The Journal of Experimental Medicine
BioSymposia
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Published 7 March 2005. doi:10.1084/jem.20040429
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 201, Number 5, 755-767
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ARTICLE

 Mycobacterial catalase–peroxidase is a tissue antigen and target of the adaptive immune response in systemic sarcoidosis

Zhimin Song1, Lisa Marzilli2, Brian M. Greenlee1, Edward S. Chen1, Richard F. Silver5, Frederic B. Askin3, Alvin S. Teirstein6, Ying Zhang4, Robert J. Cotter2, and David R. Moller1

1 Division of Pulmonary and Critical Care Medicine, Department of Medicine
2 Department of Pharmacology and Molecular Sciences, The Johns Hopkins University Bloomberg School of Public Health, The Johns Hopkins University School of Medicine, Baltimore, MD 21205
3 Department of Pathology, The Johns Hopkins University Bloomberg School of Public Health, The Johns Hopkins University School of Medicine, Baltimore, MD 21205
4 Department of Molecular Microbiology and Immunology, The Johns Hopkins University Bloomberg School of Public Health, The Johns Hopkins University School of Medicine, Baltimore, MD 21205
5 Department of Medicine, Case Western Reserve School of Medicine, Cleveland, OH 441063
6 Division of Pulmonary and Critical Care Medicine, Mount Sinai Medical Center, New York, NY 10029

CORRESPONDENCE David R. Moller: dmoller{at}jhmi.edu

Sarcoidosis is a disease of unknown etiology characterized by noncaseating epithelioid granulomas, oligoclonal CD4+ T cell infiltrates, and immune complex formation. To identify pathogenic antigens relevant to immune-mediated granulomatous inflammation in sarcoidosis, we used a limited proteomics approach to detect tissue antigens that were poorly soluble in neutral detergent and resistant to protease digestion, consistent with the known biochemical properties of granuloma-inducing sarcoidosis tissue extracts. Tissue antigens with these characteristics were detected with immunoglobulin (Ig)G or F(ab')2 fragments from the sera of sarcoidosis patients in 9 of 12 (75%) sarcoidosis tissues (150–160, 80, or 60–64 kD) but only 3 of 22 (14%) control tissues (all 62–64 kD; P = 0.0006). Matrix-assisted laser desorption/ionization time of flight mass spectrometry identified Mycobacterium tuberculosis catalase–peroxidase (mKatG) as one of these tissue antigens. Protein immunoblotting using anti-mKatG monoclonal antibodies independently confirmed the presence of mKatG in 5 of 9 (55%) sarcoidosis tissues but in none of 14 control tissues (P = 0.0037). IgG antibodies to recombinant mKatG were detected in the sera of 12 of 25 (48%) sarcoidosis patients compared with 0 of 11 (0%) purified protein derivative (PPD)– (P = 0.0059) and 4 of 10 (40%) PPD+ (P = 0.7233) control subjects, suggesting that remnant mycobacterial catalase–peroxidase is one target of the adaptive immune response driving granulomatous inflammation in sarcoidosis.

Abbreviations used: BCG, Bacille Calmette-Guerin; DIG, digoxigenin; HRP, horseradish peroxidase; ISH, in situ hybridization; MALDI-TOF, matrix-assisted laser desorption/ionization time of flight; mHsp65, Mycobacterium bovis Hsp65 protein; mKatG, Mycobacterium tuberculosis catalase–peroxidase; MOWSE, mol wt search; Mtb, Mycobacterium tuberculosis; Pe, precipitated cell pellets; PK, proteinase K; PPD, purified protein derivative; TSA, tyramide signal amplification; TX100, Triton X-100.

L. Marzilli's present address is Wyeth Biopharma Co., Andover, MA 01810.


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