Dtsch Med Wochenschr 2014; 139(S 04): S116-S120
DOI: 10.1055/s-0034-1387452
Übersicht | Review article
Pneumologie
© Georg Thieme Verlag KG Stuttgart · New York

Die pulmonal arterielle Hypertonie – auch eine Erkrankung des Immunsystems?

Pulmonary arterial hypertension – a disease of the immune system?
G. Riemekasten
1   Rheumatologie, Institut für Medizin, Charité – Universitätsmedizin Berlin, Deutschland
,
W. M. Kuebler
2   Institut für Physiologie, Charité – Universitätsmedizin Berlin in Kooperation mit dem Deutschen Herzzentrum Berlin, Deutschland
,
R. Schermuly
3   Pulmonale Pharmakotherapie, Zentrum für Innere Medizin und Deutsches Zentrum für Lungenforschung (DZL), Justus-Liebig   Universität Giessen
,
H.-J. Seyfarth
4   Abteilung Pneumologie (Department für Innere Medizin, Neurologie und Dermatologie), Universitätsklinikum Leipzig, Deutschland
,
J. Behr
5   Klinik für Innere Medizin V, Klinikum Großhadern, München, Deutschland
,
C. Grohe
6   Evangelische Lungenklinik Berlin, Berlin, Deutschland
,
M. M. Hoeper
7   Klinik für Pneumologie und Deutsches Zentrum für Lungenforschung (DZL), Medizinische Hochschule Hannover, Deutschland
,
A. Olschewski
8   Universitätsklinik für Anästhesiologie und Intensivmedizin, Medizinische Universität Graz
9   Ludwig Boltzmann Institut für Lungengefäßforschung, Graz, Österreich
,
G. Kwapiszewska
8   Universitätsklinik für Anästhesiologie und Intensivmedizin, Medizinische Universität Graz
9   Ludwig Boltzmann Institut für Lungengefäßforschung, Graz, Österreich
,
S. Ulrich
10   Klinik für Pneumologie, Universitäts-Spital Zürich, Schweiz
,
R. Voswinckel
11   Innere Medizin, Gesundheitszentrum Wetterau, Friedberg, Deutschland
,
N. Weissmann
12   Excellence Cluster Cardiopulmonary System (ECCPS), Universities of Giessen and Marburg Lung Center (UGMLC), Deutsches Zentrum     für Lungenforschung (DZL)
,
H Worth
13   Klinik für Herz- und Lungenerkrankungen, Klinikum Fürth, Deutschland
,
R. R. Viales
14   Institut für Humangenetik, Universitätsklinikum Heidelberg, Deutschland
,
S. S. Pullamsetti
3   Pulmonale Pharmakotherapie, Zentrum für Innere Medizin und Deutsches Zentrum für Lungenforschung (DZL), Justus-Liebig   Universität Giessen
,
G. Grunig
15   Dept. Environmental Medicine, Dept. Medicine (Pulmonary Medicine), New York University School of Medicine, New York, NY, USA
› Author Affiliations
Further Information

Publication History

15 October 2014

23 October 2014

Publication Date:
09 December 2014 (online)

