Abstract
Interstitial pneumonia (IP) is an important complication in collagen vascular diseases (CVDs). We examined the distribution of helper T cell subsets in lung biopsies of cases of IP associated with CVD (CVD-IP). The tissues from 27 CVD-IP patients with rheumatoid arthritis (RA), 8 with polymyositis or dermatomyositis (PM/DM), and 8 with systemic sclerosis (SSc) were compared with those from 10 patients with idiopathic pulmonary fibrosis (IPF) in our previous study. The expressions of CXCR3 and CCR4 (chemokine receptors associated in vitro with Th1 and Th2 cells, respectively) in the mononuclear infiltrate were analyzed immunohistochemically. The positive cells were semiquantified in fibrosing areas of the CVD-IP and IPF cases. The number of CXCR3-positive cells was significantly greater in RA-IP than in PM/DM-IP, SSc-IP, or IPF, whereas there were fewer CCR4-positive cells in RA-IP, PM/DM-IP, and SSc-IP than in IPF. The CXCR3-/CCR4-positive cells ratio was significantly higher in RA-IP and PM/DM-IP (but not in SSc-IP) than in IPF. These results support previous reports of the dominance of Th2 cells in some SSc-IP and IPF cases. However, Th1-type immune responses may predominate in RA-IP and PM/DM-IP. Our findings suggest that the pathogenesis of CVD-IPs differs with the helper T cell subset.
Similar content being viewed by others
References
Aleksza M, Szegedi A, Antal-Szalmas P, Irinyi B, Gergely L, Ponyi A, Hunyadi J, Sipka S, Zeher M, Szegedi G, Danko K (2005) Altered cytokine expression of peripheral blood lymphocytes in polymyositis and dermatomyositis. Ann Rheum Dis 64:1485–1489
Atamas SP, Yurovsky VV, Wise R, Wigley FM, Goter Robinson CJ, Henry P, Alms WJ, White B (1999) Production of type 2 cytokines by CD8+ lung cells is associated with greater decline in pulmonary function in patients with systemic sclerosis. Arthritis Rheum 42:1168–1178
Balbi B, Cosulich E, Risso A, Sacco O, Balzano E, Rossi GA (1987) The interstitial lung disease associated with rheumatoid arthritis: evidence for imbalance of helper T-lymphocyte subpopulations at sites of disease activity. Bull Eur Physiopathol Respir 23:241–247
Berner B, Akca D, Jung T, Muller GA, Reuss-Borst MA (2000) Analysis of Th1 and Th2 cytokines expressing CD4+ and CD8+ T cells in rheumatoid arthritis by flow cytometry. J Rheumatol 27:1128–1135
Bolster MB, Ludwicka A, Sutherland SE, Strange C, Silver RM (1997) Cytokine concentrations in bronchoalveolar lavage fluid of patients with systemic sclerosis. Arthritis Rheum 40:743–751
Bonecchi R, Bianchi G, Bordignon PP, D’Ambrosio D, Lang R, Borsatti A, Sozzani S, Allavena P, Gray PA, Mantovani A, Sinigaglia F (1998) Differential expression of chemokine receptors and chemotactic responsiveness of type 1 T helper cells (Th1s) and Th2s. J Exp Med 187:129–134
Bonnefoy O, Ferretti G, Calaque O, Coulomb M, Begueret H, Beylot-Barry M, Laurent F (2004) Serial chest CT findings in interstitial lung disease associated with polymyositis-dermatomyositis. Eur J Radiol 49:235–244
Clark-Lewis I, Mattioli I, Gong JH, Loetscher P (2003) Structure–function relationship between the human chemokine receptor CXCR3 and its ligands. J Biol Chem 278:289–295
Colby TV (1998) Pulmonary pathology in patients with systemic autoimmune diseases. Clin Chest Med 19:587–612, vii
Curbishley SM, Eksteen B, Gladue RP, Lalor P, Adams DH (2005) CXCR 3 activation promotes lymphocyte transendothelial migration across human hepatic endothelium under fluid flow. Am J Pathol 167:887–899
Del Papa N, Colombo G, Fracchiolla N, Moronetti LM, Ingegnoli F, Maglione W, Comina DP, Vitali C, Fantini F, Cortelezzi A (2004) Circulating endothelial cells as a marker of ongoing vascular disease in systemic sclerosis. Arthritis Rheum 50:1296–1304
