Polyfunctional T cells in human tuberculosis Wilkinson, Katalin A.; Wilkinson, Robert J.
European journal of immunology,
August 2010, 2010-Aug, 2010-08-00, 20100801, Letnik:
40, Številka:
8
Journal Article
Recenzirano
Odprti dostop
Studies of chronic viral infections have highlighted the phenotypic and functional heterogeneity of antigen‐specific T cells and suggested that polyfunctional T cells that secrete multiple cytokines ...and are able to proliferate on encounter with antigen are more likely than single cytokine secretors to represent correlates of protective immunity. These findings have prompted the evaluation of such T–cell responses in chronic bacterial infections, such as tuberculosis (TB). A number of studies in humans suggested that polyfunctional T cells may indeed be involved in mediating protection in TB; however, studies that question these findings are also emerging, including a study published in this issue of the European Journal of Immunology. These differing findings highlight the difficulties of studying human immunity to TB and the need for polyfunctional T cells to be evaluated in longitudinal studies as opposed to case‐control analyses.
CAPTURE (NCT03226886) is a prospective cohort study of COVID-19 immunity in patients with cancer. Here we evaluated 585 patients following administration of two doses of BNT162b2 or AZD1222 vaccines, ...administered 12 weeks apart. Seroconversion rates after two doses were 85% and 59% in patients with solid and hematological malignancies, respectively. A lower proportion of patients had detectable neutralizing antibody titers (NAbT) against SARS-CoV-2 variants of concern (VOCs) vs wildtype (WT). Patients with hematological malignancies were more likely to have undetectable NAbT and had lower median NAbT vs solid cancers against both WT and VOCs. In comparison with individuals without cancer, patients with haematological, but not solid, malignancies had reduced NAb responses. Seroconversion showed poor concordance with NAbT against VOCs. Prior SARS-CoV-2 infection boosted NAb response including against VOCs, and anti-CD20 treatment was associated with undetectable NAbT. Vaccine-induced T-cell responses were detected in 80% of patients, and were comparable between vaccines or cancer types. Our results have implications for the management of cancer patients during the ongoing COVID-19 pandemic.
Effusive constrictive pericarditis (ECP) is visceral constriction in conjunction with compressive pericardial effusion. The prevalence of proven tuberculous ECP is unknown. Whilst ECP is ...distinguished from effusive disease on hemodynamic grounds, it is unknown whether effusive-constrictive physiology has a distinct cytokine profile. We conducted a prospective study of prevalence and cytokine profile of effusive-constrictive disease in patients with tuberculous pericardial effusion.
From July 2006 through July 2009, the prevalence of ECP and serum and pericardial levels of inflammatory cytokines were determined in adults with tuberculous pericardial effusion. The diagnosis of ECP was made by combined pericardiocentesis and cardiac catheterization.
Of 91 patients evaluated, 68 had tuberculous pericarditis. The 36/68 patients (52.9%; 95% confidence interval CI: 41.2-65.4) with ECP were younger (29 versus 37 years, P=0.02), had a higher pre-pericardiocentesis right atrial pressure (17.0 versus 10.0 mmHg, P<0.0001), serum concentration of interleukin-10 (IL-10) (38.5 versus 0.2 pg/ml, P<0.001) and transforming growth factor-beta (121.5 versus 29.1 pg/ml, P=0.02), pericardial concentration of IL-10 (84.7 versus 20.4 pg/ml, P=0.006) and interferon-gamma (2,568.0 versus 906.6 pg/ml, P=0.03) than effusive non-constrictive cases. In multivariable regression analysis, right atrial pressure > 15 mmHg (odds ratio OR = 48, 95%CI: 8.7-265; P<0.0001) and IL-10 > 200 pg/ml (OR=10, 95%CI: 1.1, 93; P=0.04) were independently associated with ECP.
Effusive-constrictive disease occurs in half of cases of tuberculous pericardial effusion, and is characterized by greater elevation in the pre-pericardiocentesis right atrial pressure and pericardial and serum IL-10 levels compared to patients with effusive non-constrictive tuberculous pericarditis.