 
  • Literatur

  • 1 Pullamsetti SS, Savai R, Janssen W et al. Inflammation, immunological reaction and role of infection in pulmonary hypertension. Clin Microbiol Infection 2011; 17: 7-14
  • 2 Groth A, Vrugt B, Brock M et al. Inflammatory cytokines in pulmonary hypertension. Respir Res 2014; 15: 47
  • 3 Becker MO, Kill A, Kutsche M et al. Vascular receptor autoantibodies as biomarkers of pulmonary arterial hypertension associated with systemic sclerosis. Am J Respir Crit Care Med 2014; 190: 808-817
  • 4 Butrous G, Ghofrani HA, Grimminger F. Pulmonary vascular disease in the developing world. Circulation 2008; 118: 1758-66
  • 5 Seimetz M, Parajuli N, Pichl A et al. Inducible NOS inhibition reverses tobacco-smoke-induced emphysema and pulmonary hypertension in mice. Cell 2011; 147: 293-305
  • 6 Grunig G, Marsh LM, Esmaeil N et al. Perspective: ambient air pollution: inflammatory response and effects on the lung’s vasculature. Pulm Circ 2014; 4: 25-35
  • 7 Price LC, Wort SJ, Perros F et al. Inflammation in pulmonary arterial hypertension. Chest 2012; 141: 210-21
  • 8 Savai R, Pullamsetti SS, Kolbe J et al. Immune and inflammatory cell involvement in the pathology of idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med 2012; 186: 897-908
  • 9 El Kasmi KC, Pugliese SC, Riddle SR et al. Adventitial fibroblasts induce a distinct proinflammatory/profibrotic macrophage phenotype in pulmonary hypertension. J Immunol 2014; 193: 597-609
  • 10 Hoffmann J, Yin J, Kukucka M et al. Mast cells promote lung vascular remodelling in pulmonary hypertension. Eur Respir J 2011; 37: 1400-10
  • 11 Ehrlich P. Beiträge zur Kenntniss der granulirten Bindegewebszellen und der eosinophilen Leukocythen. Archiv fuer Anatomie und Physiologie: Physiologische Abteilung 1879; 166-9
  • 12 Tian W, Jiang X, Tamosiuniene R et al. Blocking macrophage leukotriene b4 prevents endothelial injury and reverses pulmonary hypertension. Science Translat Med 2013; 5: 200ra117
  • 13 Perros F, Dorfmuller P, Montani D et al. Pulmonary lymphoid neogenesis in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med 2012; 185: 311-21
  • 14 Perros F, Dorfmuller P, Souza R et al. Dendritic cell recruitment in lesions of human and experimental pulmonary hypertension. Eur Respir J 2007; 29: 462-8
  • 15 Szabo SJ, Kim ST, Costa GL et al. A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell 2000; 100: 655-69
  • 16 Ray A, Cohn L. Th2 cells and GATA-3 in asthma: new insights into the regulation of airway inflammation. J Clin Invest 1999; 104: 985-93
  • 17 Zhou L, Chong MM, Littman DR. Plasticity of CD4+ T cell lineage differentiation. Immunity 2009; 30: 646-55
  • 18 Liu X, Chen X, Zhong B et al. Transcription factor achaete-scute homologue 2 initiates follicular T-helper-cell development. Nature 2014; 507: 513-8
  • 19 Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nature Immunol 2003; 4: 330-6
  • 20 Perros F, Cohen-Kaminsky S, Gambaryan N et al. Cytotoxic cells and granulysin in pulmonary arterial hypertension and pulmonary veno-occlusive disease. Am J Respir Crit Care Med 2013; 187: 189-96
  • 21 Corren J, Lemanske RF, Hanania NA et al. Lebrikizumab treatment in adults with asthma. NEJM 2011; 365: 1088-98
  • 22 Rose T, Grutzkau A, Hirseland H et al. IFNalpha and its response proteins, IP-10 and SIGLEC-1, are biomarkers of disease activity in systemic lupus erythematosus. Ann Rheum Dis 2013; 72: 1639-45
  • 23 Christmann RB, Hayes E, Pendergrass S et al. Interferon and alternative activation of monocyte/macrophages in systemic sclerosis-associated pulmonary arterial hypertension. Arthritis Rheum 2011; 63: 1718-28
  • 24 Daley E, Emson C, Guignabert C et al. Pulmonary arterial remodeling induced by a Th2 immune response. J Exp Med 2008; 205: 361-72
  • 25 Graham BB, Mentink-Kane MM, El-Haddad H et al. Schistosomiasis-induced experimental pulmonary hypertension: role of interleukin-13 signaling. Am J Pathol 2010; 177: 1549-61