Denton CP, Shi-Wen X, Sutton A, Abraham DJ, Black CM, Pearson JD (1998) Scleroderma fibroblasts promote migration of mononuclear leucocytes across endothelial cell monolayers. Clin Exp Immunol 114:293–300
Dixon AE, Mandac JB, Madtes DK, Martin PJ, Clark JG (2000) Chemokine expression in Th1 cell-induced lung injury: prominence of IFN-gamma-inducible chemokines. Am J Physiol Lung Cell Mol Physiol 279:L592–L599
Eksteen B, Miles A, Curbishley SM, Tselepis C, Grant AJ, Walker LS, Adams DH (2006) Epithelial inflammation is associated with CCL28 production and the recruitment of regulatory T Cells expressing CCR10. J Immunol 177:593–603
Foxman EF, Campbell JJ, Butcher EC (1997) Multistep navigation and the combinatorial control of leukocyte chemotaxis. J Cell Biol 139:1349–1360
Freemont AJ, Hoyland J, Fielding P, Hodson N, Jayson MI (1992) Studies of the microvascular endothelium in uninvolved skin of patients with systemic sclerosis: direct evidence for a generalized microangiopathy. Br J Dermatol 126:561–568
Fujisawa T, Suda T, Nakamura Y, Enomoto N, Ide K, Toyoshima M, Uchiyama H, Tamura R, Ida M, Yagi T, Yasuda K, Genma H, Hayakawa H, Chida K, Nakamura H (2005) Differences in clinical features and prognosis of interstitial lung diseases between polymyositis and dermatomyositis. J Rheumatol 32:58–64
Hunninghake GW, Fauci AS (1979) Pulmonary involvement in the collagen vascular diseases. Am Rev Respir Dis 119:471–503
Ishida T, Utsunomiya A, Iida S, Inagaki H, Takatsuka Y, Kusumoto S, Takeuchi G, Shimizu S, Ito M, Komatsu H, Wakita A, Eimoto T, Matsushima K, Ueda R (2003) Clinical significance of CCR4 expression in adult T-cell leukemia/lymphoma: its close association with skin involvement and unfavorable outcome. Clin Cancer Res 9:3625–3634
Ishida T, Iida S, Akatsuka Y, Ishii T, Miyazaki M, Komatsu H, Inagaki H, Okada N, Fujita T, Shitara K, Akinaga S, Takahashi T, Utsunomiya A, Ueda R (2004) The CC chemokine receptor 4 as a novel specific molecular target for immunotherapy in adult T-cell leukemia/lymphoma. Clin Cancer Res 10:7529–7539
Ito WD, Arras M, Winkler B, Scholz D, Schaper J, Schaper W (1997) Monocyte chemotactic protein-1 increases collateral and peripheral conductance after femoral artery occlusion. Circ Res 80:829–837
Jinnin M, Ihn H, Asano Y, Yamane K, Yazawa N, Tamaki K (2003) Effect of D-penicillamine on pulmonary fibrosis in patients with systemic sclerosis. Ann Rheum Dis 62:1019–1020
Kang EH, Lee EB, Shin KC, Im CH, Chung DH, Han SK, Song YW (2005) Interstitial lung disease in patients with polymyositis, dermatomyositis and amyopathic dermatomyositis. Rheumatology 44:1282–1286
Katchar K, Eklund A, Grunewald J (2003) Expression of Th1 markers by lung accumulated T cells in pulmonary sarcoidosis. J Intern Med 254:564–571
Kim CH, Rott L, Kunkel EJ, Genovese MC, Andrew DP, Wu L, Butcher EC (2001) Rules of chemokine receptor association with T cell polarization in vivo. J Clin Invest 108:1331–1339
Lepidi H, Frances V, Figarella-Branger D, Bartoli C, Machado-Baeta A, Pellissier JF (1998) Local expression of cytokines in idiopathic inflammatory myopathies. Neuropathol Appl Neurobiol 24:73–79
Loetscher P, Pellegrino A, Gong JH, Mattioli I, Loetscher M, Bardi G, Baggiolini M, Clark-Lewis I (2001) The ligands of CXC chemokine receptor 3, I-TAC, Mig, and IP10, are natural antagonists for CCR3. J Biol Chem 276:2986–2991
Majumdar S, Li D, Ansari T, Pantelidis P, Black CM, Gizycki M, du Bois RM, Jeffery PK (1999) Different cytokine profiles in cryptogenic fibrosing alveolitis and fibrosing alveolitis associated with systemic sclerosis: a quantitative study of open lung biopsies. Eur Respir J 14:251–257
