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Dynamics of adrenal steroids are related to variations in Th1 and Treg populations during Mycobacterium tuberculosis infection in HIV positive persons.

Quiroga MF, Angerami MT, Santucci N, Ameri D, Francos JL, Wallach J, Sued O, Cahn P, Salomón H, Bottasso O - PLoS ONE (2012)

Bottom Line: DHEA levels were diminished in HIV-TB and HIV-TB IRIS patients compared to healthy donors (HD), HIV+ individuals and HIV+ individuals with latent TB (HIV-LTB), whereas dehydroepiandrosterone sulfate (DHEA-s) levels were markedly diminished in HIV-TB IRIS individuals.HIV-TB and IRIS patients presented a cortisol/DHEA ratio significantly higher than HIV+, HIV-LTB and HD individuals.We observed an inverse correlation between DHEA-s plasma level and Treg frequency in co-infected individuals, and CD4+FoxP3+ Treg frequency was increased in HIV-TB and IRIS patients compared to other groups.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, National Reference Center for AIDS, University of Buenos Aires School of Medicine, Buenos Aires, Argentina. fquiroga@fmed.uba.ar

ABSTRACT
Tuberculosis (TB) remains the most frequent cause of illness and death from an infectious agent, and its interaction with HIV has devastating effects. We determined plasma levels of dehydroepiandrosterone (DHEA), its circulating form DHEA-suphate (DHEA-s) and cortisol in different stages of M. tuberculosis infection, and explored their role on the Th1 and Treg populations during different scenarios of HIV-TB coinfection, including the immune reconstitution inflammatory syndrome (IRIS), a condition related to antiretroviral treatment. DHEA levels were diminished in HIV-TB and HIV-TB IRIS patients compared to healthy donors (HD), HIV+ individuals and HIV+ individuals with latent TB (HIV-LTB), whereas dehydroepiandrosterone sulfate (DHEA-s) levels were markedly diminished in HIV-TB IRIS individuals. HIV-TB and IRIS patients presented a cortisol/DHEA ratio significantly higher than HIV+, HIV-LTB and HD individuals. A positive correlation was observed between DHEA-s and CD4 count among HIV-TB individuals. Conversely, cortisol plasma level inversely correlated with CD4 count within HIV-TB individuals. M. tuberculosis-specific Th1 lymphocyte count was increased after culturing PBMC from HIV-TB individuals in presence of DHEA. We observed an inverse correlation between DHEA-s plasma level and Treg frequency in co-infected individuals, and CD4+FoxP3+ Treg frequency was increased in HIV-TB and IRIS patients compared to other groups. Strikingly, we observed a prominent CD4+CD25-FoxP3+ population across HIV-TB and HIV-TB IRIS patients, which frequency correlated with DHEA plasma level. Finally, DHEA treatment negatively regulated FoxP3 expression without altering Treg frequency in co-infected patients. These data suggest an enhancing role for DHEA in the immune response against M. tuberculosis during HIV-TB coinfection and IRIS.

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DHEA modulates the expression of the FoxP3 transcription factor in coinfected individuals. A and B.Percentages of Treg cells (defined as CD4+FoxP3+CD25+) in PBMC from A. HIV-TB and B. HD individuals stimulated with M. tuberculosis antigen in the presence or absence of DHEA at the indicated concentrations for 3 days. Bars indicate the mean ± SEM for each experimental condition. C and D. Relative FoxP3 Median florescence intensity (MFI) in Treg lymphocytes from C. HIV-TB patients and D. HD volunteers after culturing PBMC as detailed in A. Bars indicate the mean ± SEM for each treatment. Data are representative of four different experiments. *: p < 0.05; **: p < 0.01. E. Representative flow cytometry graphs depicting the results obtained from culturing PBMC from HIV-TB and HD individuals as indicated above.
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pone-0033061-g005: DHEA modulates the expression of the FoxP3 transcription factor in coinfected individuals. A and B.Percentages of Treg cells (defined as CD4+FoxP3+CD25+) in PBMC from A. HIV-TB and B. HD individuals stimulated with M. tuberculosis antigen in the presence or absence of DHEA at the indicated concentrations for 3 days. Bars indicate the mean ± SEM for each experimental condition. C and D. Relative FoxP3 Median florescence intensity (MFI) in Treg lymphocytes from C. HIV-TB patients and D. HD volunteers after culturing PBMC as detailed in A. Bars indicate the mean ± SEM for each treatment. Data are representative of four different experiments. *: p < 0.05; **: p < 0.01. E. Representative flow cytometry graphs depicting the results obtained from culturing PBMC from HIV-TB and HD individuals as indicated above.

