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

Abstract

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-4␦2, 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-4␦2 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.

Diagnosing TB infection in children: analysis of discordances using in vitro tests and the tuberculin skin test

“…It has been shown, in animal models, that a decreased production of IFN-c and a decrease in the number of IFN-c-producing cells are predictive of an increased risk of developing TB [40]. In contact patients, it has been observed that the progression to disease was associated with a decrease in IFN-c, and an increase in interleukin (IL)-10 and IL-4 levels [41,42]. Some data suggest that in individuals with a recent exposure to TB, the protective response shifts from Th1 to Th2, even before the clinical symptoms appear [43].…”

Is Interleukin-4δ3 Splice Variant Expression in Bovine Tuberculosis a Marker of Protective Immunity?

“…on May 11, 2018 by guest http://iai.asm.org/ identify groups of individuals infected with M. tuberculosis whose elevated IL-4␦2 levels appeared to correlate with their ability to control infection (10,11). BCG vaccination-induced protection model.…”

“…Pertinently, increased levels of IL-4␦2 mRNA were recently found in people latently infected with Mycobacterium tuberculosis compared with uninfected healthy controls or patients with active pulmonary TB (10). Increased IL-4␦2 mRNA levels have also been found in TB contacts compared with noncontacts, and the authors hypothesized that the ratio of IL-4 to IL-4␦2 might be important in the progression to active disease (11,14). Lastly, chemotherapy of TB patients resulted in increased expression of IL-4␦2 in both pulmonary TB and in human immunodeficiency virus-TB coinfection (12).…”

“…Previous clinical studies have shown that the IL-4␦2 splice variant is found in unstimulated PBMC (10)(11)(12)14). Therefore, we used freshly isolated PBMC from all cattle in this study.…”

Differential Early Secreted Antigen Target (ESAT) 6 kDa–induced IFN-γ and SOCS1 expression distinguishes latent and active tuberculosis

“…Further clinical studies have shown an association between immune reactivity to ESAT6 with that of the increased bacterial load and disease pathology in tuberculosis [29]. ESAT6 has shown to induce altered cytokine profile with decreased IFN-γ and increased IL4 responses in individuals with advanced disease [30].…”