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The Role of Inflammation and Autoimmunity in the Pathophysiology of Pulmonary Arterial Hypertension

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Abstract

Pulmonary arterial hypertension is characterized by a remodeling of pulmonary arteries with endothelial cell, fibroblast, and vascular smooth muscle cell activation and proliferation. Since pulmonary arterial hypertension occurs frequently in autoimmune conditions such as systemic sclerosis, inflammation and autoimmunity have been suspected to play a critical role in both idiopathic pulmonary arterial hypertension and systemic sclerosis-associated pulmonary arterial hypertension. High levels of pro-inflammatory cytokines such as interleukin-1 and interleukin-6, platelet-derived growth factor, or macrophage inflammatory protein 1 have been found in lung samples of patients with pulmonary arterial hypertension, along with inflammatory cell infiltrates mainly composed of macrophages and dendritic cells, T and B lymphocytes. In addition, circulating autoantibodies are found in the peripheral blood of patients. Thus, autoimmunity and inflammation probably play a role in the development of pulmonary arterial hypertension. In this setting, it would be important to set-up new experimental models of pulmonary arterial hypertension, in order to define novel therapeutics that specifically target immune disturbances in this devastating condition.

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References

  1. Rubin LJ (1997) Primary pulmonary hypertension. N Engl J Med 336:111–117

    Article  PubMed  CAS  Google Scholar 

  2. Simonneau G, Robbins IM, Beghetti M et al (2009) Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 54:S43–S54

    Article  PubMed  Google Scholar 

  3. Mukerjee D, St George D, Coleiro B et al (2003) Prevalence and outcome in systemic sclerosis associated pulmonary arterial hypertension: application of a registry approach. Ann Rheum Dis 62:1088–1093

    Article  PubMed  CAS  Google Scholar 

  4. Hachulla E, Gressin V, Guillevin L et al (2005) Early detection of pulmonary arterial hypertension in systemic sclerosis: a French nationwide prospective multicenter study. Arthritis Rheum 52:3792–3800

    Article  PubMed  Google Scholar 

  5. Le Pavec J, Humbert M, Mouthon L, Hassoun PM (2010) Systemic sclerosis-associated pulmonary arterial hypertension. Am J Respir Crit Care Med 181:1285–1293

    Article  PubMed  Google Scholar 

  6. Deng Z, Morse JH, Slager SL et al (2000) Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. Am J Hum Genet 67:737–744

    Article  PubMed  CAS  Google Scholar 

  7. Trembath RC, Thomson JR, Machado RD et al (2001) Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia. N Engl J Med 345:325–334

    Article  PubMed  CAS  Google Scholar 

  8. Chaouat A, Coulet F, Favre C et al (2004) Endoglin germline mutation in a patient with hereditary haemorrhagic telangiectasia and dexfenfluramine associated pulmonary arterial hypertension. Thorax 59:446–448

    Article  PubMed  CAS  Google Scholar 

  9. Dorfmuller P, Perros F, Balabanian K, Humbert M (2003) Inflammation in pulmonary arterial hypertension. Eur Respir J 22:358–363

    Article  PubMed  CAS  Google Scholar 

  10. Nicolls MR, Taraseviciene-Stewart L, Rai PR, Badesch DB, Voelkel NF (2005) Autoimmunity and pulmonary hypertension: a perspective. Eur Respir J 26:1110–8

    Article  PubMed  CAS  Google Scholar 

  11. Badesch DB, Wynne KM, Bonvallet S, Voelkel NF, Ridgway C, Groves BM (1993) Hypothyroidism and primary pulmonary hypertension: an autoimmune pathogenetic link? Ann Intern Med 119:44–46

    PubMed  CAS  Google Scholar 

  12. Tamby MC, Chanseaud Y, Humbert M et al (2005) Anti-endothelial cell antibodies in idiopathic and systemic sclerosis associated pulmonary arterial hypertension. Thorax 60:765–772

    Article  PubMed  CAS  Google Scholar 

  13. Tamby MC, Humbert M, Guilpain P et al (2006) Antibodies to fibroblasts in idiopathic and scleroderma-associated pulmonary hypertension. Eur Respir J 28:799–807