  • 26 Cho W, Chen N, Tang C et al. IL-13-induces Vascular Remodeling And Pulmonary Arterial Hyptertension Via Arginase 2-dependent Pathway. Am J Respir Crit Care Med 2010; 181: A6323
  • 27 Park SH, Chen WC, Esmaeil N et al. IL-13 and IL-17A induced pulmonary-hypertension-phenotype due to inhalation of antigen and fine particles from air pollution. Pulm Circ 2014; in press
  • 28 Greenblatt MB, Sargent JL, Farina G et al. Interspecies comparison of human and murine scleroderma reveals IL-13 and CCL2 as disease subset-specific targets. Am J Pathol 2012; 180: 1080-94
  • 29 Islam SA, Ling MF, Leung J et al. Identification of human CCR8 as a CCL18 receptor. J Exp Med 2013; 210: 1889-98
  • 30 Humbert M, Monti G, Brenot F et al. Increased interleukin-1 and interleukin-6 serum concentrations in severe primary pulmonary hypertension. Am J Respir Crit Care Med 1995; 151: 1628-31
  • 31 Soon E, Holmes AM, Treacy CM et al. Elevated levels of inflammatory cytokines predict survival in idiopathic and familial pulmonary arterial hypertension. Circulation 2010; 122: 920-7
  • 32 Steiner MK, Syrkina OL, Kolliputi N et al. Interleukin-6 overexpression induces pulmonary hypertension. Circulation Res 2009; 104: 236-44, 28p following 44
  • 33 Brock M, Trenkmann M, Gay RE et al. Interleukin-6 modulates the expression of the bone morphogenic protein receptor type II through a novel STAT3-microRNA cluster 17/92 pathway. Circulation Res 2009; 104: 1184-91
  • 34 Hagen M, Fagan K, Steudel W et al. Interaction of interleukin-6 and the BMP pathway in pulmonary smooth muscle. Am J Physiol Lung Cell Mol Physiol 2007; 292: L1473-9
  • 35 Radstake TR, van Bon L, Broen J et al. The pronounced Th17 profile in systemic sclerosis (SSc) together with intracellular expression of TGFbeta and IFNgamma distinguishes SSc phenotypes. PLoS One 2009; 4: e5903
  • 36 Park SH, Chen WC, Hoffman C et al. Modification of hemodynamic and immune responses to exposure with a weak antigen by the expression of a hypomorphic BMPR2 gene. PLoS One 2013; 8: e55180
  • 37 Mushaben EM, Hershey GK, Pauciulo MW et al. Chronic allergic inflammation causes vascular remodeling and pulmonary hypertension in BMPR2 hypomorph and wild-type mice. PLoS One 2012; 7: e32468
  • 38 Davies RJ, Holmes AM, Deighton J et al. BMP type II receptor deficiency confers resistance to growth inhibition by TGF-beta in pulmonary artery smooth muscle cells: role of proinflammatory cytokines. Am J Physiol Lung Cell Mol Physiol 2012; 302: L604-15
  • 39 Tamosiuniene R, Tian W, Dhillon G et al. Regulatory T cells limit vascular endothelial injury and prevent pulmonary hypertension. Circulation Res 2011; 109: 867-79
  • 40 Ulrich S, Taraseviciene-Stewart L, Huber LC et al. Peripheral blood B lymphocytes derived from patients with idiopathic pulmonary arterial hypertension express a different RNA pattern compared with healthy controls: a cross sectional study. Respir Res 2008; 9: 20
  • 41 Bussone G, Tamby MC, Calzas C et al. IgG from patients with pulmonary arterial hypertension and/or systemic sclerosis binds to vascular smooth muscle cells and induces cell contraction. Ann Rheum Dis 2012; 71: 596-605
  • 42 Dib H, Tamby MC, Bussone G et al. Targets of anti-endothelial cell antibodies in pulmonary hypertension and scleroderma. Eur Respir J 2012; 39: 1405-14
  • 43 Dandel M, Wallukat G, Englert A et al. Immunoadsorption therapy for dilated cardiomyopathy and pulmonary arterial hypertension. Atherosclerosis Supplements 2013; 14: 203-11
  • 44 Colvin KL, Cripe PJ, Ivy DD et al. Bronchus-associated lymphoid tissue in pulmonary hypertension produces pathologic autoantibodies. Am J Respir Crit Care Med 2013; 188: 1126-36
  • 45 Arends SJ, Damoiseaux JG, Duijvestijn AM et al. Functional implications of IgG anti-endothelial cell antibodies in pulmonary arterial hypertension. Autoimmunity 2013; 46: 463-70
  • 46 Bussone G, Dib H, Tamby MC et al. Identification of new autoantibody specificities directed at proteins involved in the transforming growth factor beta pathway in patients with systemic sclerosis. Arthritis Res Ther 2011; 13: R74
