Interleukin 13– and Interleukin 17A–Induced Pulmonary Hypertension Phenotype Due to Inhalation of Antigen and Fine Particles from Air Pollution

Park, Sung Hyun; Chen, Wen‐Chi; Esmaeil, Nafiseh; Lucas, Benjamin; Marsh, Leigh M.; Reibman, Joan; Grünig, Gabriele

doi:10.1086/678511

Cited by 31 publications

(64 citation statements)

References 80 publications

(181 reference statements)

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“…All three markers were significantly increased by exposure to the antigen and PM 2.5 as expected [16] in wild type mice and also in B cell KO mice (Fig 5C–5E). Compared with wild type animals, B cell KO mice exposed to antigen and PM 2.5 had increased RELMβ expression in the lungs, that reached statistical significance in the group of B cell KO mice injected with antigen specific IgG1 (Fig 5D).…”

Section: Resultssupporting

confidence: 84%

The Effects of Antigen-Specific IgG1 Antibody for the Pulmonary-Hypertension-Phenotype and B Cells for Inflammation in Mice Exposed to Antigen and Fine Particles from Air Pollution

et al. 2015

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Air pollution is known to exacerbate chronic inflammatory conditions of the lungs including pulmonary hypertension, cardiovascular diseases and autoimmune diseases. Directly pathogenic antibodies bind pro-inflammatory cell receptors and cause or exacerbate inflammation. In contrast, anti-inflammatory antibody isotypes (e.g. mouse immunoglobulin G1, IgG1) bind inhibitory cell receptors and can inhibit inflammation. Our previous studies showed that co-exposure to antigen and urban ambient particulate matter (PM2.5) induced severe pulmonary arterial thickening and increased right ventricular systolic pressures in mice via T-cell produced cytokines, Interleukin (IL)-13 and IL-17A. The aim of the current study was to understand how B cell and antibody responses integrate into this T cell cytokine network for the pulmonary hypertension phenotype. Special focus was on antigen-specific IgG1 that is the predominant antibody in the experimental response to antigen and urban ambient PM2.5. Wild type and B cell-deficient mice were primed with antigen and then challenged with antigen and urban particulate matter and injected with antibodies as appropriate. Our data surprisingly showed that B cells were necessary for the development of increased right ventricular pressures and molecular changes in the right heart in response to sensitization and intranasal challenge with antigen and PM2.5. Further, our studies showed that both, the increase in right ventricular systolic pressure and right ventricular molecular changes were restored by reconstituting the B cell KO mice with antigen specific IgG1. In addition, our studies identified a critical, non-redundant role of B cells for the IL-17A-directed inflammation in response to exposure with antigen and PM2.5, which was not corrected with antigen-specific IgG1. In contrast, IL-13-directed inflammatory markers, as well as severe pulmonary arterial remodeling induced by challenge with antigen and PM2.5 were similar in B cell-deficient and wild type mice. Our studies have identified B cells and antigen specific IgG1 as potential therapeutic targets for pulmonary hypertension associated with immune dysfunction and environmental exposures.

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Section: Resultssupporting

confidence: 84%

The Effects of Antigen-Specific IgG1 Antibody for the Pulmonary-Hypertension-Phenotype and B Cells for Inflammation in Mice Exposed to Antigen and Fine Particles from Air Pollution

et al. 2015

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“…15 However, blocking either the T H 2 or T H 17 pathway with anti–IL-13 or anti–IL-17 alone has been shown not to be sufficient for the treatment of allergic asthma because such treatment resulted in upregulation of the other pathway. 18 Similarly, a recent study by Park et al 34 demonstrated that coadministration of anti–IL-17 and anti–IL-13 reduced both T H 2 and T H 17 cell responses in the lung in an animal model of antigen-induced pulmonary arterial remodeling, whereas anti–IL-17 or anti–IL-13 alone resulted in upregulation of T H 2 or T H 17 downstream effector genes, respectively. Collectively, these reports imply that simultaneous targeting of both T H 2 and T H 17 cell responses would be a promising strategy for the treatment of allergic asthma, whereas targeting either pathway alone might be ineffective because of activation of the other pathway.…”

Section: Discussionmentioning

confidence: 88%

Concomitant suppression of TH2 and TH17 cell responses in allergic asthma by targeting retinoic acid receptor–related orphan receptor γt