    Article  PubMed  CAS  Google Scholar 

  14. Terrier B, Tamby MC, Camoin L et al (2008) Identification of target antigens of antifibroblast antibodies in pulmonary arterial hypertension. Am J Respir Crit Care Med 177:1128–1134

    Article  PubMed  CAS  Google Scholar 

  15. Balabanian K, Foussat A, Dorfmuller P et al (2002) CX(3)C chemokine fractalkine in pulmonary arterial hypertension. Am J Respir Crit Care Med 165:1419–1425

    Article  PubMed  Google Scholar 

  16. Bull TM, Cool CD, Serls AE et al (2003) Primary pulmonary hypertension, Castleman’s disease and human herpesvirus-8. Eur Respir J 22:403–407

    Article  PubMed  CAS  Google Scholar 

  17. Hassoun PM, Mouthon L, Barbera JA et al (2009) Inflammation, growth factors, and pulmonary vascular remodeling. J Am Coll Cardiol 54:S10–S19

    Article  PubMed  CAS  Google Scholar 

  18. Humbert M, Monti G, Brenot F et al (1995) Increased interleukin-1 and interleukin-6 serum concentrations in severe primary pulmonary hypertension. Am J Respir Crit Care Med 151:1628–1631

    PubMed  CAS  Google Scholar 

  19. Lesprit P, Godeau B, Authier FJ et al (1998) Pulmonary hypertension in POEMS syndrome: a new feature mediated by cytokines. Am J Respir Crit Care Med 157:907–911

    PubMed  CAS  Google Scholar 

  20. Savale L, Tu L, Rideau D et al (2009) Impact of interleukin-6 on hypoxia-induced pulmonary hypertension and lung inflammation in mice. Respir Res 10:6

    Article  PubMed  Google Scholar 

  21. Bhargava A, Kumar A, Yuan N, Gewitz MH, Mathew R (1999) Monocrotaline induces interleukin-6 mRNA expression in rat lungs. Heart Dis 1:126–132

    PubMed  CAS  Google Scholar 

  22. Matsuyama M, Suzuki T, Tsuboi H et al (2007) Anti-interleukin-6 receptor antibody (tocilizumab) treatment of multicentric Castleman’s disease. Intern Med 46:771–774

    Article  PubMed  Google Scholar 

  23. Nishimoto N, Terao K, Mima T, Nakahara H, Takagi N, Kakehi T (2008) Mechanisms and pathologic significances in increase in serum interleukin-6 (IL-6) and soluble IL-6 receptor after administration of an anti-IL-6 receptor antibody, tocilizumab, in patients with rheumatoid arthritis and Castleman disease. Blood 112:3959–3964

    Article  PubMed  CAS  Google Scholar 

  24. Song SN, Tomosugi N, Kawabata H, Ishikawa T, Nishikawa T, Yoshizaki K (2010) Down-regulation of hepcidin resulting from long-term treatment with an anti-IL-6 receptor antibody (tocilizumab) improves anemia of inflammation in multicentric Castleman disease. Blood 116:3627–3634

    Article  PubMed  CAS  Google Scholar 

  25. Furuya Y, Satoh T, Kuwana M (2010) Interleukin-6 as a potential therapeutic target for pulmonary arterial hypertension. Int J Rheumatol 2010:720305

    PubMed  Google Scholar 

  26. Perros F, Dorfmuller P, Souza R et al (2007) Fractalkine-induced smooth muscle cell proliferation in pulmonary hypertension. Eur Respir J 29:937–943

    Article  PubMed  CAS  Google Scholar 

  27. Sanchez O, Marcos E, Perros F et al (2007) Role of endothelium-derived CC chemokine ligand 2 in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med 176:1041–1047

    Article  PubMed  CAS  Google Scholar 

  28. Heresi GA, Aytekin M, Newman J, Dweik RA (2010) CXC-chemokine ligand 10 in idiopathic pulmonary arterial hypertension: marker of improved survival. Lung 188:191–7

