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Infection and Immunity, November 2002, p. 6509-6511, Vol. 70, No. 11
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.11.6509-6511.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

LETTER TO THE EDITOR


Authors' Reply


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LETTER
 
We read with interest the letter of Dr. Gey van Pittius et al. in response to our recent paper (6). Both the ESAT-6 and CFP-10 antigens have over the years been analyzed extensively for their distribution in mycobacterial species (13), and their diagnostic relevance has been discussed (11). As Dr. Gey van Pittius et al. state, thus far homologous genes have been detected in a number of species outside the Mycobacterium tuberculosis complex. As a consequence, the expression of these antigens in other mycobacteria may in theory confound specific diagnosis of Mycobacterium tuberculosis and Mycobacterium bovis infections.

The question, however, is what consequences does this have for clinical and epidemiological practice in tuberculosis control. The presence of ESAT-6 and CFP-10 homologues in other species, for example, does not seem to confound the detection of M. tuberculosis-associated specific responses in the large number of studies conducted by different groups over the last 5 years (1-3, 9, 10). At present it remains unknown whether these genes are truly expressed in nonpathogenic as opposed to pathogenic mycobacteria and if the amino acid identity observed is enough to trigger a highly specific T-cell response. Particularly important for this discussion is the observation that T-cell responses to ESAT-6 and CFP-10 are apparently associated with active ongoing infection and as such have prognostic protential (5, 14). Therefore, T-cell responses to these antigens are presumably not associated with exposure to nonpathogenic strains such as M. smegmatis and M. scrofulaceum. Even in highly sensitive enzyme-linked immunospot assays that detect single ESAT-6-positive T cells, control individuals were negative (8). This conclusion is also supported by the many studies conducted in cattle where these reagent are highly specific indicators of ongoing M. bovis infection although cattle must be exposed daily to nonpathogenic mycobacteria from soil and natural water sources (4, 12, 14). That (rare) clinical infection with the two pathogenic strains M. marinum and M. kansasii, on the other hand, actually can trigger ESAT-6- and CFP-10-specific T-cell responses was recently convincingly demonstrated (S. M. Arend, K. E. van Meijgaarden, K. de Boer, E. Cerdá de Palou, D. van Soolingen, T. H. M. Ottenhoff, and J. T. van Dissel, submitted for publication). The same holds true for M. leprae as discussed above (6). While some caution may therefore be needed in the immunodiagnosis of clinical tuberculosis since infections with these three pathogens cannot be excluded by ESAT-6- and CFP-10-based tests, in practice only infections with M. kansasii may, though rarely, pose a differential diagnostic problem.

We agree with Dr. Gey van Pittius et al. that there is an urgent need for good diagnostic tools in the developing world. We assume that the major complicating factor for the application of reagents such as ESAT-6 and CFP-10 in the diagnosis of tuberculosis in countries of endemicity, however, is not the presence of environmental mycobacteria but the enormous reservoir of latent human tuberculosis (7).

Thus, despite the fact that antigens such as ESAT-6 and CFP-10 are not restricted to M. tuberculosis, they hold promise for the specific detection of M. tuberculosis infection.