Tuberculosis (TB) remains the single biggest infectious cause of death globally, claiming almost two million lives and causing disease in over 10 million individuals annually. Matrix ...metalloproteinases (MMPs) are a family of proteolytic enzymes with various physiological roles implicated as key factors contributing to the spread of TB. They are involved in the breakdown of lung extracellular matrix and the consequent release of
bacilli into the airways. Evidence demonstrates that MMPs also play a role in central nervous system (CNS) tuberculosis, as they contribute to the breakdown of the blood brain barrier and are associated with poor outcome in adults with tuberculous meningitis (TBM). However, in pediatric TBM, data indicate that MMPs may play a role in both pathology and recovery of the developing brain. MMPs also have a significant role in HIV-TB-associated immune reconstitution inflammatory syndrome in the lungs and the brain, and their modulation offers potential novel therapeutic avenues. This is a review of recent research on MMPs in pulmonary and CNS TB in adults and children and in the context of co-infection with HIV. We summarize different methods of MMP investigation and discuss the translational implications of MMP inhibition to reduce immunopathology.
The antioxidant enzyme heme oxygenase-1 (HO-1) is implicated in the pathogenesis of tuberculosis (TB) and has been proposed as a biomarker of active disease. Nevertheless, the mechanisms by which
(
) ...induces HO-1 as well as how its expression is affected by HIV-1 coinfection and successful antitubercular therapy (ATT) are poorly understood. We found that HO-1 expression is markedly increased in rabbits, mice, and non-human primates during experimental
infection and gradually decreased during ATT. In addition, we examined circulating concentrations of HO-1 in a cohort of 130 HIV-1 coinfected and uninfected pulmonary TB patients undergoing ATT to investigate changes in expression of this biomarker in relation to HIV-1 status, radiological disease severity, and treatment outcome. We found that plasma levels of HO-1 were elevated in untreated HIV-1 coinfected TB patients and correlated positively with HIV-1 viral load and negatively with CD4
T cell count. In both HIV-1 coinfected and
monoinfected patients, HO-1 levels were substantially reduced during successful TB treatment but not in those who experienced treatment failure or subsequently relapsed. To further delineate the molecular mechanisms involved in induction of HO-1 by
, we performed a series of
experiments using mouse and human macrophages. We found that
-induced HO-1 expression requires NADPH oxidase-dependent reactive oxygen species production induced by the early-secreted antigen ESAT-6, which in turn triggers nuclear translocation of the transcription factor NRF-2. These observations provide further insight into the utility of HO-1 as a biomarker of both disease and successful therapy in TB monoinfected and HIV-TB coinfected patients and reveal a previously undocumented pathway linking expression of the enzyme with oxidative stress.
We have described a clinical relationship between HIV-Tuberculosis Immune Reconstitution Inflammatory Syndrome (TB-IRIS) and anti-tubercular drug resistance. Here we studied the immune response of ...TB-IRIS patients from whom a drug-resistant (n = 11) or drug-susceptible (n = 25) Mycobacterium tuberculosis (MTB) strain was isolated after presenting with TB-IRIS. ELISpot analysis and multiplex cytokine analysis of the supernatant collected from peripheral blood mononuclear cells stimulated overnight with the heat-killed H37Rv MTB laboratory strain was used. Although there was no statistical difference in IFN-gamma ELISpot responses between the two groups, the results point towards higher bacterial load in the drug-resistant patients, possibly due to failed therapy. The ratio between secreted IFN-gamma/IL-10 and IL-2/IL-10 was significantly lower in TB-IRIS patients in whom the cause of TB was a drug-resistant strain compared to those with a fully sensitive strain (p = 0.02). Since host immune responses are dependent on the bacterial load, we hypothesise that the impaired cytokine balance is likely to be caused by the poorly controlled bacterial growth in these patients.
Background. Cryptococcal meningitis remains a significant cause of death among human immunodeficiency virus type 1 (HIV)–infected persons in Africa. We aimed to better understand the pathogenesis and ...identify immune correlates of mortality, particularly the role of monocyte activation. Methods. A prospective cohort study was conducted in Cape Town, South Africa. Patients with a first episode of cryptococcal meningitis were enrolled, and their immune responses were assessed in unstimulated and stimulated blood specimens, using flow cytometry and cytokine analysis. Results. Sixty participants were enrolled (median CD4+ T-cell count, 34 cells/μL). Mortality was 23% (14 of 60 participants) at 14 days and 39% (22 of 57) at 12 weeks. Nonsurvivors were more likely to have an altered consciousness and higher cerebrospinal fluid fungal burden at presentation. Principal component analysis identified an immune signature associated with early mortality, characterized by monocyte deactivation (reduced HLA-DR expression and tumor necrosis factor α response to lipopolysaccharide); increased serum interleukin 6, CXCL10, and interleukin 10 levels; increased neutrophil counts; and decreased T-helper cell type 1 responses. This immune signature remained an independent predictor of early mortality after adjustment for consciousness level and fungal burden and was associated with higher serum titers of cryptococcal glucuronoxylomannan. Conclusions. Cryptococcal-related mortality is associated with monocyte deactivation and an antiinflammatory blood immune signature, possibly due to Cryptococcus modulation of the host immune response. Validation in other cohorts is required.
