Abstract
Purpose
Idiopathic pulmonary fibrosis (IPF) is a restrictive fibrotic lung disease of uncertain etiology. Alveolar epithelial injury may be one of the inciting triggers in the pathogenesis of this disorder. We hypothesized that circulating antibodies to alveolar epithelial and endothelial cells may be involved in the pathogenesis of IPF.
Methods
Antibodies to alveolar epithelial and endothelial cells were analyzed by indirect immunofluorescence using alveolar epithelial cells (A549) and human umbilical vein endothelial cells respectively. IgG and IgM antibodies in patients’ serum were evaluated. Patterns of immunofluorescence, including membranous, cytoplasmic, and nuclear staining, were analyzed by fluorescence microscopy. The severity of immunofluorescence was divided into mild, moderate, and severe categories. Fifty-six patients (IPF = 28, non-IPF ILD = 9, non-ILD control = 19) were evaluated for antiepithelial antibodies, and 28 patients (IPF = 12, non-IPF ILD = 3, non-ILD control = 13) were studied for antiendothelial antibodies.
Results
Compared with control subjects, serum from IPF patients displayed significantly higher IgG binding to alveolar epithelial cells (P = 0.041) with a membranous pattern of immunofluorescence. However, there was no significant difference in immunofluorescence with IgG on endothelial cells (P = 0.165). In terms of IgM antibodies, there was no differential fluorescence observed for either epithelial or endothelial cells.
Conclusions
There is evidence of increased IgG antibodies directed against alveolar epithelium in IPF. These antibodies may play a significant role in the pathogenesis of this fibrotic disorder. The findings of this study suggest further evaluation of the role of immune mediated alveolar epithelial injury in IPF.
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References
Lynch JP III, Wurfel M, Flaherty K, White E, Martinez F, Travis W, Raghu G (2001) Usual interstitial pneumonia. Semin Respir Crit Care Med 22(4):357–386
King TE Jr, Safrin S, Starko KM, Brown KK, Noble PW, Raghu G, Schwartz DA (2005) Analyses of efficacy end points in a controlled trial of interferon-gamma1b for idiopathic pulmonary fibrosis. Chest 127(1):171–177
King TE Jr, Behr J, Brown KK, Du Bois RM, Lancaster L, de Andrade JA, Stahler G, Leconte I, Roux S, Raghu G (2008) BUILD-1: a randomized placebo-controlled trial of bosentan in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 177(1):75–81
Raghu G, Brown KK, Bradford WZ, Starko K, Noble PW, Schwartz DA, King TE Jr (2004) A placebo-controlled trial of interferon gamma-1b in patients with idiopathic pulmonary fibrosis. N Engl J Med 350(2):125–133
Raghu G, Brown KK, Costabel U, Cottin V, Du Bois RM, Lasky JA, Thomeer M, Utz JP, Khandker RK, McDermott L, Fatenejad S (2008) Treatment of idiopathic pulmonary fibrosis with etanercept: an exploratory, placebo-controlled trial. Am J Respir Crit Care Med 178(9):948–955
Carrington CB, Gaensler EA, Coutu RE, FitzGerald MX, Gupta RG (1978) Natural history and treated course of usual and desquamative interstitial pneumonia. N Engl J Med 298(15):801–809
Katzenstein AA, Askin FB (1982) Surgical pathology of non-neoplastic lung disease. Major Probl Pathol 13:1–430
Feghali-Bostwick CA, Tsai CG, Valentine VG, Kantrow S, Stoner MW, Pilewski JM, Gadgil A, George MP, Gibson KF, Choi AM, Kaminski N, Zhang Y, Duncan SR (2007) Cellular and humoral autoreactivity in idiopathic pulmonary fibrosis. J Immunol 179(4):2592–2599
