title: The mast cell-B cell axis in lung vascular remodeling and pulmonary hypertension.
abstract: Over past years, a critical role for the immune system and, in particular, for mast cells in the pathogenesis of pulmonary hypertension (PH) has emerged. However, the way in which mast cells promote PH is still poorly understood. Here, we investigated the mechanisms by which mast cells may contribute to PH, specifically focusing on the interaction between the innate and adaptive immune response and the role of B cells and autoimmunity. Experiments were performed in Sprague-Dawley rats and B cell-deficientJH-KOrats in the monocrotaline, Sugen/hypoxia, and the aortic banding model of PH. Hemodynamics, cell infiltration, IL-6 expression, and vascular remodeling were analyzed. Gene array analyses revealed constituents of immunoglobulins as most prominently regulated mast cell-dependent genes in the lung in experimental PH. IL-6 was shown to link mast cells to B cells, as1) IL-6 was upregulated and colocalized with mast cells and was reduced by mast-cell stabilizers and2) IL-6 or mast cell blockade reduced B cells in lungs of monocrotaline-treated rats. A functional role for B cells in PH was demonstrated in that either blocking B cells by an anti-CD20 antibody or B-cell deficiency inJH-KOrats attenuated right ventricular systolic pressure and vascular remodeling in experimental PH. We here identify a mast cell-B cell axis driven by IL-6 as a critical immune pathway in the pathophysiology of PH. Our results provide novel insights into the role of the immune system in PH, which may be therapeutically exploited by targeted immunotherapy.
authors.affiliation: Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.|Institute for Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany.
authors.forename: Siegfried
authors.initials: S
authors.lastname: Breitling
authors.affiliation: Institute of Physiology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Zhang
authors.initials: Z
authors.lastname: Hui
authors.affiliation: Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Diana
authors.initials: D
authors.lastname: Zabini
authors.affiliation: Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Yijie
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Institute of Physiology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Hoffmann
authors.affiliation: Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Neil M
authors.initials: NM
authors.lastname: Goldenberg
authors.affiliation: Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.|Institute of Physiology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Arata
authors.initials: A
authors.lastname: Tabuchi
authors.affiliation: Open Monoclonal Technology, Incorporated, Palo Alto, California.
authors.forename: Roland
authors.initials: R
authors.lastname: Buelow
authors.affiliation: Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Claudia
authors.initials: C
authors.lastname: Dos Santos
authors.affiliation: Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada; wolfgang.kuebler@charite.de.|Institute of Physiology, Charité-Universitätsmedizin Berlin, Berlin, Germany.|Departments of Surgery and Physiology, University of Toronto, Toronto, Ontario, Canada; and.|German Heart Institute Berlin, Berlin, Germany.
authors.forename: Wolfgang M
authors.initials: WM
authors.lastname: Kuebler
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000378:metabolism; D001402:B-Lymphocytes / Q000378:metabolism*; D001794:Blood Pressure; D006352:Heart Ventricles / Q000473:pathology / Q000503:physiopathology; D006976:Hypertension, Pulmonary / Q000503:physiopathology*; D015850:Interleukin-6 / Q000378:metabolism; D008168:Lung / Q000098:blood supply* / Q000503:physiopathology*; D008297:Male; D008407:Mast Cells / Q000378:metabolism*; D008954:Models, Biological; D020411:Oligonucleotide Array Sequence Analysis; D017207:Rats, Sprague-Dawley; D013599:Systole; D013997:Time Factors; D066253:Vascular Remodeling
chemical_list: D001323:Autoantibodies; D015850:Interleukin-6
keywords: B cells; inflammation; mast cells; pulmonary hypertension