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REFERENCES
 
    1
  1. Arend, S. M., P. Andersen, K. E. van Meijgaarden, R. L. Skjot, Y. W. Subronto, J. T. van Dissel, and T. H. Ottenhoff. 2000. Detection of active tuberculosis infection by T cell responses to early-secreted antigenic target 6-kDa protein and culture filtrate protein 10. J. Infect. Dis. 181: 1850-1854.[CrossRef][Medline]
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  2. Arend, S. M., A. Geluk, K. E. van Meijgaarden, J. T. van Dissel, M. Theisen, P. Andersen, and T. H. Ottenhoff. 2000. Antigenic equivalence of human T-cell responses to Mycobacterium tuberculosis-specific RD1-encoded protein antigens ESAT-6 and culture filtrate protein 10 and to mixtures of synthetic peptides. Infect. Immun. 68:3314-3321.[Abstract/Free Full Text]
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  3. Arend, S. M., T. H. Ottenhoff, P. Andersen, and J. T. van Dissel. 2001. Uncommon presentations of tuberculosis: the potential value of a novel diagnostic assay based on the Mycobacterium tuberculosis-specific antigens ESAT-6 and CFP-10. Int. J. Tuberc Lung Dis. 5:680-686.[Medline]
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  5. Doherty, T. M., A. Demissie, J. Olobo, D. Wolday, S. Britton, T. Eguale, P. Ravn, and P. Andersen. 2002. Immune responses to the Mycobacterium tuberculosis-specific antigen ESAT-6 signal subclinical infection among contacts of tuberculosis patients. J. Clin. Microbiol. 40:704-706.[Abstract/Free Full Text]
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  6. Geluk, A., K. E. van Meijgaarden, K. L. M. C. Franken, Y. W. Subronto, B. Wieles, S. M. Arend, E. P. Sampaio, T. de Boer, W. R. Faber, B. Naafs, and T. H. M. Ottenhoff. 2002. Identification and characterization of the ESAT-6 homologue of Mycobacterium leprae and T-cell cross-reactivity with Mycobacterium tuberculosis. Infect. Immun. 70:2544-2548.[Abstract/Free Full Text]
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  7. Lalvani, A., P. Nagvenkar, Z. Udwadia, A. A. Pathan, K. A. Wilkinson, J. S. Shastri, K. Ewer, A. V. Hill, A. Mehta, and C. Rodrigues. 2001. Enumeration of T cells specific for RD1-encoded antigens suggests a high prevalence of latent Mycobacterium tuberculosis infection in healthy urban Indians. J. Infect. Dis. 183: 469-477.[CrossRef][Medline]
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  8. Lalvani, A., A. A. Pathan, H. Durkan, K. A. Wilkinson, A. Whelan, J. J. Deeks, W. H. Reece, M. Latif, G. Pasvol, and A. V. Hill. 2001. Enhanced contact tracing and spatial tracking of Mycobacterium tuberculosis infection by enumeration of antigen-specific T cells. Lancet 357:2017-2021.[CrossRef][Medline]
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  9. Lein, A. D., C. F. von Reyn, P. Ravn, C. R. Horsburgh, Jr., L. N. Alexander, and P. Andersen. 1999. Cellular immune responses to ESAT-6 discriminate between patients with pulmonary disease due to Mycobacterium avium complex and those with pulmonary disease due to Mycobacterium tuberculosis. Clin. Diagn. Lab. Immunol. 6:606-609.[Abstract/Free Full Text]
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  10. Munk, M. E., S. M. Arend, I. Brock, T. H. Ottenhoff, and P. Andersen. 2001. Use of ESAT-6 and CFP-10 antigens for diagnosis of extrapulmonary tuberculosis. J. Infect. Dis. 183: 175-176.[CrossRef][Medline]
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  11. Pollock, J. M., and P. Andersen. 1997. The potential of the ESAT-6 antigen secreted by virulent mycobacteria for specific diagnosis of tuberculosis. J. Infect. Dis. 175: 1251-1254.[Medline]
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  12. Pollock, J. M., B. M. Buddle, and P. Andersen. 2001. Towards more accurate diagnosis of bovine tuberculosis using defined antigens. Tuberculosis 81:65-69.
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  13. Sorensen, A. L., S. Nagai, G. Houen, P. Andersen, and A. B. Andersen. 1995. Purification and characterization of a low-molecular-mass T-cell antigen secreted by Mycobacterium tuberculosis. Infect. Immun. 63:1710-1717.[Abstract]
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  14. Vordermeier, H. M., M. A. Chambers, P. J. Cockle, A. O. Whelan, J. Simmons, and R. G. Hewinson. 2002. Correlation of ESAT-6-specific gamma interferon production with pathology in cattle following Mycobacterium bovis BCG vaccination against experimental bovine tuberculosis. Infect. Immun. 70:3026-3032.
A. Geluk1
T. H. M. Ottenhoff1*
S. M. Arend2
P. Andersen3
T. M. Doherty3
Department of Immunohematology and  Blood Transfusion, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands,1
Department of Infectious Diseases, Leiden University Medical Center, 2300 RC Leiden, The Netherlands,2
Department of TB Immunology, Statens Serum Institute, Copenhagen, Denmark,2

* Phone: 31-71-5263800 Fax: 31-71-5216751 E-mail: t.h.m.ottenhoff{at}lumc.nl.

Infection and Immunity, November 2002, p. 6509-6511, Vol. 70, No. 11
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.11.6509-6511.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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