Endocrine and cytokine responses in humans with pulmonary tuberculosis

Rey, Adriana del; Mahuad, Carolina; Bozza, Verónica; Bogué, Cristina; Farroni, Miguel A.; Bay, María Luisa; Bottasso, Óscar; Besedovsky, Hugo O.

doi:10.1016/j.bbi.2006.06.005

Cited by 93 publications

(83 citation statements)

References 49 publications

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“…This observation indicates a mixed state of Th1/Th2 phenotypes of cells with a shift toward Th2 cytokines. These results are compatible with previous findings reporting dominance of Th2 cytokines in TB patients (4,43). The mixed pattern of Th1/Th2 cytokines may be due either to the activation of Th0 cells or to simultaneous activation of both Th1 and Th2 cells, resulting in a Th0 phenotype of the cytokines released.…”

Section: Discussionsupporting

confidence: 83%

“…The only vaccine currently available for humans is Mycobacterium bovis bacillus CalmetteGuérin (BCG), a live attenuated strain of M. bovis. In spite of being the most used vaccine in the world, with proven efficacy against childhood TB meningitis and miliary TB (41,49), BCG has failed to reduce the global burden of TB (43). The efficacy of BCG against pulmonary TB in adults has varied between 0 and 80% (16).…”

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confidence: 99%

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Characterization of Human Cellular Immune Responses to NovelMycobacterium tuberculosisAntigens Encoded by Genomic Regions Absent inMycobacterium bovisBCG

Al‐Attiyah

Mustafa

2008

Infect Immun

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Comparative genomics has identified several regions of differences (RDs) between the infectious Mycobacterium tuberculosis and the vaccine strains of Mycobacterium bovis BCG. We aimed to evaluate the cellular immune responses induced by antigens encoded by genes predicted in 11 RDs. Synthetic peptides covering the sequences of RD1, RD4 to RD7, RD9 to RD13, and RD15 were tested for antigen-induced proliferation and secretion of Th1 cytokine, gamma interferon (IFN-␥), by peripheral blood mononuclear cells (PBMC) obtained from culture-proven pulmonary tuberculosis (TB) patients and M. bovis BCG-vaccinated healthy subjects. Among the peptide pools, RD1 induced the best responses in both donor groups and in both assays. In addition, testing of TB patients' PBMC for secretion of proinflammatory cytokines (tumor necrosis factor alpha Mycobacterium tuberculosis is among the most successful human pathogens and is the primary cause of human tuberculosis (TB) in the world. Globally, about 2 billion people are infected with M. tuberculosis, 8 to 10 million develop active disease, and 2 million die from TB every year (53). An overwhelming majority of TB patients reside in the developing countries, which suffer from marked poverty, lack of healthy living conditions, and inadequate medical facilities (53).The global control of TB requires effective vaccines and reagents for specific diagnosis. The only vaccine currently available for humans is Mycobacterium bovis bacillus CalmetteGuérin (BCG), a live attenuated strain of M. bovis. In spite of being the most used vaccine in the world, with proven efficacy against childhood TB meningitis and miliary TB (41, 49), BCG has failed to reduce the global burden of TB (43). The efficacy of BCG against pulmonary TB in adults has varied between 0 and 80% (16). Furthermore, vaccination with M. bovis BCG faces two additional problems. First, it induces a delayed-type hypersensitivity response that cannot be distinguished from infection with M. tuberculosis, and therefore, it compromises the use of purified protein derivative (PPD) of M. tuberculosis in skin tests for diagnostic or epidemiological purposes (25,26). Second, M. bovis BCG, as a live vaccine, is contraindicated in human immunodeficiency virus-infected patients for fear of causing disease (11). PPD, the commonly used diagnostic reagent, is nonspecific because of the presence of antigens crossreactive with M. bovis BCG and environmental mycobacteria (14, 25). Thus, there is a need to identify M. tuberculosisspecific antigens to develop new protective vaccines and specific diagnostic reagents against TB.Comparative genome analyses of the M. tuberculosis genome and M. bovis BCG have shown that 16 genomic regions of M. tuberculosis are deleted or lacking in some or all strains of M. bovis and/or M. bovis BCG (9). Among these regions of differences (RDs), 11 regions (RD1, RD4 to RD7, RD9 to RD13, and RD15) covering 89 open reading frames (ORFs) of M. tuberculosis H37Rv are absent in all M. bovis BCG substrains currently used as vaccin...

