Host Immune Responses Differ between M. africanum- and M. tuberculosis-Infected Patients following Standard Anti-tuberculosis Treatment.

Epidemiological differences exist between Mycobacterium africanum (Maf)- and Mycobacterium tuberculosis (Mtb)-infected patients, but to date, contributing host factors have not been characterised. We analysed clinical outcomes, as well as soluble markers and gene expression profiles in unstimulated, and ESAT6/CFP-10-, whole-Maf- and Mtb-stimulated blood samples of 26 Maf- and 49 Mtb-HIV-negative tuberculosis patients before, and after 2 and 6 months of anti-tuberculosis therapy. Before treatment, both groups had similar clinical parameters, but differed in few cytokines concentration and gene expression profiles. Following treatment the body mass index, skinfold thickness and chest X-ray scores showed greater improvement in the Mtb- compared to Maf-infected patients, after adjusting for age, sex and ethnicity (p = 0.02; 0.04 and 0.007, respectively). In addition, in unstimulated blood, IL-12p70, IL12A and TLR9 were significantly higher in Maf-infected patients, while IL-15, IL-8 and MIP-1α were higher in Mtb-infected patients. Overnight stimulation with ESAT-6/CFP-10 induced significantly higher levels of IFN-γ and TNF-α production, as well as gene expression of CCL4, IL1B and TLR4 in Mtb- compared to Maf-infected patients. Our study confirms differences in clinical features and immune genes expression and concentration of proteins associated with inflammatory processes between Mtb- and Maf-infected patients following anti-tuberculosis treatment These findings have public health implications for treatment regimens, and biomarkers for tuberculosis diagnosis and susceptibility.

Skewing of the CD4(+) T-cell pool toward monofunctional antigen-specific responses in patients with immune reconstitution inflammatory syndrome in The Gambia.

BACKGROUND: A common complication of starting antiretroviral therapy (ART) for human immunodeficiency virus (HIV) is the development of immune reconstitution inflammatory syndrome (IRIS) in approximately 25% of patients. Despite similarities with paradoxical reactions to tuberculosis and reversal reactions in leprosy, the exact mechanisms, and therefore potential determinants, of IRIS are still unknown. METHODS: In this longitudinal cohort study, we analyzed 20 patients who developed IRIS following initiation of ART and 16 patients who did not, matched for ART time point. Peripheral blood mononuclear cells were stimulated overnight with a positive control antigen and 2 tuberculosis-specific antigens (purified protein derivative [PPD] and ESAT-6/CFP10), followed by polychromatic flow cytometry for analysis of cytokine production from CD4(+) and CD8(+) T cells. RESULTS: Responses to PPD were significantly higher in IRIS patients compared to controls during the IRIS time point, but CD4(+) and CD8(+) T-cell responses to the positive control stimulation were significantly lower in IRIS patients at all time points. Furthermore, whereas control patients had rejuvenated polyfunctional T-cell responses by 3 months after ART, IRIS patients were strikingly monofunctional (generally interferon γ alone), even up to 6 months of ART in response to all stimulations. CONCLUSIONS: Our findings suggest that the peripheral T-cell responses to the underlying pathogen are exaggerated in IRIS patients but that the overall quality of the peripheral T-cell pool is significantly reduced compared to non-IRIS patients. Furthermore, these effects are apparent at least up to 3 months after cessation of IRIS.

Humoral response to Mycobacterium tuberculosis antigens in patients with tuberculosis in the Gambia.

OBJECTIVE: To determine and compare the sensitivity and specificity of four common mycobacterial antigens with three RD-1 region antigens in the serological diagnosis of active pulmonary tuberculosis (PTB) in the Gambia. DESIGN: Serum from 300 Gambians (100 with active PTB, 100 of their household contacts, and 100 community controls) was tested using an ELISA method to detect antibodies to seven mycobacterial antigens (three encoded in the RD-1 region [ESAT-6, CFP-10 and Rv3871] and four common [38 kDa, GLU-S, 19 kDa and 14 kDa]). Individuals with active TB were recruited from one of the National Leprosy and TB Control Program clinics in the western region of the Gambia, and neighborhood controls were an age-matched individual living within five houses of the case. RESULTS: The sensitivity of the RD-1 antigens ranged from 34% to 67%, while specificity ranged from 51% to 71%. The sensitivity of the common antigens ranged from 24% to 75% and specificity from 26% to 75%. CONCLUSION: In countries with high rates of TB, such as the Gambia, the clinical utility of serological testing to diagnose active TB remains limited, even with newer antigens encoded in the RD-1 region of Mycobacterium tuberculosis.

Understanding the genetic basis of susceptibility to mycobacterial infection.

Genetic factors have long been suspected of determining susceptibility and resistance to mycobacterial infection. The recent identification of families with a unique susceptibility to mycobacterial infection, and the identification of mutations in the genes for either the interferon-gamma (IFN-gamma) receptor or the interleukin (IL)-12 receptor as the cause of the defect, has provided an important clue to the pathways critical for resistance to mycobacterial infection in humans. Although the genetically determined absence of key cytokines or their receptors results in susceptibility to lethal mycobacterial infections in early childhood, it is likely that more subtle mutations that result in only partial dysfunction of macrophage upregulation pathways may play a role in susceptibility to tuberculosis (TB) and leprosy in the general population.