Fujita J, Dobashi N, Ohtsuki Y, Yamadori I, Yoshinouchi T, Kamei T, Tokuda M, Hojo S, Okada H, Takahara J (1999) Elevation of anti-cytokeratin 19 antibody in sera of the patients with idiopathic pulmonary fibrosis and pulmonary fibrosis associated with collagen vascular disorders. Lung 177(5):311–319
Fujita J, Takeuchi T, Dobashi N, Ohtsuki Y, Tokuda M, Takahara J (1999) Detection of anti-ADAM 10 antibody in serum of a patient with pulmonary fibrosis associated with dermatomyositis. Ann Rheum Dis 58(12):770–772
Erlinger R, Rauh G, Behr J, Schumacher U, Welsch U, Zollner N (1991) Similar frequency of autoantibodies against pneumocytes type II and Clara cells in patients with interstitial lung diseases and healthy persons. Klin Wochenschr 69(7):297–302
Meliconi R, Bestagno M, Sturani C, Negri C, Galavotti V, Sala C, Facchini A, Ciarrocchi G, Gasbarrini G, Astaldi Ricotti GC (1989) Autoantibodies to DNA topoisomerase II in cryptogenic fibrosing alveolitis and connective tissue disease. Clin Exp Immunol 76(2):184–189
Meliconi R, Negri C, Borzi RM, Facchini A, Sturani C, Fasano L, Fabbri M, Astaldi Ricotti GC (1993) Antibodies to topoisomerase II in idiopathic pulmonary fibrosis. Clin Rheumatol 12(3):311–315
Wallace WA, Roberts SN, Caldwell H, Thornton E, Greening AP, Lamb D, Howie SE (1994) Circulating antibodies to lung protein(s) in patients with cryptogenic fibrosing alveolitis. Thorax 49(3):218–224
Taille C, Grootenboer-Mignot S, Boursier C, Michel L, Debray MP, Fagart J, Barrientos L, Mailleux A, Cigna N, Tubach F, Marchal-Somme J, Soler P, Chollet-Martin S, Crestani B (2011) Identification of periplakin as a new target for autoreactivity in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 183(6):759–766
American Thoracic Society (2000) Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. American Thoracic Society (ATS), and the European Respiratory Society (ERS) [Review] [234 refs]. Am J Respir Crit Care Med 161(2 Pt 1):646–664
Kim JH, Jang YS, Eom KS, Hwang YI, Kang HR, Jang SH, Kim CH, Park YB, Lee MG, Hyun IG, Jung KS, Kim DG (2007) Transforming growth factor beta1 induces epithelial-to-mesenchymal transition of A549 cells. J Korean Med Sci 22(5):898–904
Strieter RM (2005) Pathogenesis and natural history of usual interstitial pneumonia: the whole story or the last chapter of a long novel. Chest 128(5 Suppl 1):526S–532S
Dobashi N, Fujita J, Ohtsuki Y, Yamadori I, Yoshinouchi T, Kamei T, Tokuda M, Hojo S, Bandou S, Ueda Y, Takahara J (2000) Circulating cytokeratin 8: anti-cytokeratin 8 antibody immune complexes in sera of patients with pulmonary fibrosis. Respiration 67(4):397–401
Dobashi N, Fujita J, Murota M, Ohtsuki Y, Yamadori I, Yoshinouchi T, Ueda R, Bandoh S, Kamei T, Nishioka M, Ishida T, Takahara J (2000) Elevation of anti-cytokeratin 18 antibody and circulating cytokeratin 18: anti-cytokeratin 18 antibody immune complexes in sera of patients with idiopathic pulmonary fibrosis. Lung 178(3):171–179
Dobashi N, Fujita J, Ohtsuki Y, Yamadori I, Yoshinouchi T, Kamei T, Takahara J (1999) Elevated serum and BAL cytokeratin 19 fragment in pulmonary fibrosis and acute interstitial pneumonia. Eur Respir J 14(3):574–578
Fujita J, Bandoh S, Ohtsuki Y, Dobashi N, Hiroi M, Takeuchi T, Fukunaga Y, Miyaue H, Onishi S, Ishida T, Takahara J (2000) The role of anti-epithelial cell antibodies in the pathogenesis of bilateral radiation pneumonitis caused by unilateral thoracic irradiation. Respir Med 94(9):875–880