Lim

Choi

et al. 2018

Journal of Allergy and Clinical Immunology

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Background Allergic asthma is a heterogeneous chronic inflammatory disease of the airways with a massive infiltration of eosinophils or neutrophils mediated by allergen-specific TH2 and TH17 cells, respectively. Therefore successful treatment of allergic asthma will require suppression of both TH2 and TH17 cells. Objective We sought to investigate the role of the TH17 cell pathway in regulating TH2 cell responses in allergic asthma. Methods Allergic asthma was induced by intranasal challenge with proteinase allergens in C57BL/6, Il17a−/−Il17f−/−, and retinoic acid receptor–related orphan receptor γt (RORγt)gfp/gfp mice. A pharmacologic RORγt inhibitor was used to evaluate its preventive and therapeutic effects in allergic asthma. Characteristics of allergic airway inflammation were analyzed by using flow cytometry, histology, quantitative real-time PCR, and ELISA. Mixed bone marrow chimeric mice, fate mapping analysis, short hairpin RNA transduction, and in vitro T-cell differentiation were used for mechanistic studies. Results Mice deficient in IL-17A and IL-17F, as well as RORγt, exhibited a significant reduction not only in TH17 cell responses but also in TH2 cell responses in an animal model of allergic asthma. Similarly, mice treated with an RORγt inhibitor had significantly diminished TH17 and TH2 cell responses, leading to reduced neutrophil and eosinophil numbers in the airway. RORγt-deficient T cells were intrinsically defective in differentiating into TH2 cells and expressed increased levels of B-cell lymphoma 6 (Bcl6). Bcl6 knockdown resulted in a remarkable restoration of TH2 cell differentiation in RORγt- deficient T cells. Blockade of RORγt also significantly hampered the differentiation of human TH2 and TH17 cells from naive CD4+ T cells. Conclusion RORγt in T cells is required for optimal TH2 cell differentiation by suppressing Bcl6 expression; this finding suggests that targeting RORγt might be a promising approach for the treatment of allergic asthma by concomitantly suppressing TH17 and TH2 cell responses in the airway.

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“…Die Blockierung von IL-13/IL-4 vermindert diese Läsion hoch signifikant [24,27]. IL-13 und IL-4-assoziierte Biomarker sind im Blut von einer Subgruppe von Patienten gefunden worden, die an einer systemischen Sklerose erkrankt sind [23,28].…”

Section: T-zell-assoziierte Zytokine Und Ph (Qabb 1a)unclassified

“…TGFβ kann von fast allen Zellen produziert werden und kann von vielen Zelltypen aktiviert werden. Genetische Modelle weisen ebenfalls auf die Rolle einer gestörten Th17/Treg-Balance und des veränderten Zusammenspiels der Th17-und Th2-Antwort [27]. Mäuse, die ein defektes BMPR2-Transgen exprimieren, haben eine veränderte Immunantwort [34,36,37] mit einem gestörten Gleichgewicht von TGFβ-Signalen [38].…”

Section: T-zell-assoziierte Zytokine Und Ph (Qabb 1a)unclassified

See 1 more Smart Citation

Die pulmonal arterielle Hypertonie – auch eine Erkrankung des Immunsystems?

Riemekasten

Kuebler

Schermuly

et al. 2014

Dtsch med Wochenschr

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Institutsangaben am Ende der Arbeit Die zelluläre Immunantwort bei PAH ▼ Die Immunantwort ist ein integraler Bestandteil der molekularen Pathogenese der pulmonalen Hypertonie (PH), was neuere Untersuchungen zeigen [1, 2]. Dies konnte nicht nur für die mit Autoimmunerkrankungen assoziierte PH gezeigt werden [1-3], sondern auch für die PH bei parasitären Infektionen (z. B. mit Schistosomen [4]), COPD [5] oder bei Umweltexposition [6]. Eine erhöhte Immunantwort konnte auch bei der hereditären oder idiopathischen PAH [7, 8], der Hypoxie-assoziierten PH [9] sowie der PH infolge von Linksherzinsuffizienz [10] nachgewiesen werden. Schon lange ist bekannt, dass in der Lunge von PH-Erkrankten Makrophagen und Mastzellen[11] in erhöhter Anzahl vorkommen und dass diese Zellen einen aktivierten Phänotyp zeigen. Neue Tiermodellstudien haben diese Zellen weiter charakterisiert und kausale Beziehungen z. B. zwischen Mastzellen [10], Makrophagen [12] und der PH gezeigt. In Hypoxie-induzierter PH wurden kürzlich Lungenmakrophagen mit einem spezifischen Transkriptions-Profil entdeckt, die über Interleukin (IL)-6 kontrolliert werden [9]. Ein weiterer Hinweis auf ein aktiviertes Immunsystem in der Lunge von PH-Erkrankten ist der Befund von Lymphknoten-artigen Gebilden in der Lunge [13] mit aktivierten Dendritischen Zellen (DZ) [14]. Lymphozyten sind ein Sammelbegriff für mehrere Zellarten. Zur adaptiven Immunantwort gehören die T-und B-Zellen, zur angeborenen (innaten) Immunantwort die NK (natural killer) und ILC (Innate Lymphoid Cells). Für die Pathogenese der PH ist es wichtig zu bedenken, dass auch NK-Zellen, ILC, und Mastzellen die Fähigkeit haben, bestimmte Botenstoffe (Zytokine) zu produzieren, die sonst hauptsächlich von T Zellen gebildet und ausgeschüttet werden.

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Interleukin 13– and Interleukin 17A–Induced Pulmonary Hypertension Phenotype Due to Inhalation of Antigen and Fine Particles from Air Pollution

Cited by 31 publications

References 80 publications

The Effects of Antigen-Specific IgG1 Antibody for the Pulmonary-Hypertension-Phenotype and B Cells for Inflammation in Mice Exposed to Antigen and Fine Particles from Air Pollution

The Effects of Antigen-Specific IgG1 Antibody for the Pulmonary-Hypertension-Phenotype and B Cells for Inflammation in Mice Exposed to Antigen and Fine Particles from Air Pollution

Concomitant suppression of TH2 and TH17 cell responses in allergic asthma by targeting retinoic acid receptor–related orphan receptor γt

Die pulmonal arterielle Hypertonie – auch eine Erkrankung des Immunsystems?

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