker for disease progression in IPF.
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spelling pubmed-68140432019-10-31 Enhanced Bruton’s tyrosine kinase in B-cells and autoreactive IgA in patients with idiopathic pulmonary fibrosis Heukels, Peter van Hulst, Jennifer A. C. van Nimwegen, Menno Boorsma, Carian E. Melgert, Barbro N. von der Thusen, Jan H. van den Blink, Bernt Hoek, Rogier A. S. Miedema, Jelle R. Neys, Stefan F. H. Corneth, Odilia B. J. Hendriks, Rudi W. Wijsenbeek, Marlies S. Kool, Mirjam Respir Res Research RATIONALE: Idiopathic Pulmonary Fibrosis (IPF) is thought to be triggered by repeated alveolar epithelial cell injury. Current evidence suggests that aberrant immune activation may contribute. However, the role of B-cell activation remains unclear. We determined the phenotype and activation status of B-cell subsets and evaluated the contribution of activated B-cells to the development of lung fibrosis both in humans and in mice. METHODS: B-cells in blood, mediastinal lymph node, and lung single-cell suspensions of IPF patients and healthy controls (HC) were characterized using 14-color flow cytometry. Mice were exposed to bleomycin to provoke pulmonary fibrosis. RESULTS: More IgA(+) memory B-cells and plasmablasts were found in blood (n = 27) and lungs (n = 11) of IPF patients compared to HC (n = 21) and control lungs (n = 9). IPF patients had higher levels of autoreactive IgA in plasma, which correlated with an enhanced decline of forced vital capacity (p = 0.002, r = − 0.50). Bruton’s tyrosine kinase expression was higher in circulating IPF B-cells compared to HC, indicating enhanced B-cell activation. Bleomycin-exposed mice had increased pulmonary IgA(+) germinal center and plasma cell proportions compared to control mice. The degree of lung fibrosis correlated with pulmonary germinal center B-cell proportions (p = 0.010, r = 0.88). CONCLUSION: Our study demonstrates that IPF patients have more circulating activated B-cells and autoreactive IgA, which correlate with disease progression. These B-cell alterations were also observed in the widely used mouse model of experimental pulmonary fibrosis. Autoreactive IgA could be useful as a biomarker for disease progression in IPF. BioMed Central 2019-10-24 2019 /pmc/articles/PMC6814043/ /pubmed/31651327 http://dx.doi.org/10.1186/s12931-019-1195-7 Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Heukels, Peter
van Hulst, Jennifer A. C.
van Nimwegen, Menno
Boorsma, Carian E.
Melgert, Barbro N.
von der Thusen, Jan H.
van den Blink, Bernt
Hoek, Rogier A. S.
Miedema, Jelle R.
Neys, Stefan F. H.
Corneth, Odilia B. J.
Hendriks, Rudi W.
Wijsenbeek, Marlies S.
Kool, Mirjam
Enhanced Bruton’s tyrosine kinase in B-cells and autoreactive IgA in patients with idiopathic pulmonary fibrosis
title Enhanced Bruton’s tyrosine kinase in B-cells and autoreactive IgA in patients with idiopathic pulmonary fibrosis
title_full Enhanced Bruton’s tyrosine kinase in B-cells and autoreactive IgA in patients with idiopathic pulmonary fibrosis
title_fullStr Enhanced Bruton’s tyrosine kinase in B-cells and autoreactive IgA in patients with idiopathic pulmonary fibrosis
title_full_unstemmed Enhanced Bruton’s tyrosine kinase in B-cells and autoreactive IgA in patients with idiopathic pulmonary fibrosis
title_short Enhanced Bruton’s tyrosine kinase in B-cells and autoreactive IgA in patients with idiopathic pulmonary fibrosis
title_sort enhanced bruton’s tyrosine kinase in b-cells and autoreactive iga in patients with idiopathic pulmonary fibrosis
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814043/
https://www.ncbi.nlm.nih.gov/pubmed/31651327
http://dx.doi.org/10.1186/s12931-019-1195-7
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