    Article  PubMed  CAS  Google Scholar 

  29. Heldin CH, Westermark B (1999) Mechanism of action and in vivo role of platelet-derived growth factor. Physiol Rev 79:1283–1316

    PubMed  CAS  Google Scholar 

  30. Katayose D, Ohe M, Yamauchi K et al (1993) Increased expression of PDGF A- and B-chain genes in rat lungs with hypoxic pulmonary hypertension. Am J Physiol 264:L100–L106

    PubMed  CAS  Google Scholar 

  31. Hertz MI, Henke CA, Nakhleh RE et al (1992) Obliterative bronchiolitis after lung transplantation: a fibroproliferative disorder associated with platelet-derived growth factor. Proc Natl Acad Sci USA 89:10385–10389

    Article  PubMed  CAS  Google Scholar 

  32. Perros F, Montani D, Dorfmuller P et al (2008) Platelet-derived growth factor expression and function in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med 178:81–88

    Article  PubMed  CAS  Google Scholar 

  33. Schermuly RT, Dony E, Ghofrani HA et al (2005) Reversal of experimental pulmonary hypertension by PDGF inhibition. J Clin Invest 115:2811–2821

    Article  PubMed  CAS  Google Scholar 

  34. Merklinger SL, Jones PL, Martinez EC, Rabinovitch M (2005) Epidermal growth factor receptor blockade mediates smooth muscle cell apoptosis and improves survival in rats with pulmonary hypertension. Circulation 112:423–431

    Article  PubMed  CAS  Google Scholar 

  35. Jones PL, Rabinovitch M (1996) Tenascin-C is induced with progressive pulmonary vascular disease in rats and is functionally related to increased smooth muscle cell proliferation. Circ Res 79:1131–1142

    Article  PubMed  CAS  Google Scholar 

  36. Jones PL, Crack J, Rabinovitch M (1997) Regulation of tenascin-C, a vascular smooth muscle cell survival factor that interacts with the alpha v beta 3 integrin to promote epidermal growth factor receptor phosphorylation and growth. J Cell Biol 139:279–293

    Article  PubMed  CAS  Google Scholar 

  37. Tuder RM, Groves B, Badesch DB, Voelkel NF (1994) Exuberant endothelial cell growth and elements of inflammation are present in plexiform lesions of pulmonary hypertension. Am J Pathol 144:275–285

    PubMed  CAS  Google Scholar 

  38. Ulrich S, Taraseviciene-Stewart L, Huber LC, Speich R, Voelkel N (2008) 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 9:20

    Article  PubMed  Google Scholar 

  39. Crispin JC, Martinez A, Alcocer-Varela J (2003) Quantification of regulatory T cells in patients with systemic lupus erythematosus. J Autoimmun 21:273–276

    Article  PubMed  Google Scholar 

  40. Liu MF, Wang CR, Fung LL, Wu CR (2004) Decreased CD4+CD25+ T cells in peripheral blood of patients with systemic lupus erythematosus. Scand J Immunol 59:198–202

    Article  PubMed  Google Scholar 

  41. Ingegnoli F, Trabattoni D, Saresella M, Fantini F, Clerici M (2003) Distinct immune profiles characterize patients with diffuse or limited systemic sclerosis. Clin Immunol 108:21–28

    Article  PubMed  CAS  Google Scholar 

  42. Benveniste O, Cherin P, Maisonobe T et al (2001) Severe perturbations of the blood T cell repertoire in polymyositis, but not dermatomyositis patients. J Immunol 167:3521–3529

    PubMed  CAS  Google Scholar 

  43. Mandl T, Bredberg A, Jacobsson LT, Manthorpe R, Henriksson G (2004) CD4+ T-lymphocytopenia–a frequent finding in anti-SSA antibody seropositive patients with primary Sjogren’s syndrome. J Rheumatol 31:726–728

