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T Cell Responses to Mycobacterial Catalase-Peroxidase Profile a Pathogenic Antigen in Systemic Sarcoidosis¹

Edward S. Chen^2,*, Jan Wahlström^2,, Zhimin Song^2,*, Matthew H. Willett^*, Maria Wikén, Rex C. Yung^*, Erin E. West^*, John F. McDyer^*, Ying Zhang, Anders Eklund, Johan Grunewald^3, and David R. Moller^3,*

^* Division of Pulmonary and Critical Care Medicine, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; Respiratory Medicine Unit, Department of Medicine at Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden; and Department of Molecular Microbiology and Immunology, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205

Sarcoidosis is a systemic granulomatous disease associated with local epithelioid granulomas, CD4⁺ T cells, and Th1 cytokines. The tissue Ags that drive this granulomatous inflammation are uncertain. In this study, we used IFN--ELISPOT assays and flow cytometry to assess lung and blood T cell responses to the candidate pathogenic Ag, Mycobacterium tuberculosis catalase-peroxidase (mKatG) in patients with sarcoidosis from two centers. Despite differences in patient phenotypic, genetic, and prognostic characteristics, we report that T cell responses to mKatG were remarkably similar in these cohorts, with higher frequencies of mKatG-reactive, IFN--expressing T cells in the blood of sarcoidosis patients compared with nontuberculosis sensitized healthy controls, and (in a subset) in greater numbers than T cells reactive to purified protein derivative. In sarcoidosis, mKatG-reactive CD4⁺ Th1 cells preferentially accumulated in the lung, indicating a compartmentalized response. Patients with or without Löfgren syndrome had similar frequencies of mKatG specific IFN--expressing blood T cells. Circulating mKatG-reactive T cells were found in chronic active sarcoidosis but not in patients with inactive disease. Together, these results demonstrate that T cell responses to mKatG in sarcoidosis fit a profile expected for a pathogenic Ag, supporting an immunotherapeutic approach to this disease.

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 by National Institutes of Health Grants HL-68019, HL-77732, and HL-83870 (to D.R.M.), HL-71100 (to E.S.C.), by the Life and Breath Foundation, and the Hospital for the Consumptives of Maryland (Eudowood).

² E.S.C., J.W., and Z.S. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Johan Grunewald, Lung Research Laboratory L4:01, Karolinska University Hospital Solna, S-171 76 Stockholm, Sweden or Dr. David R. Moller, 5501 Hopkins Bayview Circle, Baltimore, MD 21224. E-mail addresses: johan.grunewald{at}ki.se and dmoller{at}jhmi.edu

⁴ Abbreviations used in this paper: mKatG, Mycobacterium tuberculosis catalase-peroxidase; PPD, purified protein derivative; BCG, Bacillus Calmette-Guérin; BAL, bronchoalveolar lavage; sfc, spot forming cell; SEB, staphylococcal enterotoxin B; Be, beryllium; Treg, regulatory T cell; CTCM, complete tissue culture medium.

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