  • 47 Wallukat G, Homuth V, Fischer T et al. Patients with preeclampsia develop agonistic autoantibodies against the angiotensin AT1 receptor. J Clin Invest 1999; 103: 945-52
  • 48 Riemekasten G, Philippe A, Nather M et al. Involvement of functional autoantibodies against vascular receptors in systemic sclerosis. Ann Rheum Dis 2011; 70: 530-6
  • 49 Iglarz M, Clozel M. At the heart of tissue: endothelin system and end-organ damage. Clin Science 2010; 119: 453-63
  • 50 Kill A, Tabeling C, Undeutsch R et al. Autoantibodies to angiotensin and endothelin receptors in systemic sclerosis induce cellular and systemic events associated with disease pathogenesis. Arthritis Res Ther 2014; 16: R29
  • 51 de Man FS, Tu L, Handoko ML et al. Dysregulated renin-angiotensin-aldosterone system contributes to pulmonary arterial hypertension. Am J Respir Crit Care Med 2012; 186: 780-9
  • 52 Eferl R, Hasselblatt P, Rath M et al. Development of pulmonary fibrosis through a pathway involving the transcription factor Fra-2/AP-1. Proc Nat Acad Sci USA 2008; 105: 10525-30
  • 53 Kerem A, Yin J, Kaestle SM et al. Lung endothelial dysfunction in congestive heart failure: role of impaired Ca2+ signaling and cytoskeletal reorganization. Circulation Res 2010; 106: 1103-16
  • 54 Gunther J, Kill A, Becker MO et al. Angiotensin receptor type 1 and endothelin receptor type A on immune cells mediate migration and the expression of IL-8 and CCL18 when stimulated by autoantibodies from systemic sclerosis patients. Arthritis Res Ther 2014; 16: R65
  • 55 Lukitsch I, Kehr J, Chaykovska L et al. Renal ischemia and transplantation predispose to vascular constriction mediated by angiotensin II type 1 receptor-activating antibodies. Transplantation 2012; 94: 8-13
  • 56 Wenzel S, Ford L, Pearlman D et al. Dupilumab in persistent asthma with elevated eosinophil levels. NEJM 2013; 368: 2455-66
  • 57 Langley RG, Elewski BE, Lebwohl M et al. Secukinumab in Plaque Psoriasis – Results of Two Phase 3 Trials. NEJM 2014;
  • 58 Leonardi C, Matheson R, Zachariae C et al. Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaque psoriasis. NEJM 2012; 366: 1190-9
  • 59 Genovese MC, Greenwald M, Cho CS et al. A Phase II Randomized Study of Subcutaneous Ixekizumab, an Anti-Interleukin-17 Monoclonal Antibody, in Rheumatoid Arthritis Patients Who Were Naive to Biologic Agents or Had an Inadequate Response to Tumor Necrosis Factor Inhibitors. Arthritis Rheumatol 2014; 66: 1693-704
  • 60 Farha S, Sharp J, Asosingh K et al. Mast cell number, phenotype, and function in human pulmonary arterial hypertension. Pulm Circ 2012; 2: 220-8
  • 61 Padilla-Ibarra J, Sanchez-Ortiz A, Sandoval-Castro C et al. Rituximab treatment for pulmonary arterial hypertension in adult-onset Still's disease. Clin Exp Rheumatol 2013; 31: 657-8
  • 62 Hennigan S, Channick RN, Silverman GJ. Rituximab treatment of pulmonary arterial hypertension associated with systemic lupus erythematosus: a case report. Lupus 2008; 17: 754-6
  • 63 Genovese MC, Fleischmann RM, Greenwald M et al. Tabalumab, an anti-BAFF monoclonal antibody, in patients with active rheumatoid arthritis with an inadequate response to TNF inhibitors. Ann Rheum Dis 2013; 72: 1461-8
  • 64 Ginzler EM, Wax S, Rajeswaran A et al. Atacicept in combination with MMF and corticosteroids in lupus nephritis: results of a prematurely terminated trial. Arthritis REs Ther 2012; 14: R33
  • 65 Sanchez O, Sitbon O, Jais X et al. Immunosuppressive therapy in connective tissue diseases-associated pulmonary arterial hypertension. Chest 2006; 130: 182-9
  • 66 Groen H, Bootsma H, Postma DS et al. Primary pulmonary hypertension in a patient with systemic lupus erythematosus: partial improvement with cyclophosphamide. J Rheumatol 1993; 20: 1055-7
  • 67 Riemekasten G, Dragun D. [Clinical risk-adapted therapies in systemic sclerosis]. Z Rheumatol 2007; 66: 672-4, 6-8