    PubMed  Google Scholar 

  44. Ulrich S, Nicolls MR, Taraseviciene L, Speich R, Voelkel N (2008) Increased regulatory and decreased CD8+ cytotoxic T cells in the blood of patients with idiopathic pulmonary arterial hypertension. Respiration 75:272–280

    Article  PubMed  CAS  Google Scholar 

  45. Perros F, Dorfmuller P, Souza R et al (2007) Dendritic cell recruitment in lesions of human and experimental pulmonary hypertension. Eur Respir J 29:462–468

    Article  PubMed  CAS  Google Scholar 

  46. van Rijt LS, Lambrecht BN (2005) Dendritic cells in asthma: a function beyond sensitization. Clin Exp Allergy 35:1125–1134

    Article  PubMed  Google Scholar 

  47. Palucka AK, Blanck JP, Bennett L, Pascual V, Banchereau J (2005) Cross-regulation of TNF and IFN-alpha in autoimmune diseases. Proc Natl Acad Sci USA 102:3372–3377

    Article  PubMed  CAS  Google Scholar 

  48. Gabrilovich DI, Corak J, Ciernik IF, Kavanaugh D, Carbone DP (1997) Decreased antigen presentation by dendritic cells in patients with breast cancer. Clin Cancer Res 3:483–490

    PubMed  CAS  Google Scholar 

  49. Morelli AE, Thomson AW (2000) Role of dendritic cells in the immune response against allografts. Curr Opin Nephrol Hypertens 9:607–613

    Article  PubMed  CAS  Google Scholar 

  50. Conejo-Garcia JR, Benencia F, Courreges MC et al (2004) Tumor-infiltrating dendritic cell precursors recruited by a beta-defensin contribute to vasculogenesis under the influence of Vegf-A. Nat Med 10:950–958

    Article  PubMed  CAS  Google Scholar 

  51. Sitbon O, Lascoux-Combe C, Delfraissy JF et al (2008) Prevalence of HIV-related pulmonary arterial hypertension in the current antiretroviral therapy era. Am J Respir Crit Care Med 177:108–113

    Article  PubMed  Google Scholar 

  52. Hsue PY, Deeks SG, Farah HH et al (2008) Role of HIV and human herpesvirus-8 infection in pulmonary arterial hypertension. AIDS 22:825–833

    Article  PubMed  CAS  Google Scholar 

  53. Kanmogne GD, Primeaux C, Grammas P (2005) Induction of apoptosis and endothelin-1 secretion in primary human lung endothelial cells by HIV-1 gp120 proteins. Biochem Biophys Res Commun 333:1107–1115

    Article  PubMed  CAS  Google Scholar 

  54. Duffy P, Wang X, Lin PH, Yao Q, Chen C (2009) HIV Nef protein causes endothelial dysfunction in porcine pulmonary arteries and human pulmonary artery endothelial cells. J Surg Res 156:257–264

    Article  PubMed  CAS  Google Scholar 

  55. Toborek M, Lee YW, Pu H et al (2003) HIV-Tat protein induces oxidative and inflammatory pathways in brain endothelium. J Neurochem 84:169–179

    Article  PubMed  CAS  Google Scholar 

  56. Marecki JC, Cool CD, Parr JE et al (2006) HIV-1 Nef is associated with complex pulmonary vascular lesions in SHIV-nef-infected macaques. Am J Respir Crit Care Med 174:437–445

    Article  PubMed  CAS  Google Scholar 

  57. Barnier A, Frachon I, Dewilde J, Gut-Gobert C, Jobic Y, Leroyer C (2009) Improvement of HIV-related pulmonary hypertension after the introduction of an antiretroviral therapy. Eur Respir J 34:277–278

    Article  PubMed  CAS  Google Scholar 

  58. Desrosiers RC, Sasseville VG, Czajak SC et al (1997) A herpesvirus of rhesus monkeys related to the human Kaposi’s sarcoma-associated herpesvirus. J Virol 71:9764–9769

    PubMed  CAS  Google Scholar 

  59. Cool CD, Rai PR, Yeager ME et al (2003) Expression of human herpesvirus 8 in primary pulmonary hypertension. N Engl J Med 349:1113–1122

