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Infection and Immunity, May 2006, p. 2817-2822, Vol. 74, No. 5
0019-9567/06/$08.00+0     doi:10.1128/IAI.74.5.2817-2822.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

The 6-Kilodalton Early Secreted Antigenic Target-Responsive, Asymptomatic Contacts of Tuberculosis Patients Express Elevated Levels of Interleukin-4 and Reduced Levels of Gamma Interferon

Abebech Demissie,¹ Liya Wassie,¹ Markos Abebe,¹ Abraham Aseffa,¹ Graham Rook,³ Alimuddin Zumla,³ Peter Andersen,² T. Mark Doherty,^2* and the VACSEL Study Group

Armauer Hansen Research Institute, Addis Ababa, Ethiopia,¹ Department of Tuberculosis Immunology, Statens Serum Institute, Copenhagen, Denmark,² Centre for Infectious Diseases and International Health, Windeyer Institute of Medical Sciences, Royal Free and University College Medical School, London, United Kingdom³

Received 19 October 2005/ Returned for modification 20 December 2005/ Accepted 1 February 2006

It is well known that the majority of healthy individuals exposed to Mycobacterium tuberculosis do not become clinically ill. We have previously shown that in recently exposed healthy contacts of tuberculosis (TB) patients, a strong immune response to the M. tuberculosis 6-kDa early secreted antigenic target (ESAT-6) virulence factor correlated with a higher risk of subsequent disease, although the mechanism was unclear at that time. Inspired by recent reports that elevated expression of interleukin-4 (IL-4) in health care workers exposed to M. tuberculosis also correlated with a higher risk of their subsequently developing disease, we examined expression of IL-4, its competitive antagonist IL-42, and gamma interferon (IFN-) in healthy household contacts of TB patients from Ethiopia. We then compared cytokine expression to their recognition of ESAT-6 (which is largely restricted to members of the tuberculosis complex and which serves as a reliable marker of infection) or to Ag85A (an antigen that is conserved among the mycobacteria and serves as a nonspecific control). Our study shows that in these recently exposed individuals, there is a correlation between a strong response to ESAT-6 and elevated expression of IL-4. Further, elevated expression of IL-4 is associated with lower expression of its antagonistic splice variant IL-42 and with the Th1 cytokine IFN-, suggesting that in these at-risk individuals, immunity is skewed away from a protective Th1 response, even before the development of clinical symptoms.

Editor: J. L. Flynn

The VACSEL study group also includes Helen Fletcher, University College, London, United Kingdom (until 2003); Chifumbe Chintu, Gina Mulundu, and Peter Mwaba, University of Zambia School of Medicine, Lusaka, Zambia; and K. P. W. J. McAdam (until 2003), Patrick Owiafe, David Warndorff (2001), Christian Lienhardt (until 2001), R. Brookes, and Phillip Hill (from 2001), MRC, Gambia.

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