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* Department of Respirology (B2), Graduate School of Medicine, Chiba University, Chiba, Japan; and
Division of Pulmonary and Critical Care Medicine, Department of Medicine, School of Medicine, New York University, New York, NY 10016
Consistent with the hypothesis that pulmonary epithelial apoptosis is the key to the acute exacerbation of idiopathic pulmonary fibrosis (IPF), we conducted serological identification of Ags by recombinant expression cloning (SEREX) analysis using type II alveolar cell carcinoma (A549) cell lines to identify disease-related Abs. In a survey of Abs to the recombinant autoantigens identified by SEREX analysis, five Abs were identified as novel candidates for the acute exacerbation of IPF. Abs to annexin 1 were detected in 47 and 53% of the sera and bronchoalveolar lavage materials from patients with acute exacerbation of IPF. Some identical TCR Vβ genes were identified in sequential materials obtained at 1–3 mo in all 10 acute exacerbation IPF cases, suggesting that some infiltrating CD4-positive T cells sharing limited epitopes expand by Ag-driven stimulation during disease extension. The CDR3 region of these identical TCR Vβ genes showed high homology with the N-terminal portion of annexin 1, including in the HLA-DR ligand epitopes predicted by TEPITOPE analysis. By Western blotting analysis and observation of the CD4-positive T cell responses in bronchoalveolar lavage samples, the N-terminal portion of annexin 1 was cleaved and found to induce marked proliferative responses of CD4-positive T cells in three patients. Our study demonstrates that annexin 1 is an autoantigen that raises both Ab production and T cell response in patients with acute exacerbation of IPF, and that the N-terminal portion of annexin 1 plays some role in the pathogenesis of acute exacerbation in IPF patients.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by a grant for scientific research from the Japanese Ministry of Education (15590798).
2 Address correspondence and reprint requests to Dr. Katsushi Kurosu, Department of Respirology (B2), Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. E-mail address: kurosu{at}faculty.chiba-u.jp
3 Abbreviations used in this paper: IPF, idiopathic pulmonary fibrosis; SEREX, serological analysis of the cDNA expression library; SLE, systemic lupus erythematosis; RA, rheumatoid arthritis; BAL, bronchoalveolar lavage; TGF, transforming growth factor; VATS, video-associated thoracic surgery; IP-CVD, interstitial pneumonia related to collagen vascular disease; PM/DM, polymyositis/dermatomyositis; Ssc, scleroderma; HP, hypersensitivity pneumonitis; ER, endoplasmic reticulum.
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