    Article  PubMed  CAS  Google Scholar 

  60. Henke-Gendo C, Mengel M, Hoeper MM, Alkharsah K, Schulz TF (2005) Absence of Kaposi’s sarcoma-associated herpesvirus in patients with pulmonary arterial hypertension. Am J Respir Crit Care Med 172:1581–1585

    Article  PubMed  Google Scholar 

  61. Bendayan D, Sarid R, Cohen A, Shitrit D, Shechtman I, Kramer MR (2008) Absence of human herpesvirus 8 DNA sequences in lung biopsies from Israeli patients with pulmonary arterial hypertension. Respiration 75:155–157

    Article  PubMed  CAS  Google Scholar 

  62. Valmary S, Dorfmuller P, Montani D, Humbert M, Brousset P, Degano B (2011) Human gamma-herpesviruses EBV and HHV-8 are not detected in the lungs of patients with severe pulmonary arterial hypertension. Chest (in press)

  63. Graham BB, Bandeira AP, Morrell NW, Butrous G, Tuder RM (2010) Schistosomiasis-associated pulmonary hypertension: pulmonary vascular disease: the global perspective. Chest 137:20S–29S

    Article  PubMed  Google Scholar 

  64. Lapa M, Dias B, Jardim C et al (2009) Cardiopulmonary manifestations of hepatosplenic schistosomiasis. Circulation 119:1518–1523

    Article  PubMed  Google Scholar 

  65. Tuder RM (2009) Pathology of pulmonary arterial hypertension. Semin Respir Crit Care Med 30:376–385

    Article  PubMed  Google Scholar 

  66. dos Santos Fernandes CJ, Jardim CV, Hovnanian A et al (2010) Survival in schistosomiasis-associated pulmonary arterial hypertension. J Am Coll Cardiol 56:715–720

    Article  PubMed  Google Scholar 

  67. Crosby A, Jones FM, Southwood M et al (2010) Pulmonary vascular remodeling correlates with lung eggs and cytokines in murine schistosomiasis. Am J Respir Crit Care Med 181:279–88

    Article  PubMed  CAS  Google Scholar 

  68. Freitas TC, Jung E, Pearce EJ (2007) TGF-beta signaling controls embryo development in the parasitic flatworm Schistosoma mansoni. PLoS Pathog 3:e52

    Article  PubMed  Google Scholar 

  69. Mouthon L, Guillevin L, Humbert M (2005) Pulmonary arterial hypertension: an autoimmune disease? Eur Respir J 26:986–988

    Article  PubMed  CAS  Google Scholar 

  70. Morse JH, Barst RJ, Fotino M et al (1997) Primary pulmonary hypertension, tissue plasminogen activator antibodies, and HLA-DQ7. Am J Respir Crit Care Med 155:274–278

    PubMed  CAS  Google Scholar 

  71. Grigolo B, Mazzetti I, Meliconi R et al (2000) Anti-topoisomerase II alpha autoantibodies in systemic sclerosis-association with pulmonary hypertension and HLA-B35. Clin Exp Immunol 121:539–543

    Article  PubMed  CAS  Google Scholar 

  72. Ulanet DB, Wigley FM, Gelber AC, Rosen A (2003) Autoantibodies against B23, a nucleolar phosphoprotein, occur in scleroderma and are associated with pulmonary hypertension. Arthritis Rheum 49:85–92

    Article  PubMed  Google Scholar 

  73. Negi VS, Tripathy NK, Misra R, Nityanand S (1998) Antiendothelial cell antibodies in scleroderma correlate with severe digital ischemia and pulmonary arterial hypertension. J Rheumatol 25:462–466

    PubMed  CAS  Google Scholar 

  74. Carvalho D, Savage CO, Black CM, Pearson JD (1996) IgG antiendothelial cell autoantibodies from scleroderma patients induce leukocyte adhesion to human vascular endothelial cells in vitro. Induction of adhesion molecule expression and involvement of endothelium-derived cytokines. J Clin Invest 97:111–119