Mentions: When assessing CD4+ CD25+ FoxP3+ Treg frequency, we observed similar percentages among groups, except the HIV-LTB group that showed lower values, statistically significant in relation to HIV-TB patients (Fig. 3A and D). Strikingly, we observed the emergence of a prominent population of Treg lacking CD25 expression among co-infected and IRIS patients (Fig. 3B and D), significantly higher than HIV+, HIV-LTB individuals and HD. When analyzing total FoxP3+ expression in CD4 T cells irrespective of CD25 expression, we observed the same differences among groups (Fig. 3C and D). We thoroughly studied Treg populations within each group, and observed higher significant proportions of FoxP3+ CD25- Treg compared to FoxP3+ CD25+ in HIV-TB and IRIS patients (Fig. 4A and B), whereas HIV, HIV-LTB individuals and HD showed significantly increased percentages of FoxP3+ CD25+ Treg compared to FoxP3+ CD25- cells (Fig. 4C, D and E). Moreover, the frequency of these “unconventional” FoxP3+ CD25- Treg cell negatively correlated with DHEA-s plasma levels (Fig. 5F, rs = -0.6473, p = 0.0006, n = 24). Finally, we examined the stability of FoxP3 by culturing PBMC from HIV-TB individuals in the presence of media, with no variation in FoxP3 expression in the CD25 negative population being observed (data not shown).


Dynamics of adrenal steroids are related to variations in Th1 and Treg populations during Mycobacterium tuberculosis infection in HIV positive persons.

Quiroga MF, Angerami MT, Santucci N, Ameri D, Francos JL, Wallach J, Sued O, Cahn P, Salomón H, Bottasso O - PLoS ONE (2012)

DHEA modulates the expression of the FoxP3 transcription factor in coinfected individuals. A and B.Percentages of Treg cells (defined as CD4+FoxP3+CD25+) in PBMC from A. HIV-TB and B. HD individuals stimulated with M. tuberculosis antigen in the presence or absence of DHEA at the indicated concentrations for 3 days. Bars indicate the mean ± SEM for each experimental condition. C and D. Relative FoxP3 Median florescence intensity (MFI) in Treg lymphocytes from C. HIV-TB patients and D. HD volunteers after culturing PBMC as detailed in A. Bars indicate the mean ± SEM for each treatment. Data are representative of four different experiments. *: p < 0.05; **: p < 0.01. E. Representative flow cytometry graphs depicting the results obtained from culturing PBMC from HIV-TB and HD individuals as indicated above.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3303789&req=5