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Section: Discussionsupporting

confidence: 83%

mentioning

confidence: 99%

Characterization of Human Cellular Immune Responses to NovelMycobacterium tuberculosisAntigens Encoded by Genomic Regions Absent inMycobacterium bovisBCG

Al‐Attiyah

Mustafa

2008

Infect Immun

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“…It is clear that macrophage activity and cytokine production is affected by glucocorticoids [40,41] and mycobacterial antigens [37,42,43] . These same cytokines that are induced by exposure to surface TDM glycolipids, including IL-6, IL-1 ␤ and TNF-␣ [11] , cause glucocorticoids to be released into the bloodstream.…”

Section: Discussionmentioning

confidence: 99%

11β-Hydroxysteroid Dehydrogenases Are Regulated during the Pulmonary Granulomatous Response to the Mycobacterial Glycolipid Trehalose-6,6′-Dimycolate

Abbott¹,

Guidry²,

Welsh³

et al. 2009

Neuroimmunomodulation

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Objective: Tuberculosis has a staggering influence on world health, resulting in nearly 2 million deaths per year. The influence of glucocorticoids during Mycobacterium tuberculosis infection has been under investigation for decades; however, the identity of mycobacterial factors and the mechanism by which glucocorticoids are tissue specifically regulated to influence immune function during acute granuloma formation are unknown. Methods: One factor implicated in initiating immunopathology during M. tuberculosis infection is trehalose-6,6′-dimycolate (TDM), a glycolipid component of the mycobacterial cell wall. Intravenous administration of TDM causes inflammatory responses in lungs of mice similar to M. tuberculosis infection and has been used as a successful model to examine proinflammatory regulation and early events involved in the manifestation of pathology. Results and Conclusion: IL-6, IL-1α and TNF-α mRNA and protein peaked during the initiation of granuloma formation. Pulmonary corticosterone levels were elevated when the proinflammatory response was greatest, dropping to half of that upon the establishment of granuloma pathology on day 7. It is hypothesized that once corticosterone reaches the site of inflammation, the enzymes 11β-hydroxysteroid dehydrogenases (11βHSDs) can influence bioavailability by interconverting corticosterone and the inert metabolite 11-dehydrocorticosterone. RT-PCR demonstrated that pulmonary 11βHSD type 1 mRNA decreased 4-fold and 11βHSD type 2 (11βHSD2) mRNA expression increased 2.5-fold on day 3 after injection, suggesting that corticosterone regulation in the lung, specifically the reduction of active corticosterone by 11βHSD2, may influence the progression of granuloma formation in response to the mycobacterial glycolipid.

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“…Indeed, other investigators have shown sitespecific regulation of the HPA activation in response to pro-inflammatory inducing stimuli [54] . In human TB disease IL-6 (and other cytokines) are elevated [55] . Serum IL-6 levels correlated positively with cortisol [13,56] .…”

Section: Discussionmentioning

confidence: 99%

IL-6 Mediates 11βHSD Type 2 to Effect Progression of the Mycobacterial Cord Factor Trehalose 6,6′-Dimycolate-Induced Granulomatous Response

Abbott

Welsh

Hwang

et al. 2011

Neuroimmunomodulation

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Granulomatous structures are highly dynamic during active mycobacterial infection, with accompanying responsive inflammation contributing to modulation of pathology throughout the course of disease. The heightened inflammatory response coinciding with initiation and maintenance of newly developing granulomatous structures must be limited to avoid excessive damage to bystander tissue. Modulating the cellular bioavailability of glucocorticoids by local regulation of 11βHSD enzymes within responding tissue and parenchyma would allow controlled inflammatory response during infection. Mycobacterial glycolipid trehalose 6,6′-dimycolate was used to induce strong pulmonary granulomatous inflammation immunopathology. Pulmonary corticosterone was significantly increased at days 3 and 5 after administration. An inverse relationship of 11βHSD1 and 11βHSD2 message correlated with pathology development. Immunohistochemical analysis also demonstrated that 11βHSD2 is expressed in proximity to granulomatous lesions. A role for pro-inflammatory IL-6 cytokine in regulation of converting enzymes to control the granulomatous response was confirmed using gene-disrupted IL-6–/– mice. A model is proposed linking IL-6 to endocrine-derived factors which allows modification of active corticosterone into inert 11-dehydrocorticosterone at the site of granuloma formation to limit excessive parenchymal damage.

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Endocrine and cytokine responses in humans with pulmonary tuberculosis

Cited by 93 publications

References 49 publications

Characterization of Human Cellular Immune Responses to NovelMycobacterium tuberculosisAntigens Encoded by Genomic Regions Absent inMycobacterium bovisBCG

Characterization of Human Cellular Immune Responses to NovelMycobacterium tuberculosisAntigens Encoded by Genomic Regions Absent inMycobacterium bovisBCG

11β-Hydroxysteroid Dehydrogenases Are Regulated during the Pulmonary Granulomatous Response to the Mycobacterial Glycolipid Trehalose-6,6′-Dimycolate

IL-6 Mediates 11βHSD Type 2 to Effect Progression of the Mycobacterial Cord Factor Trehalose 6,6′-Dimycolate-Induced Granulomatous Response

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