Tuberculosis, anti-glucocorticoids and the immune system

According to a recent estimate by the World Health Organisation, by the year 2000 tuberculosis (TB) will kill 4 million people a year. This dramatic increase, from 3 million in 1992 to 4 million by year 2000, is an alarming signal for health workers. Endocrinological abnormalities have been observed in TB that may explain the tendency for patients to develop an inappropriate TH2 response to M. tuberculosis. These abnormalities include a fall in the ratio of antiglucocorticoid hormones (dehydroepiandrosterone; DHEA) to glucocorticoid, and a marked decrease in conversion of the major glucocorticoid cortisol to inactive cortisone. This project was designed to investigate the significance for human tuberculosis of these two endocrine changes. Three approaches were used. 1) The antiglucocorticoid properties of DHEA and some of its metabolites, were tested in order to select the optimum metabolite and schedule for in vivo experiments in tuberculosis in mice. 2) The ability of live M. tuberculosis to convert DHEA sulphate (present in human serum at up to 4 µg/ml) into active metabolites was examined; 3) The hypothesis that the enzyme that interconverts cortisol and cortisone in the lung is susceptible to local regulation by cytokines was tested. Antiglucocorticoid effects of DHEA and a series of its metabolites were tested in vivo for their ability to protect the thymus from apoptosis induced by corticosterone, and to block the effects of glucocorticoid on non-specific inflammation. The metabolite 3 β,17β-androstenediol (AED) proved most active. The optimum dose level was identified and has since proved strongly protective in a model of murine tuberculosis that is used by collaborators in Mexico. These metabolites were then tested in vitro for their effects on proliferation and cytokine production by murine and human lymphocytes, alone or in the presence of glucocorticoid. DHEA and AED increased the production of IFNy by murine splenocytes, and antagonised the inhibitory effects of cortisol on IFNỿ production by human T cells. The in vivo model has subsequently confirmed that AED upregulates TH1 and proinflammatory cytokines, while downregulating TH2 cytokine release. Mycobacterium tuberculosis cleaved DHEA to a number of metabolites, visualised by thin layer chromatography, including AED and reduced forms of AED that were identified by gas chromatography and mass spectrometry. 11β-HSD activity was measured in different organs at different intervals after intravenous challenge with live BGC. On day three conversion to cortisone in the lung was reduced in the BCG group compared to normal mice, indicating that the activity of 11β-HSD was mainly dehydrogenase. However 10 days later the activity shifted towards reductase since conversion to cortisone was markedly increased not only in lung but also in spleen and thymus. The equilibrium point (i.e. the ratio of cortisol to cortisone) did not change in liver or kidney. These results suggest that 11β-HSD is regulated during the inflammatory response induced by live BCG. The above data are discussed in relation to the immunological abnormalities that accompany human tuberculosis, and the effects of manipulating the AED/corticosterone balance in the murine tuberculosis model. They help to explain the changing pattern of immunopathology in human tuberculosis of different ages, and correlation of these disease patterns with age-related changes in DHEAS levels

Al-Hajoj, “Emergence of clinically relevant non-tuberculous mycobacterial infections

Background: Non-Tuberculous Mycobacteria (NTM) are emerging around the world due to a higher prevalence of immunosuppressive illness and therapy. Saudi Arabia is not an exception as there have been novel mycobacterial species also identified. In addition, several published case reports from different parts of the country suggest a growing pathogenic potential of NTM. As the first nationwide study, we sought to gain an insight into the species diversity of NTM clinical isolates. Methodology/Principal findings: During June 2009–July 2010, 95 clinical isolates were collected from tuberculosis reference laboratories in major provinces within Saudi Arabia and subjected to standard line probe assay techniques to identify their species. Diagnostic guidelines of the American Thoracic Society were applied to determine the clinical relevance of respiratory isolates. Species diversity (13 species) was very high and dominated (61.0%) by rapid growing NTM. The major species obtained were Mycobacterium abscessus, M. fortuitum, M. intracellulare followed by M. kansassi, M. gordanae and M. avium. Interestingly this study reports for the first time the clinical relevance of M. celatum, M. xenopi, M. scrofulceum, M. lentiflavum, M. asiaticum and M. simiae in Saudi Arabia. Of the total, 67.1 % were clinically relevant respiratory cases, 23.2 % were non-respiratory cases and 9.7 % were respiratory colonizers. Coexisting illness was reported in 53.7 % of the studied cases. The major risk factors observed among the patients were previous history of tuberculosis, chroni