pone-0033061-g005: DHEA modulates the expression of the FoxP3 transcription factor in coinfected individuals. A and B.Percentages of Treg cells (defined as CD4+FoxP3+CD25+) in PBMC from A. HIV-TB and B. HD individuals stimulated with M. tuberculosis antigen in the presence or absence of DHEA at the indicated concentrations for 3 days. Bars indicate the mean ± SEM for each experimental condition. C and D. Relative FoxP3 Median florescence intensity (MFI) in Treg lymphocytes from C. HIV-TB patients and D. HD volunteers after culturing PBMC as detailed in A. Bars indicate the mean ± SEM for each treatment. Data are representative of four different experiments. *: p < 0.05; **: p < 0.01. E. Representative flow cytometry graphs depicting the results obtained from culturing PBMC from HIV-TB and HD individuals as indicated above.
Mentions: When assessing CD4+ CD25+ FoxP3+ Treg frequency, we observed similar percentages among groups, except the HIV-LTB group that showed lower values, statistically significant in relation to HIV-TB patients (Fig. 3A and D). Strikingly, we observed the emergence of a prominent population of Treg lacking CD25 expression among co-infected and IRIS patients (Fig. 3B and D), significantly higher than HIV+, HIV-LTB individuals and HD. When analyzing total FoxP3+ expression in CD4 T cells irrespective of CD25 expression, we observed the same differences among groups (Fig. 3C and D). We thoroughly studied Treg populations within each group, and observed higher significant proportions of FoxP3+ CD25- Treg compared to FoxP3+ CD25+ in HIV-TB and IRIS patients (Fig. 4A and B), whereas HIV, HIV-LTB individuals and HD showed significantly increased percentages of FoxP3+ CD25+ Treg compared to FoxP3+ CD25- cells (Fig. 4C, D and E). Moreover, the frequency of these “unconventional” FoxP3+ CD25- Treg cell negatively correlated with DHEA-s plasma levels (Fig. 5F, rs = -0.6473, p = 0.0006, n = 24). Finally, we examined the stability of FoxP3 by culturing PBMC from HIV-TB individuals in the presence of media, with no variation in FoxP3 expression in the CD25 negative population being observed (data not shown).

Bottom Line: DHEA levels were diminished in HIV-TB and HIV-TB IRIS patients compared to healthy donors (HD), HIV+ individuals and HIV+ individuals with latent TB (HIV-LTB), whereas dehydroepiandrosterone sulfate (DHEA-s) levels were markedly diminished in HIV-TB IRIS individuals.HIV-TB and IRIS patients presented a cortisol/DHEA ratio significantly higher than HIV+, HIV-LTB and HD individuals.We observed an inverse correlation between DHEA-s plasma level and Treg frequency in co-infected individuals, and CD4+FoxP3+ Treg frequency was increased in HIV-TB and IRIS patients compared to other groups.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, National Reference Center for AIDS, University of Buenos Aires School of Medicine, Buenos Aires, Argentina. fquiroga@fmed.uba.ar

ABSTRACT
Tuberculosis (TB) remains the most frequent cause of illness and death from an infectious agent, and its interaction with HIV has devastating effects. We determined plasma levels of dehydroepiandrosterone (DHEA), its circulating form DHEA-suphate (DHEA-s) and cortisol in different stages of M. tuberculosis infection, and explored their role on the Th1 and Treg populations during different scenarios of HIV-TB coinfection, including the immune reconstitution inflammatory syndrome (IRIS), a condition related to antiretroviral treatment. DHEA levels were diminished in HIV-TB and HIV-TB IRIS patients compared to healthy donors (HD), HIV+ individuals and HIV+ individuals with latent TB (HIV-LTB), whereas dehydroepiandrosterone sulfate (DHEA-s) levels were markedly diminished in HIV-TB IRIS individuals. HIV-TB and IRIS patients presented a cortisol/DHEA ratio significantly higher than HIV+, HIV-LTB and HD individuals. A positive correlation was observed between DHEA-s and CD4 count among HIV-TB individuals. Conversely, cortisol plasma level inversely correlated with CD4 count within HIV-TB individuals. M. tuberculosis-specific Th1 lymphocyte count was increased after culturing PBMC from HIV-TB individuals in presence of DHEA. We observed an inverse correlation between DHEA-s plasma level and Treg frequency in co-infected individuals, and CD4+FoxP3+ Treg frequency was increased in HIV-TB and IRIS patients compared to other groups. Strikingly, we observed a prominent CD4+CD25-FoxP3+ population across HIV-TB and HIV-TB IRIS patients, which frequency correlated with DHEA plasma level. Finally, DHEA treatment negatively regulated FoxP3 expression without altering Treg frequency in co-infected patients. These data suggest an enhancing role for DHEA in the immune response against M. tuberculosis during HIV-TB coinfection and IRIS.

Show MeSH
Related in: MedlinePlus