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Cellular and Humoral Autoreactivity in Idiopathic Pulmonary Fibrosis¹

Carol A. Feghali-Bostwick^2,*,, Christopher G. Tsai^2,*, Vincent G. Valentine, Stephen Kantrow, Michael W. Stoner^*, Joseph M. Pilewski^*, Aneal Gadgil^*, M. Patricia George^*, Kevin F. Gibson^*,, Augustine M. K. Choi^*, Naftali Kaminski^*,, Yingze Zhang^*, and Steven R. Duncan^3,*

^* Division of Pulmonary, Allergy, and Critical Care Medicine, and Dorothy P. and Richard P. Simmons Center for Interstitial Lung Disease, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, and Division of Pulmonary Medicine, Ochsner Clinic Foundation, New Orleans, LA 70112

Idiopathic pulmonary fibrosis (IPF) is a morbid, refractory lung disorder with an unknown pathogenesis. To investigate potential adaptive immune mechanisms in IPF, we compared phenotypes and effector functions of peripheral CD4 T cells, autoantibody production, and proliferative responses of pulmonary hilar lymph node CD4 T cells to autologous lung extracts from afflicted patients and normals. Our results show that greater proportions of peripheral CD4 T lymphocytes in IPF subjects expressed MHC class II and CD154 (CD40L), and they more frequently elaborated TGF-1, IL-10, and TNF-. Abnormal CD4 T cell clonal expansions were found in all IPF patients, and 82% of these subjects also had IgG autoantibodies against cellular Ags. IPF lung extracts stimulated proliferations of autologous CD4 T cells, unlike preparations from normals or those with other lung diseases, and the IPF proliferative responses were enhanced by repeated cycles of stimulation. Thus, CD4 T cells from IPF patients have characteristics typical of cell-mediated pathologic responses, including augmented effector functions, provision of facultative help for autoantibody production, oligoclonal expansions, and proliferations driven by an Ag present in diseased tissues. Recognition that an autoreactive immune process is present in IPF can productively focus efforts toward identifying the responsible Ag, and implementing more effective therapies.

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 research was supported in part by U.S. National Institutes of Health Grants 1R01HL64192, 1R01HL073241, 1P50HL084932, 1R01AR050840, and a donation from the Dorothy P. and Richard P. Simmons family.

² C.A.F.-B. and C.G.T. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Steven R. Duncan, Pulmonary, Allergy, and Critical Care Medicine, 628 NW Montefiore-University Hospital, 3459 Fifth Avenue, University of Pittsburgh, PA 15213. E-mail address: duncsr{at}upmc.edu

⁴ Abbreviations used in this paper: IPF, idiopathic pulmonary fibrosis; FVC, forced vital capacity; COPD, chronic obstructive pulmonary disease; TCRBV, T cell Ag receptor -chain variable region.

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