Nanki T, Lipsky PE (2000) Lack of correlation between chemokine receptor and T(h)1/T(h)2 cytokine expression by individual memory T cells. Int Immunol 12:1659–1667
Nomura S, Ishii K, Kanazawa S, Inami N, Kamitsuji Y, Uoshima N, Ishida H, Yoshihara T, Kitayama H, Hayashi K (2006) Role of platelet-derived chemokines (RANTES and ENA-78) after stem cell transplantation. Transpl Immunol 15:247–253
Pignatti P, Brunetti G, Moretto D, Yacoub MR, Fiori M, Balbi B, Balestrino A, Cervio G, Nava S, Moscato G (2006) Role of the chemokine receptors CXCR3 and CCR4 in human pulmonary fibrosis. Am J Respir Crit Care Med 173:310–317
Qin S, Rottman JB, Myers P, Kassam N, Weinblatt M, Loetscher M, Koch AE, Moser B, Mackay CR (1998) The chemokine receptors CXCR3 and CCR5 mark subsets of T cells associated with certain inflammatory reactions. J Clin Invest 101:746–754
Roschmann RA, Rothenberg RJ (1987) Pulmonary fibrosis in rheumatoid arthritis: a review of clinical features and therapy. Semin Arthritis Rheum 16:174–185
Rossi GA, Bitterman PB, Rennard SI, Ferrans VJ, Crystal RG (1985) Evidence for chronic inflammation as a component of the interstitial lung disease associated with progressive systemic sclerosis. Am Rev Respir Dis 131:612–617
Rottoli P, Magi B, Perari MG, Liberatori S, Nikiforakis N, Bargagli E, Cianti R, Bini L, Pallini V (2005) Cytokine profile and proteome analysis in bronchoalveolar lavage of patients with sarcoidosis, pulmonary fibrosis associated with systemic sclerosis and idiopathic pulmonary fibrosis. Proteomics 5:1423–1430
Selva-O’Callaghan A, Labrador-Horrillo M, Munoz-Gall X, Martinez-Gomez X, Majo-Masferrer J, Solans-Laque R, Simeon-Aznar CP, Morell-Brotard F, Vilardell-Tarres M (2005) Polymyositis/dermatomyositis-associated lung disease: analysis of a series of 81 patients. Lupus 14:534–542
Shimizu S, Yoshinouchi T, Ohtsuki Y, Fujita J, Sugiura Y, Banno S, Yamadori I, Eimoto T, Ueda R (2002) The appearance of S-100 protein-positive dendritic cells and the distribution of lymphocyte subsets in idiopathic nonspecific interstitial pneumonia. Respir Med 96:770–776
Shimizu S, Yoshinouchi T, Naniwa T, Nakamura M, Sato S, Ohtsuki Y, Fujita J, Yamadori I, Eimoto T, Ueda R (2004) Distribution of CXCR3- or CCR4-positive cells in interstitial pneumonia associated with primary Sjögren’s syndrome. Virchows Arch 445:477–484
Steen VD (2005) The lung in systemic sclerosis. J Clin Rheumatol 11:40–46
Takashima H, Smith DR, Fukaura H, Khoury SJ, Hafler DA, Weiner HL (1998) Pulse cyclophosphamide plus methylprednisolone induces myelin-antigen-specific IL-4-secreting T cells in multiple sclerosis patients. Clin Immunol Immunopathol 88:28–34
Tokuyama H, Ueha S, Kurachi M, Matsushima K, Moriyasu F, Blumberg RS, Kakimi K (2005) The simultaneous blockade of chemokine receptors CCR2, CCR5 and CXCR3 by a non-peptide chemokine receptor antagonist protects mice from dextran sodium sulfate-mediated colitis. Int Immunol 17:1023–1034
Acknowledgements
We thank Kyowa Hakko, Tokyo, Japan, and Dr. Masamichi Koike for supplying the CCR4 antibody. We also thank Mr. Seino Nagaya, Department of Pathology, Nagoya City University Medical School, for his excellent technical assistance.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Shimizu, S., Yoshinouchi, T., Niimi, T. et al. Differing distributions of CXCR3- and CCR4-positive cells among types of interstitial pneumonia associated with collagen vascular diseases. Virchows Arch 450, 51–58 (2007). https://doi.org/10.1007/s00428-006-0330-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00428-006-0330-2