Fujita J, Ohtsuki Y, Bandoh S, Takashima H, Ueda Y, Wu F, Tojo Y, Kubo A, Ishida T (2004) Elevation of cytokeratin 19 fragment (CYFRA 21-1) in serum of patients with radiation pneumonitis: possible marker of epithelial cell damage. Respir Med 98(4):294–300
Ward PA (1979) Immune complex injury of the lung. Am J Pathol 97(1):85–92
Magro CM, Ross P, Marsh CB, Allen JN, Liff D, Knight DA, Waldman WJ, Cowden DJ (2007) The role of anti-endothelial cell antibody-mediated microvascular injury in the evolution of pulmonary fibrosis in the setting of collagen vascular disease. Am J Clin Pathol 127(2):237–247
Magro CM, Waldman WJ, Knight DA, Allen JN, Nadasdy T, Frambach GE, Ross P, Marsh CB (2006) Idiopathic pulmonary fibrosis related to endothelial injury and antiendothelial cell antibodies. Hum Immunol 67(4–5):284–297
Magro CM, Allen J, Pope-Harman A, Waldman WJ, Moh P, Rothrauff S, Ross P Jr (2003) The role of microvascular injury in the evolution of idiopathic pulmonary fibrosis. Am J Clin Pathol 119(4):556–567
Bellon B, Bernaudin JF, Mandet C, Chamak B, Kuhn J, Druet P (1982) Immune complex-mediated lung injury produced by horseradish peroxidase (HRP) and anti-HRP antibodies in rats. Am J Pathol 107(1):16–24
Dall’Aglio PP, Pesci A, Bertorelli G, Brianti E, Scarpa S (1988) Study of immune complexes in bronchoalveolar lavage fluids. Respiration 54(Suppl 1):36–41
Dreisin RB, Schwarz MI, Theofilopoulos AN, Stanford RE (1978) Circulating immune complexes in the idiopathic interstitial pneumonias. N Engl J Med 298(7):353–357
Haslam PL, Thompson B, Mohammed I, Townsend PJ, Hodson ME, Holborow EJ, Turner-Warwick M (1979) Circulating immune complexes in patients with cryptogenic fibrosing alveolitis. Clin Exp Immunol 37(3):381–390
Bournazos S, Bournazou I, Murchison JT, Wallace WA, McFarlane P, Hirani N, Simpson AJ, Dransfield I, Hart SP (2010) Fcgamma receptor IIIb (CD16b) polymorphisms are associated with susceptibility to idiopathic pulmonary fibrosis. Lung 188(6):475–481
Bournazos S, Grinfeld J, Alexander KM, Murchison JT, Wallace WA, McFarlane P, Hirani N, Simpson AJ, Dransfield I, Hart SP (2010) Association of FcgammaR IIa R131H polymorphism with idiopathic pulmonary fibrosis severity and progression. BMC Pulm Med 10:51
Wallace WA, Schofield JA, Lamb D, Howie SE (1994) Localisation of a pulmonary autoantigen in cryptogenic fibrosing alveolitis. Thorax 49(11):1139–1145
Marrack P, Kappler J, Kotzin BL (2001) Autoimmune disease: why and where it occurs. Nat Med 7(8):899–905
Zappala CJ, Latsi PI, Nicholson AG, Colby TV, Cramer D, Renzoni EA, Hansell DM, Du Bois RM, Wells AU (2010) Marginal decline in forced vital capacity is associated with a poor outcome in idiopathic pulmonary fibrosis. Eur Respir J 35(4):830–836
Takabatake N, Arao T, Sata M, Abe S, Inoue S, Shibata Y, Takeishi Y, Kubota I (2005) Involvement of pulmonary endothelial cell injury in the pathogenesis of pulmonary fibrosis: clinical assessment by 123I-MIBG lung scintigraphy. Eur J Nucl Med Mol Imaging 32(2):221–228
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Fahim, A., Chong, M.C., Crooks, M.G. et al. Idiopathic Pulmonary Fibrosis is Associated with Circulating Antiepithelial Antibodies. Lung 190, 451–458 (2012). https://doi.org/10.1007/s00408-012-9390-z
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DOI: https://doi.org/10.1007/s00408-012-9390-z