MAIT cells are non-classically restricted T lymphocytes that recognize and rapidly respond to microbial metabolites or cytokines and have the capacity to kill bacteria-infected cells. Circulating ...MAIT cell numbers generally decrease in patients with active TB and HIV infection, but findings regarding functional changes differ.
We conducted a cross-sectional study on the effect of HIV, TB, and HIV-associated TB (HIV-TB) on MAIT cell frequencies, activation and functional profile in a high TB endemic setting in South Africa. Blood was collected from (i) healthy controls (HC,
= 26), 24 of whom had LTBI, (ii) individuals with active TB (aTB,
= 36), (iii) individuals with HIV infection (HIV,
= 50), 37 of whom had LTBI, and (iv) individuals with HIV-associated TB (HIV-TB,
= 26). All TB participants were newly diagnosed and sampled before treatment, additional samples were also collected from 18 participants in the aTB group after 10 weeks of TB treatment. Peripheral blood mononuclear cells (PBMC) stimulated with BCG-expressing GFP (BCG-GFP) and heat-killed (HK)
(
) were analyzed using flow cytometry. MAIT cells were defined as CD3
CD161
Vα7.2
T cells.
Circulating MAIT cell frequencies were depleted in individuals with HIV infection (
= 0.009). MAIT cells showed reduced CD107a expression in aTB (
= 0.006), and reduced IFNγ expression in aTB (
< 0.001) and in HIV-TB (
< 0.001) in response to BCG-GFP stimulation. This functional impairment was coupled with a significant increase in activation (defined by HLA-DR expression) in resting MAIT cells from HIV (
< 0.001), aTB (
= 0.019), and HIV-TB (
= 0.005) patients, and higher HLA-DR expression in MAIT cells expressing IFNγ in aTB (
= 0.009) and HIV-TB (
= 0.002) after stimulation with BCG-GFP and HK-
. After 10 weeks of TB treatment, there was reversion in the observed functional impairment in total MAIT cells, with increases in CD107a (
= 0.020) and IFNγ (
= 0.010) expression.
Frequencies and functional profile of MAIT cells in response to mycobacterial stimulation are significantly decreased in HIV infected persons, active TB and HIV-associated TB, with a concomitant increase in MAIT cell activation. These alterations may reduce the capacity of MAIT cells to play a protective role in the immune response to these two pathogens.
Tuberculosis immune reconstitution inflammatory syndrome (TB-IRIS) remains incompletely understood. Neutrophils are implicated in tuberculosis pathology but detailed investigations in TB-IRIS are ...lacking. We sought to further explore the biology of TB-IRIS and, in particular, the role of neutrophils.
Two observational, prospective cohort studies in HIV/TB coinfected patients starting antiretroviral therapy (ART), 1 to analyze gene expression and subsequently 1 to explore neutrophil biology.
nCounter gene expression analysis was performed in patients with TB-IRIS (n = 17) versus antiretroviral-treated HIV/TB coinfected controls without IRIS (n = 17) in Kampala, Uganda. Flow cytometry was performed in patients with TB-IRIS (n = 18) and controls (n = 11) in Cape Town, South Africa to determine expression of neutrophil surface activation markers, intracellular cytokines, and human neutrophil peptides (HNPs). Plasma neutrophil elastase and HNP1-3 were quantified using enzyme-linked immunosorbent assay. Lymph node immunohistochemistry was performed on 3 further patients with TB-IRIS.
There was a significant increase in gene expression of S100A9 (P = 0.002), NLRP12 (P = 0.018), COX-1 (P = 0.025), and IL-10 (P = 0.045) 2 weeks after ART initiation in Ugandan patients with TB-IRIS versus controls, implicating neutrophil recruitment. Patients with IRIS in both cohorts demonstrated increases in blood neutrophil count, plasma HNP and elastase concentrations from ART initiation to week 2. CD62L (L-selectin) expression on neutrophils increased over 4 weeks in South African controls whereas patients with IRIS demonstrated the opposite. Intense staining for the neutrophil marker CD15 and IL-10 was seen in necrotic areas of the lymph nodes of the patients with TB-IRIS.
Neutrophils in TB-IRIS are activated, recruited to sites of disease, and release granule contents, contributing to pathology.
PDF