    Article  PubMed  CAS  Google Scholar 

  75. Bordron A, Dueymes M, Levy Y et al (1998) The binding of some human antiendothelial cell antibodies induces endothelial cell apoptosis. J Clin Invest 101:2029–2035

    Article  PubMed  CAS  Google Scholar 

  76. Arends SJ, Damoiseaux J, Duijvestijn A et al (2010) Prevalence of anti-endothelial cell antibodies in idiopathic pulmonary arterial hypertension. Eur Respir J 35:923–925

    Article  PubMed  CAS  Google Scholar 

  77. Li MT, Ai J, Tian Z et al (2010) Prevalence of anti-endothelial cell antibodies in patients with pulmonary arterial hypertension associated with connective tissue diseases. Chin Med Sci J 25:27–31

    Article  PubMed  Google Scholar 

  78. Arends SJ, Damoiseaux J, Duijvestijn A, et al (2010) Functional heterogeinity of IgG anti-endothelial cell antibodies in pulmonary arterial hypertension. In: 7th International Congress on Autoimmunity, Ljubljana, Slovenia.

  79. Chizzolini C, Raschi E, Rezzonico R et al (2002) Autoantibodies to fibroblasts induce a proadhesive and proinflammatory fibroblast phenotype in patients with systemic sclerosis. Arthritis Rheum 46:1602–1613

    Article  PubMed  CAS  Google Scholar 

  80. Baroni SS, Santillo M, Bevilacqua F et al (2006) Stimulatory autoantibodies to the PDGF receptor in systemic sclerosis. N Engl J Med 354:2667–2676

    Article  PubMed  CAS  Google Scholar 

  81. Classen JF, Henrohn D, Rorsman F et al (2009) Lack of evidence of stimulatory autoantibodies to platelet-derived growth factor receptor in patients with systemic sclerosis. Arthritis Rheum 60:1137–1144

    Article  PubMed  CAS  Google Scholar 

  82. Loizos N, Lariccia L, Weiner J et al (2009) Lack of detection of agonist activity by antibodies to platelet-derived growth factor receptor alpha in a subset of normal and systemic sclerosis patient sera. Arthritis Rheum 60:1145–1151

    Article  PubMed  CAS  Google Scholar 

  83. Fineschi S, Cozzi F, Burger D, Dayer JM, Meroni PL, Chizzolini C (2007) Anti-fibroblast antibodies detected by cell-based ELISA in systemic sclerosis enhance the collagenolytic activity and matrix metalloproteinase-1 production in dermal fibroblasts. Rheumatol Oxf 46:1779–1785

    Article  CAS  Google Scholar 

  84. Fineschi S, Goffin L, Rezzonico R et al (2008) Antifibroblast antibodies in systemic sclerosis induce fibroblasts to produce profibrotic chemokines, with partial exploitation of toll-like receptor 4. Arthritis Rheum 58:3913–3923

    Article  PubMed  CAS  Google Scholar 

  85. Henault J, Robitaille G, Senecal JL, Raymond Y (2006) DNA topoisomerase I binding to fibroblasts induces monocyte adhesion and activation in the presence of anti-topoisomerase I autoantibodies from systemic sclerosis patients. Arthritis Rheum 54:963–973

    Article  PubMed  CAS  Google Scholar 

  86. Robitaille G, Christin MS, Clement I, Senecal JL, Raymond Y (2009) Nuclear autoantigen CENP-B transactivation of the epidermal growth factor receptor via chemokine receptor 3 in vascular smooth muscle cells. Arthritis Rheum 60:2805–2816

    Article  PubMed  CAS  Google Scholar 

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Acknowledgement

We thank Ms. Monisokha LY (monisokha@gmail.com) for the design of the figure.

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Correspondence to Mathieu C. Tamby.

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Kherbeck, N., Tamby, M.C., Bussone, G. et al. The Role of Inflammation and Autoimmunity in the Pathophysiology of Pulmonary Arterial Hypertension. Clinic Rev Allerg Immunol 44, 31–38 (2013). https://doi.org/10.1007/s12016-011-8265-z

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