Emergence of clinically relevant Non-Tuberculous Mycobacterial infections in Saudi Arabia.

BACKGROUND: Non-Tuberculous Mycobacteria (NTM) are emerging around the world due to a higher prevalence of immunosuppressive illness and therapy. Saudi Arabia is not an exception as there have been novel mycobacterial species also identified. In addition, several published case reports from different parts of the country suggest a growing pathogenic potential of NTM. As the first nationwide study, we sought to gain an insight into the species diversity of NTM clinical isolates. METHODOLOGY/PRINCIPAL FINDINGS: During June 2009-July 2010, 95 clinical isolates were collected from tuberculosis reference laboratories in major provinces within Saudi Arabia and subjected to standard line probe assay techniques to identify their species. Diagnostic guidelines of the American Thoracic Society were applied to determine the clinical relevance of respiratory isolates. Species diversity (13 species) was very high and dominated (61.0%) by rapid growing NTM. The major species obtained were Mycobacterium abscessus, M. fortuitum, M. intracellulare followed by M. kansassi, M. gordanae and M. avium. Interestingly this study reports for the first time the clinical relevance of M. celatum, M. xenopi, M. scrofulceum, M. lentiflavum, M. asiaticum and M. simiae in Saudi Arabia. Of the total, 67.1% were clinically relevant respiratory cases, 23.2% were non-respiratory cases and 9.7% were respiratory colonizers. Coexisting illness was reported in 53.7% of the studied cases. The major risk factors observed among the patients were previous history of tuberculosis, chronic obstructive pulmonary disorder and human immunodeficiency virus infection. CONCLUSION/SIGNIFICANCE: The high rates of clinically confirmed respiratory cases suggest that NTM infections are indeed a new challenge to health authorities. The current findings show an opposite picture of the Western world where M. avium complex and particularly slow growing NTM are the most predominant respiratory pathogens. The complexity of species demands an immediate strengthening of the current diagnostic facilities

Mycobacterium riyadhense in Saudi Arabia

We explored in detail the nationwide existence of Mycobacterium riyadhense in Saudi Arabia. In 18 months, 12 new cases of M. riyadhense infection were observed, predominantly among Saudi nationals, as a cause of pulmonary disease. M. riyadhense may be emerging as a more common pathogen in Saudi Arabia

Summary of the 22 extra-pulmonary NTM infections observed in the study.

†<p>Lymphnode/Fine Needle Aspiration/Biopsy.</p>¶<p>Previous mycobacterium tuberculosis disease.</p>‡<p>Cystic fibrosis.</p>*<p>Human immunodeficiency virus.</p

Summary of the study subjects.

<p>Summary of the study subjects.</p

Overall species diversity of 95 clinical non-tuberculous mycobacterial isolates from Saudi Arabia.

<p>The diagram shows collective representation of pulmonary and extra-pulmonary isolates. The number of isolates with particular species are showed at the outer end of the bar diagram.</p

Summary of the 73 pulmonary samples with NTM infections during 2009–2010 from Saudi Arabia.

*<p>Based on ATS/IDSA 2007 guidelines.</p>†<p>Previous mycobacterium tuberculosis disease.</p>‡<p>Human immunodeficiency virus.</p>¶<p>Pulmonary fibrosis.</p>#<p>Cystic fibrosis.</p>±<p>Chronic obstructive pulmonary disease.</p>++<p>Continuous ambulatory peritoneal dialysis.</p