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
Rubin LJ (1997) Primary pulmonary hypertension. N Engl J Med 336:111–117
Simonneau G, Robbins IM, Beghetti M et al (2009) Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 54:S43–S54
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
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
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
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
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
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
Dorfmuller P, Perros F, Balabanian K, Humbert M (2003) Inflammation in pulmonary arterial hypertension. Eur Respir J 22:358–363
Nicolls MR, Taraseviciene-Stewart L, Rai PR, Badesch DB, Voelkel NF (2005) Autoimmunity and pulmonary hypertension: a perspective. Eur Respir J 26:1110–8
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
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
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
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
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
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
Hassoun PM, Mouthon L, Barbera JA et al (2009) Inflammation, growth factors, and pulmonary vascular remodeling. J Am Coll Cardiol 54:S10–S19
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
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
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
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
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
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
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
Furuya Y, Satoh T, Kuwana M (2010) Interleukin-6 as a potential therapeutic target for pulmonary arterial hypertension. Int J Rheumatol 2010:720305
Perros F, Dorfmuller P, Souza R et al (2007) Fractalkine-induced smooth muscle cell proliferation in pulmonary hypertension. Eur Respir J 29:937–943
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
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
Heldin CH, Westermark B (1999) Mechanism of action and in vivo role of platelet-derived growth factor. Physiol Rev 79:1283–1316
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
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
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
Schermuly RT, Dony E, Ghofrani HA et al (2005) Reversal of experimental pulmonary hypertension by PDGF inhibition. J Clin Invest 115:2811–2821
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
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
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
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
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
Crispin JC, Martinez A, Alcocer-Varela J (2003) Quantification of regulatory T cells in patients with systemic lupus erythematosus. J Autoimmun 21:273–276
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
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
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
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
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
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
van Rijt LS, Lambrecht BN (2005) Dendritic cells in asthma: a function beyond sensitization. Clin Exp Allergy 35:1125–1134
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
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
Morelli AE, Thomson AW (2000) Role of dendritic cells in the immune response against allografts. Curr Opin Nephrol Hypertens 9:607–613
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
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
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
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
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
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
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
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
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
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
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
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
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)
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
Lapa M, Dias B, Jardim C et al (2009) Cardiopulmonary manifestations of hepatosplenic schistosomiasis. Circulation 119:1518–1523
Tuder RM (2009) Pathology of pulmonary arterial hypertension. Semin Respir Crit Care Med 30:376–385
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
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
Freitas TC, Jung E, Pearce EJ (2007) TGF-beta signaling controls embryo development in the parasitic flatworm Schistosoma mansoni. PLoS Pathog 3:e52
Mouthon L, Guillevin L, Humbert M (2005) Pulmonary arterial hypertension: an autoimmune disease? Eur Respir J 26:986–988
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
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
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
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
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
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
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
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
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.
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
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
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
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
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
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
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
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
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We thank Ms. Monisokha LY (monisokha@gmail.com) for the design of the figure.
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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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DOI: https://doi.org/10.1007/s12016-011-8265-z